Clinica Chimica Acta 412 (2011) 1053–1059

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Clinica Chimica Acta

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m

C reactive protein and procalcitonin: Reference intervals for preterm and term
newborns during the early neonatal period
Claudio Chiesa a,b,⁎, Fabio Natale b, Roberto Pascone b, John F. Osborn c, Lucia Pacifico a,b,
Enea Bonci b, Mario De Curtis b
a
National Research Council, Institute of Molecular Medicine, Rome, Italy
b
Department of Pediatrics, Sapienza University of Rome, Rome, Italy
c
Department of Public Health Sciences and Infectious Diseases, Sapienza University of Rome, Rome, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Background: There is still no study evaluating the influence of gestational age (GA) per se on C reactive protein
Received 6 December 2010 (CRP) and procalcitonin (PCT) reference intervals. We therefore investigated how length of gestation, age
Received in revised form 19 January 2011 (hours), and prenatal and perinatal variables might influence the levels of CRP and PCT. We also determined
Accepted 14 February 2011 95% age-specific reference intervals for CRP and PCT in healthy preterm and term babies during the early
Available online 19 February 2011
neonatal period.
Methods: One blood sample (one observation per neonate) was taken for CRP and PCT from each newborn
Keywords:
C reactive protein
between birth and the first 4 (for term), or 5 days (for preterm newborns) of life by using a high-sensitive CRP
Procalcitonin and PCT assays.
Reference intervals Results: Independently of gender and sampling time, GA had a significantly positive effect on CRP, and a
Early neonatal period significantly negative effect on PCT. Compared with healthy term babies, healthy preterm babies had a lower
Preterm newborn and shorter CRP response, and, conversely, an earlier, higher, and longer PCT response. CRP reference intervals
Term newborn were affected by a number of pro-inflammatory risk factors.
Conclusions: Age- and GA-specific reference ranges for both CRP and PCT should be taken into account to
optimize their use in the diagnosis of early-onset neonatal sepsis.
© 2011 Elsevier B.V. All rights reserved.

1. Introduction of life, it is important to consider their normal kinetics and their

The utility of C reactive protein (CRP) for the diagnosis of early-
onset neonatal infection has been the subject of controversy because
of its unsatisfactory sensitivity. The CRP concentration increases
physiologically in newborns within the first days after birth. This
dynamic behavior may in part account for the low diagnostic accuracy
of CRP measurements in neonatal infection, particularly when
measured shortly after birth. Similarly, other markers of inflammation
including procalcitonin (PCT) demonstrate a natural increase within a
few days after birth, necessitating careful adjustments to the normal
ranges. Thus, in estimating the sensitivities and specificities of these
neonatal markers for the diagnosis of sepsis throughout the first days
Abbreviations: CRP, C reactive protein; PCT, procalcitonin; GA, gestational age; BW,
birth weight; CRPHS, C reactive protein high sensitive.
⁎ Corresponding author at: Institute of Molecular Medicine, National Research
Council, Via del Fosso del Cavaliere, 100, I-00133 Rome, Italy. Tel.: +39 06 49979215;
fax: +39 06 49979216.
E-mail addresses: claudio.chiesa@artov.inmm.cnr.it, claudio.chiesa@ift.cnr.it
(C. Chiesa).
pattern(s) of response in the healthy neonate.
Data pertaining to reference intervals for CRP during the neonatal
period are limited. In the majority of published reports, CRP upper limits
have been obtained from symptomatic uninfected patients [1–11].
There are few studies of upper limits for CRP in the healthy newborn
[12–15]. Furthermore, most of these were based on relatively small
sample sizes with wide-ranging postnatal ages [12–14]. More impor-
tant, although advances in neonatal intensive care have led to increasing
preterm birth rates, to our knowledge, there is still no study evaluating
the influence of gestational age (GA) per se in the development of CRP
reference intervals during the neonatal period. Finally, though high-
sensitivity assay for CRP has become available over the last decade in
standard clinical laboratories, there is no study assessing the CRP
postnatal changes in the healthy preterm and term neonates using this
analytic method.
Data pertaining to reference intervals for PCT are also limited. In a
previous cross-sectional study, we showed that in the healthy term
neonates circulating concentrations of PCT increase gradually from birth
to reach peak values at about 24 h of age and then decrease gradually by
48 h of life [16]. No similar normogram exists for the healthy preterm
infants even though they may have different pharmacokinetics.

0009-8981/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.cca.2011.02.020
1054 C. Chiesa et al. / Clinica Chimica Acta 412 (2011) 1053–1059
For these reasons, we sought to describe the reference ranges for
both CRP and PCT in a large sample of healthy preterm and term
newborns during the first days of life by using more sensitive CRP and
PCT assays than those previously reported [1–18].
2. Materials and methods
2.1. Subjects
Our population consisted of healthy preterm and term infants
who, from birth, were prospectively recruited over an 18-month
period to the Neonatal Unit of Policlinico Umberto I° Hospital,
Sapienza University of Rome. The study protocol was approved by
the clinical research ethics committee of the Hospital. Eligible for
enrollment were neonates who were delivered from singleton
pregnancies with birth weights (BWs) appropriate for GA and with
normal results on physical examination at birth that implied no need
for empiric management. We excluded babies born to mothers with:
(a) multiple preexistent or pregnancy-related noninfectious compli-
cations; or (b) clinically evident intra-amniotic infection. The neonate
was included in the study if all of the following criteria were met:
a) one peripheral blood sample (corresponding to one observation per
neonate) had been obtained after maternal consent for simultaneous
measurement of both CRP and PCT between birth and the first 4 (for
term), or 5 days (for preterm newborns) of life at the time of a routine
blood collection or routine newborn screening for inborn errors of
metabolism; (b) the neonate had a continuous uncomplicated postnatal
hospital stay and was discharged as healthy from the Hospital; and (c)
the neonate had normal assessments at the 2-wk (for term and
preterm) and 4-wk (for preterm neonates) follow-up visits. The time-
limit of sample collection was extended in the preterm babies to
postnatal day 5 because a previous study in symptomatic uninfected
preterm babies suggested a return to initial PCT values after 4 days of
life, implying therefore a longer PCT rise in preterm than in term infants
[17]. A total of 421 newborns qualified for analysis of CRP and PCT
reference intervals.
All antepartum and intrapartum data were collected prospectively,
and included maternal age, preexistent or pregnancy-related diseases,
prenatal steroid exposure, mode of delivery, duration of active labor,
interval between rupture of membranes and delivery, intrapartum
antimicrobial administration, and intrapartum fetal distress [19].The
institutional policy was to give penicillin or broad-spectrum anti-
biotics to all women identified as group B streptococcus (GBS) carriers
at 35–37 weeks of gestation [20]. If the results of GBS cultures were
not known at the onset of labor or rupture of membranes, intrapartum
antimicrobial prophylaxis was administered if either or both of the
following risk factors were present: preterm labor at b37 weeks of
gestation, and rupture of membranes ≥18 h before delivery [20].
Neonatal data included GA, BW, and gender. GA was established on
the basis of best obstetric estimates, including last menstrual period
and first or second trimester ultrasonography.
2.2. CRP and PCT determinations
Serum samples for duplicate CRP and PCT determinations were
stored in small aliquots at − 80 °C until assayed. CRP concentrations
were measured on a COBAS 6000 analyzer (Roche Diagnostics) with a
particle-enhanced immunoturbidimetric method using latex particles
coated with monoclonal antibodies anti-CRP antibodies and turbi-
dimetry reading of the precipitate at 552 nm [CRP high sensitive
(CRPHS) assay; Roche Diagnostics]. The limit of quantification for
CRPHS assay was 0.3 mg/L, and the day-to-day imprecision (50
determinations) was 2.9% at 0.4 mg/L and 1.9% at 12.6 mg/L. PCT was
estimated by an immuno-time-resolved amplified cryptate technol-
ogy assay (Kryptor PCT; BRAHMS). This assay is based on a sheep
polyclonal antibody against calcitonin and a monoclonal antibody
against katacalcin, which bind to the calcitonin and katacalcin sequence
of calcitonin precursor molecules. The assay is very sensitive, with a
limit of quantification of 0.06 μg/L. According to the manufacturer
the inter-assay CV is 3% on the whole PCT concentration range. CRP
and PCT determinations were performed without knowledge of the
antepartum, intrapartum, and neonatal data.
2.3. Statistical analysis
This study had two broad objectives. The first was to investigate
how length of gestation, age (hours) and other characteristics of the
mothers and babies might influence the levels of CRP and PCT. The
second was to determine 95% age-specific reference intervals for CRP
and PCT for postnatal ages up to a maximum of 120 h after birth.
From previous studies [15,16,18] it was expected that the levels of
CRP and PCT would be approximately log-normally distributed, and
when the data confirmed this, the natural logarithms of all observed
values of CRP and PCT were calculated and used in all subsequent
analyses. In order to investigate how the length of gestation, age
(hours) and other characteristics of the mothers and babies might
influence the levels of ln CRP and ln PCT, GA was classified as preterm
and term, and the multiple log-linear regression of CRP and PCT on the
independent variables was calculated. The results of these regression
analyses showed that the relationships between ln CRP and age and ln
PCT and age were not linear and this implied that the reference
intervals should be calculated using polynomial regression. The strong
effect of GA suggested that reference intervals of CRP and PCT would
be necessary for preterm and term babies separately.
The four 95% age-specific reference ranges were constructed
following the sequence of six steps described by Royston [21]. The six
steps are: (1) plot the data, (2) fit a polynomial curve, (3) assess the
residuals, (4) transform the data, (5) check the distribution throughout
the range of the independent variable and (6) calculate the reference
range. For both preterm and term babies, the plots of the data of PCT and
CRP, against age (hours) showed no outliers or peculiarities and there
was a clear tendency for the values to increase immediately after birth
reaching a peak, after which the PCT values declined while the CRP
values also decreased but more slowly. The individual points on the
scatter diagrams were not normally distributed about the trend, but
positively skewed and the variability was greater where the mean was
higher. These two observations, together with the evidence provided by
earlier studies [15,16,18], confirmed that the natural logarithms of the
PCT and CRP levels should be used for the calculation of the reference
intervals in order to normalize the distributions and stabilize the
variance of the residuals. This was checked by inspecting histograms of
the residuals, plots of the residuals against age in hours, and normal
probability plots from which the Shapiro–Francia statistic was
calculated.
To calculate the polynomial regression, the response (ln CRP or ln
PCT) was regressed first on age, x, then x and x2, then x, x2, x3 and so on
until the addition of further powers of age did not produce statistically
significant coefficients. To calculate the predicted values of ln CRP and ln
PCT, the values of age measured in hours were inserted into the
polynomial regression equation. The upper and lower limits were
calculated as the predicted value plus or minus twice the standard
deviation of the residuals.
3. Results
3.1. Subject characteristics
Table 1 presents maternal and neonatal characteristics of the study
population, of whom 221 were born at term (range 37.0–39.0 weeks)
while 200 were preterm (range 30.0–36.0 weeks), with 27 out of the
200 preterm infants (13.5%) below 33 weeks of gestational age. Most
babies (94.8%) were born to Caucasian mothers.
 C. Chiesa et al. / Clinica Chimica Acta 412 (2011) 1053–1059 1055

Table 1 This prompted us to assess separate CRP reference intervals for the
Maternal and neonatal characteristics. term and preterm neonates.
Maternal For the term neonates, the predicted CRP levels (lower and upper
Mean (SD) age, years 32.7 (5.8) limits) were, at birth, 0.1 (0.01–0.65) mg/L, increased gradually to 1.5
Parity, n (%) (0.2–10.0) mg/L at 21 h of age, after which they slightly increased to
0 119 (28.3%)
reach 1.9 (0.3–13.0) mg/L at 56–70 h, and then declined to 1.4 (0.2–9.0)
1 190 (45.1%)
≥2 112 (26.6%) mg/L at 96 h (Fig. 1). For the preterm infants, the predicted CRP levels
Complications during pregnancy, n (%) were 0.1 (0.01–0.64) mg/L at birth, with peak levels of 1.7 (0.3–11.0)
Gestational diabetes 19 (4.5%) mg/L at 27–36 h, and then declined to 0.7 (0.1–4.7) mg/L at about 90 h
Pregnancy-induced hypertension 49 (11.6%)
(Fig. 2). There appeared to be a tendency for the values to increase again
Mode of delivery, n (%)
Spontaneous vaginal 133 (31.6%)
after about 100 h reaching 4.9 (0.7–32.0) mg/L at 120 h but this should
Emergency cesarean section 88 (20.9%) be interpreted cautiously given that there are few observations at these
Elective cesarean section 200 (47.5%) ages. Of the 221 values used to construct CRP reference intervals in the
Use of antenatal steroids 85 (20.2%) term neonate, seven (3.2%) were higher than the upper limit and one
Median (IQR) length of active labor, h 2.0 (2.0)
(0.5%) was less than the lower limit. Of the 200 values used to construct
Median (IQR) time of ruptured membranes, h 6.1 (15.9)
Intrapartum antimicrobial prophylaxis, n (%) 98 (23.3%) CRP reference intervals in the preterm neonate, five (2.5%) were higher
Intrapartum fetal distress, n (%) 94 (22.3%) than the upper limit and five (2.5%) were less than the lower limit.
The variance of the residuals did not change with age, and they
Newborn were normally distributed. The Shapiro–Francia statistic was 0.983 for
Preterm birth
Male 115 (57.5%)
the term babies and 0.980 for the preterm babies.
Mean (SD) gestational age at delivery, completed weeks 34.4 (1.4) Of the antenatal and perinatal variables, duration of active labor,
Mean (SD) birth weight, g 2286 (446) prenatal steroids, time of ruptured membranes, and intrapartum
Term birth antimicrobial prophylaxis had a significant effect on CRP concentra-
Male, n (%) 121 (54.7%)
tions when adjusted for GA, gender, and sampling time. The mean CRP
Mean (SD) gestational age at delivery, completed weeks 38.3 (0.7)
Mean (SD) birth weight, g 3178 (341) concentration was increased by 0.4% (95% CI, 0.15%–0.67%; P b 0.05)
per hour of ruptured membranes, and by 14.5% (95% CI, 5.2%–25.0%;
IQR = interquartile range.
P b 0.01) per hour of active labor. The babies' mean CRP concentration
was increased by 40% (95% CI, 0.0%–95.5%; P b 0.05) and by 28% (95%
CI, 0.0%–64.0%; P b 0.05) if the mother had a history of prenatal steroid
3.2. C reactive protein exposure and intrapartum antimicrobial prophylaxis, respectively.
CRP concentrations were also affected by the mode of delivery. After
Using multiple log-linear regression analysis, it was found that GA adjustment for GA, gender, and neonatal age, the mean geometric CRP
had a significant, positive effect on CRP independently of gender and concentrations were significantly higher in babies born by vaginal
sampling time. Babies' mean CRP increased by 6.0% (95% CI, 1.1%– delivery than in those born by cesarean section [1.06 (95% CI, 0.92–
11.2%; P b 0.01) per week of GA at delivery. When BW was included 1.23) vs 0.56 (0.50–0.62) mg/L; P b 0.05]. The significance was much
instead of GA (because of collinearity), the mean CRP increased by greater when babies vaginally delivered were compared with those
2.4% (95% CI, 0.7%–4.2%; P b 0.01) per 100 g of BW independently of born by elective cesarean section (P b 0.01). Finally, the variable
gender and neonatal age. Babies' CRP was not associated with gender. intrapartum fetal distress approached significance (P = 0.08).

Fig. 1. Age-specific 95% reference intervals for C reactive protein (CRP) in healthy term neonates from birth to 96 h of life. The circles represent single values; the dotted lines
represent lower and upper limits; the bold line represents the predicted geometric mean. Note the logarithmic scale of CRP. For individual ages (hours) see Appendix Table 1.
1056 C. Chiesa et al. / Clinica Chimica Acta 412 (2011) 1053–1059

Fig. 2. Age-specific 95% reference intervals for C reactive protein (CRP) in healthy preterm neonates from birth to 120 h of life. The circles represent single values; the dotted lines
represent lower and upper limits; the bold line represents the predicted geometric mean. Note the logarithmic scale of CRP. For individual ages (hours) see Appendix Table 2.

3.3. Procalcitonin
In regression analysis, GA had a significant, negative effect on PCT
independently of gender and sampling time. Babies' mean PCT
decreased by 11.4% (95% CI, 6.4%–16.1%; P b0.0001) per week of GA
at delivery. When BW was included instead of GA, mean PCT
decreased by 2.2% (95% CI; 0.2%–4.1% P b 0.05) per 100 g of BW
independently of gender and sampling time. Babies' PCT was not
associated with gender. We therefore chose to construct separate PCT
reference intervals for the term and preterm neonates.
For the term neonates, the predicted PCT and normal range were,
at birth, 0.08 (0.01–0.55) μg/L, rising to peak levels of 2.9 (0.4–18.7)

Fig. 3. Age-specific 95% reference intervals for procalcitonin (PCT) in healthy term neonates from birth to 96 h of life. The circles represent single values; the dotted lines represent
lower and upper limits; the bold line represents the predicted geometric mean. Note the logarithmic scale of PCT. For individual ages (hours) see Appendix Table 3.
 C. Chiesa et al. / Clinica Chimica Acta 412 (2011) 1053–1059
μg/L at 24 h after birth, and reducing slowly to a minimum of 0.3
(0.04–1.8) μg/L at about 80 h (Fig. 3). Thereafter, the values tended to
increase slightly reaching 0.6 (0.1–4.2) μg/L at 96 h but, due to the
small number of observations at these higher ages, this trend may be
imprecise. For the preterm babies, the values were 0.07 (0.01–0.56)
μg/L at birth, rising rapidly to 6.5 (0.9–48.4) μg/L at 21 to 22 h before
declining gradually to 0.10 (0.01–0.8) μg/L at about 5 days (Fig. 4). Of
the 221 values used to construct PCT reference intervals for the term
neonates, two (0.9%) were higher than the upper limit and five (2.3%)
were less than the lower limit. Of the 200 values used to construct the
PCT reference intervals in the preterm neonate, five (2.5%) were
higher than the upper limit and seven (3.5%) were less than the lower
limit.
The variance of the residuals did not change with age, and they
were normally distributed. The Shapiro–Francia statistic was 0.987 for
the term babies and 0.984 for the preterm babies.
After adjustment for GA, gender, and neonatal age, none of the
antenatal and perinatal variables had statistically significant effects on
the values for PCT, although the variables time of ruptured
membranes and gestational diabetes approached significance
(P = 0.05, and P = 0.06, respectively).
4. Discussion
The main purpose of this study was to determine age-related
reference intervals for CRP and PCT in the preterm and term baby
during the early neonatal period. Our data show that clinical use of
CRP over the first days of life requires the use of cutoff values specific
not only to postnatal age, but also to GA. In fact, we found that healthy
preterm babies have a lower and shorter CRP response compared with
that in healthy term babies, demonstrating the effects of development
per se on CRP dynamics. This may be related to possible immature
liver function and the inability of the liver to produce sufficient
amounts of some proteins including CRP. Relevant to this, neonatal
characteristics such as a lower GA (b38 weeks) and lower BW
(b2500 g) have been reported by Ishibashi et al. to be associated with
Fig. 4. Age-specific 95% reference intervals for procalcitonin (PCT) in healthy preterm neonates from birth to 120 h of life. The circles represent single values; the dotted lines
represent lower and upper limits; the bold line represents the predicted geometric mean. Note the logarithmic scale of PCT. For individual ages (hours) see Appendix Table 4.
1057
significantly smaller CRP increases compared with those in babies
with a higher GA and higher BW [11]. However, in that study
involving symptomatic uninfected babies, the independent effect of
prematurity on CRP response was not assessed.
It is true that the sensitivity of CRP increases over time [22,23],
making serial measurements useful for those situations where one
needs to decide how long to treat [24]. However, by that point, most
newborns will be asymptomatic and will have confirmed negative
culture results. Indeed, the unsatisfactory sensitivity of CRP pattern
recognition for neonatal infection might be related to the insensitive
analytic method used to detect the CRP time course after the initial
assessment. In 1987, in a prospective study involving 249 babies (GA,
28–43 weeks; BW, 830–4820 g; and neonatal age, between birth and
27 days), Mathers and Pohlandt conducted a diagnostic audit of CRP in
neonatal infection using a method in which 6 mg/L was the lower
limit of detection [6]. They found that only 3 out of 19 infants with
proven sepsis had serum CRP over 6 mg/L on admission, and
concluded that a “normal” CRP was virtually useless for exclusion of
early septicaemia. However, three years later, in a prospective study
involving a large group of preterm neonates, Wasunna et al. showed
that none of the cord CRP levels of their infants with confirmed sepsis
was over 6 mg/L, but most were over the 95th centile value of
1.42 mg/L, as established by a radiometric monoclonal antibody
immunoassay in the cord of 104 preterm uninfected symptomatic
babies [8]. Thus a more sensitive (and precise) CRP assay such as we
have used here should be valuable during the very early neonatal
period to improve the diagnostic accuracy of CRP in the earliest course
of infection.
An unexpected finding in the preterm infant with sampling
extended into the fifth postnatal day was the spontaneous apparent
tendency to return to increased CRP levels. However, the sample sizes
at these higher ages were small. Though the newborn is initially
covered with a surface microbicidal shield to protect it during its
transition to extra-uterine life [25], the neonatal skin and gut are then
rapidly colonized with microbial flora. Thus while the birth process
initiates an acute-phase reaction in the neonate, it is possible that the
1058 C. Chiesa et al. / Clinica Chimica Acta 412 (2011) 1053–1059
reactivation of this acute-phase response may be due in the preterm
neonate to the markedly enhanced clearance and detoxification of
microbes and microbial toxins that have translocated across mucous
membranes during birth and/or initial colonization [26].
The present study indicates that CRP reference intervals may be
affected by a number of pro-inflammatory risk factors such as
prolonged rupture of membranes, preterm labor and GBS coloniza-
tion, as inferred by the need for intrapartum antimicrobial prophy-
laxis [20]. Yet, a novel finding observed is that neonates prenatally
exposed to steroids had increased CRP concentrations. About 75% of
women in preterm labor receive glucocorticoids to enhance fetal lung
maturation [27]. In clinical practice, glucocorticoids are often
administered in the presence of preterm rupture of membranes and
histological chorioamnionitis [28,29]. Thus a large number of infants
delivered prematurely are exposed to the combined effects of
antenatal glucocorticoids and a pro-inflammatory stimulus. Further
confounding variables associated with CRP increases in the healthy
neonate were vaginal delivery, a longer duration of active labor, and
possibly intrapartum fetal distress, thus confirming that CRP neonatal
response may be also related to the physical stress on babies during
delivery [11]. In contrast, our data indicate that interpretation of PCT
reference intervals may be possibly hampered by specific confoun-
ders, such as prolonged rupture of membranes and gestational
diabetes. These findings were not unexpected [16,18].
As observed with CRP, our study shows that the clinical utility of
PCT in the diagnosis of early-onset sepsis will depend upon the
establishment of reference ranges specific to both gestational and
postnatal ages. Our earlier experience in a smaller sample of healthy
full-term newborns suggested a physiologic increase in PCT levels
over the first 2 days of life [16]. Our present results confirm and
expand this. A novel finding is that, during the early neonatal period,
the healthy preterm baby has an earlier, higher, and longer PCT
response compared with that presently found in the healthy term
baby, demonstrating an inverse relationship between stage of
development and magnitude of neonatal PCT response. This is in
contradiction with the report by Turner et al. [17] whose normogram
during the first 4 days of life of preterm symptomatic uninfected
infants, stratified by gestational age (24–30 and 31–36 weeks
gestation), suggested that PCT concentrations decrease with prema-
turity. However, PCT reference intervals were calculated in their
cohort by repeated measurements on the same infant without
checking the magnitude of the bias that this might introduce.
Repeated measurements are not equivalent to independent observa-
tions. If, for example, the patients for whom repeated measurements
are made, have particular characteristics, then to include the repeated
measurements would introduce a bias into the estimates of the
reference intervals. In particular, the standard deviation would be
under-estimated and the reference intervals would tend to be too
narrow. For this reason we chose to make only one observation for
each healthy neonate.
Despite its potential clinical usefulness, surprisingly little is known
about the structure of PCT, its biological properties and source of
origin. The entire literature on PCT has long assumed a size of 116
aminoacids, PCT 1–116, a molecule with two additional aminoacids
(Ala-Pro) at the N-terminal which can be cleaved by dipeptidyl
peptidase IV leading to N-terminal truncated PCT 3–116. In 2001,
Weglöhner et al. showed by mass-spectrometric analysis that in sera
from septic patients with high PCT immune reactivity, the truncated
form PCT 3–116 was the major circulating form [30]. Nonetheless, the
function of serum PCT 3–116 in septic and healthy status as well as the
importance of the N-terminal truncation are still unknown. More
recently, with newly developed monoclonal antibodies against the
aminotermini of PCT 1–116 and PCT 3–116, Struck et al. compara-
tively assessed the kinetics of amino-terminal variants of PCT by
inducing acute systemic inflammation in 22 healthy individuals [31].
At the earliest time point that PCT was detectable (4 h after
stimulation), the initially synthesized PCT1-116 already was partially
converted to PCT3-116. Between 4 and 6 h after stimulation, de novo
PCT synthesis and proteolytic conversion apparently occurred at a
comparable rate. However, when the systemic inflammation van-
ished, the conversion rate exceeded the rate of synthesis, and the
concentrations of PCT 1–116 increased at lower rate than those of
PCT3-116 or total PCT [31]. Thus, although the results of our study
based on the total PCT cannot discriminate whether the different PCT
kinetics between preterm and term babies is mediated by the effects
of development and maturation on the synthesis of PCT1-116 as well
as on the rate of N-terminal truncation, our results clearly emphasize
the need of future studies to detail the role of both PCT species in the
age-and GA-dependent PCT reference intervals during the early
neonatal period, and therefore their usefulness in improving diagnosis
and prognosis of neonatal infection.
Prospective studies are now needed to validate these reference
intervals and to determine their predictability and usefulness in the
diagnosis of early-onset infection in both preterm and term neonates.
Supplementary materials related to this article can be found online
at doi:10.1016/j.cca.2011.02.020.
Acknowledgments
We are indebted to Silvano Castrechini for his excellent technical
assistance.
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