SERUM
C-REACTIVE
PROTEIN
IN INFECTIONS
DURING
THE
FIRST SIX MONTHS
OF
LIFE
Natalie S. Felix, M.D., Hironori Nakajima, M.D.,* and B. M. Kagan, M.D.
Departments of Pediatrics, Cedars of Lebanon Hospital Division of the Cedars-Sinai Medical Center, and the University of California Medical School, Los Angeles, California
(Submitted April 7; accepted for publication September 15, 1965.)
* PRESENT ADDRESS: (H.N.) Department of Pediatrics, School of Medicine, Chiba University, Chiba,
Japan.
REPRINTS ADDRESS: Dr. B. M. Kagan, Cedars of Lebanon Hospital, 48:33 Fountain Avenue, Los Angeles, California 90029.
PEDIATRICS, VOL. 37, No. 2, FEBRUARY 1966 270
T
HE USUAL laboratory criteria fordeter-mining the presence of infection are
often not helpful in the early months of life.
The sedimentation rate is a sensitive index
in later life, but in early infancy it is much
less helpful.’ In older infants, children, and
adults, the presence of serum C-reactive
protein is also a sensitive index of
inflammation, although generally not as
helpful as the erythrocyte sedimentation
rate. Preliminary survey, however,
suggest-ed that the test for C-reactive protein may
be quite useful in early infancy. It was,
therefore, the aim of this study to
deter-mine if serum C-reactive protein
deter-mination could be of diagnostic value in
infections during the first six months of life.
C-reactive protein, an acute phase serum
protein, is a globulin formed by the body in
response to various non-specific stimuli
such as infection, tissue necrosis, or
neo-plasm. The time of appearance and the
amount of C-reactive protein formed are
related to the time of appearance and to
the degree of the stimulus.
MATERIALS AND METHOD
Sixty-six cord blood and 595 capillary
blood specimens were collected at random
from 284 apparently normal full-term
in-fants. The number of specimens from each
infant varied from 1 to 6. Capillary blood
specimens were also collected from 385
ap-parently normal infants 1 to 6 months of
age. Serum C-reactive protein
determina-tions were done on all these specimens.
Daily determinations were done during
the first 4 days of life on 72 apparently
nor-mal full-term infants while in the nursery.
Among this group, 14 determinations were
also done on cord serum and 9 on capillary
serum specimens taken at about 1 month of age.
Serum from 266 infants, 0 to 6 months of
age, ill with known or suspected infection,
were also examined for C-reactive protein.
C-reactive protein determination was
performed by a simple antigen-antibody
precipitin test5 in a capillary tube provided
for this test, using the C-reactive protein
antiserum manufactured by Schieffelin. The
results were read after 24 hours at room
temperature and recorded according to
the height in millimeters of the column of
precipitate produced. When there was no
precipitate visible, this was designated as
negative (-); a column of precipitate less
than one millimeter as”< 1 mm”; a one
mil-limeter column as “1 mm,” etc. In the
anal-ysis of the data”< 1 mm” reading was
in-corporated with the “1 mm” reading.
The C-reactive protein determinations
were done twice in each of 12 serum
speci-mens using the same antiserum. Both tests
yielded the same results in all the serum
specimens.
For purpose of comparison, 192 blood
serum specimens were tested, using two
lots of C-reactive protein antisera
simulta-neously: one manufactured by Schieffelin
and the other by Crescent.#{176}
#{176}Generously supplied through the courtesy of
Crescent
94
7Sf 169 negative
‘23 positive
TABLE II
‘l’ABLE I
(‘o\tP&IsIsoN OF C-REACTIvE PROTEIN IN 192 S,’:uo’i
SPECIMENS USING CRPA-Sciii EFFELIN
AND CRPA-CRFSCENT
Schieffelin
94 negative
positive
‘23 (<1 nun) 2 (<1 mm)
21 (-)
67 (1 mm) 7 (1 mm)
7 (<1 mm) 53 (-)
7 (2 mm) 2 (2 iiiiii)
‘2 (1 nirn)
‘2 (<1111111)
I (-)
1 (3 mm) 1 (1mm)
Of the 192 serum specimens that were
tested simultaneously using the antisera
prepared by two different commercial
com-panies, 98 showed positive reactions with
Schieffelin in contrast to only 23 positive
reactions with Crescent (Table I). All the
negative sera with Schieffelin also yielded
negative reaction with Crescent. Of the 98
positive sera with Schieffelin, 75 of the
cor-responding sera yielded negative results
with Crescent. Only 11 had the same
de-gree of positivity as Schieffelin; 12 had
lower degree of positivity than Schieffelin.
Not only were there an increase in the
number of positive reactors but also a
greater degree of positivity with Schieffelin
than with Crescent. Therefore, in
compar-ing data from laboratory to laboratory, it
would be necessary to standardize carefully
on a particular antiserum. All the results
cited below were obtained with Schieffelin
antisera.
RESULTS
The values for serum C-reactive protein
in the normal infants 0 to 6 months of age
are shown in Table II. All but one of the 66
cord blood specimens were negative for
C-reactive protein. The positive one showed a
reaction of less than 1 mm. The incidence
of positive reactors in normal infants
in-creased soon after birth. The average
fre-quency of positive reactors during the first
week of life was 51%. After the first week to
about 1 month of age 5% had positive
reac-tions. From 1 month to 6 months of age
only 2% were positive. The intensity of the
positive reactions in the vast majority (93%)
was not greater than 1 mm. It was only
during the first week of age that 4% had
reactions of 2 mm and greater, but none
was greater than 3 mm.
Figure 1 plots the incidence of positive
reactors in 72 normal newborn infants who
had daily serial determinations during the
first 4 days of life. Cord serum specimens
from 14 newborns in this group were
exam-ined for C-reactive protein and all were
negative. A total of 344 capillary serum
specimens were collected. Of this total, 55%
SERUM C-REAcTIVE PROTEIN IN 669 APPARENTLY NORMAL INFANTS 0-6 MONThS OF AGE
Age Cord <1 Week 1 uk- <1 mo 1 ,,,o-I moo
Total Number of Specimens 66 496 99 385
Negative Positive
65 (98.5%) 1(1 .5%)
244 (49%)
252 (51%)
94 (95%)
5 (5%)
377 (98%) 8 (2%)
<1 mm
1 mm
2mm
3mm 4mm&>
1(1.5%) 0 0 0 0
77(15.5%) 156 (31 .5%)
17(3.6%) 2(0.4%) 0
2(2%)
3 (3%)
0 0 0
6(1.5%)
‘2(0.5%)
POSITIVE CRP IN SERIAL SERA OF
72 NORMAL NEWBORN INFANTS
00
AGE DAYS)
O(CORD) <I I
Fic. 1.
were positive. The incidence of positive
reactors increased soon after birth, reaching
its peak (69%) at 2 days of age. From then
on, the number of positive reactors
de-creased in number so that by 4 days of age,
only 38% was positive. The intensity of the
positive reactions in the vast majority (91%)
was not greater than 1 mm. Serum
speci-mens from 9 infants in this group at about 1
month of age were examined. All were
neg-ative for C-reactive protein.
The series of normal infants reported in
this study were all full terms. We are now
determining the incidence of C-reactive
protein in apparently healthy premature
in-fants. Preliminary survey suggests that it is
the same as in the full-term infants.
Table III shows the comparison of the
incidence of serum C-reactive protein
be-tween normal infants and infants with
in-fection during the first 6 months of life.
Eighty-seven (72%) of the 121 infants with
infection had positive reactions in contrast
to 27% in normal infants. The degree of
pos-itivity in some of the infants with infection
was greater than 4 mm, the maximum was
10 mm, while that in the normal infants was
never greater than 3 mm in reaction. In the
latter group, the intensity of the positive
reaction in the majority was only up to 1
mm, with only 2% showing 2 mm or
great-er. However, in the infants with infection,
55% showed reactions of 2 mm or greater,
38% of these having reactions of 3 mm or
greater.
The foregoing groups of infants were
subdivided into three age groups as shown
in Table IV. Of the 23 newborn infants less
than a week of age with infection, 78% had
positive reactions in contrast to 51% of the
normal newborns of the same age group.
There was a significant difference between
the two groups in the intensity of the
reac-tion. Among the normal infants, the
majori-ty of the positive reactions were only 1 mm
with only 4% having reactions of 2 mm or
30 greater but never greater than 3 mm,
whereas in those newborns with infection
the reactions were 2 mm or greater in
69.5%. There were reactions even greater
than 4 mm in the latter group; the highest
was 10 mm.
From 1 week to about 1 month of age,
76% of the infants with infection had
posi-tive reactions, in contrast to only 5% in the
normal infants of the same age group. The
intensity of the positive reactions in the
normal infants was never greater than
1 mm, whereas, among the newborn infants
with infection there were reactions even
greater than 4 mm. In the latter group,
65.5% had reactions of 2 mm or greater of
which 56.5% had reactions of 3 mm or
greater.
TABLE III
SERUM C-REAcTIvE PROTEIN IN NORMAl. INFANTS, SICK INFANTS WITh INFECTION, AND SIcK
INFANTS WIThOUT INFECTION
GrOU/) Normal
Sick Infants
. With Infection
.
ITzt ho at
Infection
Total Number
Negative Positive
1mm 2mm 3mm 4 mm & >
980
715 (73%) 265 (27%)
246 (25%) 17(1.8%)
2(0.2%) 0
121
34 (‘28%)
87 (7-2%)
20 (17%)
21 (17%)
19(16%) 27 (22%)
145
128 88%) 17 (12%)
5 (4%)
3(2%)
Age <1 Week 1 Week- <1 Month 1 Month-6 Months
Group Normal With Infection Normal With Infection Normal With Infection
Total Number 496 23 99 ‘29 385 69
Negative
Positive
244 (49%) 5 (‘22%)
252 (51%) 18 (78%)
94 (95%) 7 (24%)
5 (5%) 22 (76%)
377 (98%) 22 (32%) 8 (2%) 47 (68%)
1mm
2mm
3 mm
4mm&>
233 (47%) 2 (8.5%)
17 3
2 (4%) 6 (69 ..5%)
0 7J
5 (5%) 3 (10.5%)
0 6
0 6 (69 .5%)
0 7
8 (2%) 15 (22%)
0 12
0 7 (40%)
0 13
TABLE IV
COMPARISON OF INCIDENCE OF SERUM C-REACTIVE PROTEIN BETWEEN NORMAL INFANTS AND INFANTS WITH INFECTION BY AGE GROUPS
Among infants with infection who were 1
month to 6 months of age 68% had positive
reactions, in contrast to only 2% in normal
infants of the same age group. The
intensi-ty of the positive reactions in the normal
infants was never greater than 1 mm,
whereas among the infants with infection,
46% had reactions of 2 mm or greater, of
which 29% were reactions of 3 mm or
great-er. There were reactions even up to 8 mm
among the infants with infection.
Of the 266 sick infants tested
(
Table III),121 were finally diagnosed as having had
infection and 145 had illnesses which were
not due to infection. Of those with
infec-tion, 72% had positive reaction in contrast
to only 12% positive reactors among infants
having illness without infection. Although
the intensity of the reactions in some of the
sick infants without infection was even
greater than 4 mm, the incidence, however,
is significantly lower than that of the
in-fants with infection.
Table V shows the list of sick infants
without infection but with positive serum
C-reactive protein. Each of the three with
Caffey’s disease had a markedly positive
reaction, 2 having had 3 mm and 1 having
had 8 mm reactions. Two postmature
new-borns had 2 mm reactions. One patient with
a pericardial angioma (confirmed by
au-topsy) had a 6 mm reaction.
All
the patients with severe infection(Table VI), such as septicemia (25),
menin-gitis
(
15), peritonitis (7), and osteomyelitis(
5) had reactions of 2 mm or greater. Onehad a reaction of 10 mm
(
Listeriamonocy-togenes septicemia with meningitis). In
in-fants with upper respiratory infections or
with bronchitis, the majority of the
C-reac-tive protein reactions were negative and
those who had positive reactions had only
up to 1 mm reaction. However, in
infec-tions of the lower respiratory tract like
TABLE V
POsITIvE SERUM C-REACTIVE PROTEIN IN SICK INFANTS WITHOUT INFECTION
Age Diagnosis C-RP
5 days Pneumothorax, traumatic 1 mm
3 days Myelomeningocoele 3 mm
1 day Physiologic hyperbilirubinemia 3 mm
4 days Postmaturity 2 mm
3 days Postmaturity 2 mm
4 days Renal vein thrombosis 3 mm
51 mo 2nd post-op. day, PDA correc-tion
5 mm
1 mo 4th post-op. day, pyloromy-otomy
2 mm
2 mo Multiple congenital anomalies I mm 24 mo Herniorrhaphy, 3 hours post-op. 1 mm
1 mo Meningocoelectomy, 4th
post-op. day
< 1 mm
1 mo Convulsion, etiology unknown < 1 mm
24 mo Herniorrhaphy, 5 hours post-op. 3 mm
4 mo Caffey’s Disease 3 mm
l
mo Pericardial angioma 6 mm44 mo Caffey’s Disease 8 mm
TABLE VI
SEn ew C-REATIVE PROTEIN IN
INFANTS WITH INFECTION
Total Number
C-RP
.
Negative Positire
.
Intensity oft/me Positive Reaction
Septicemia 5 0 CS C mm-1O mm
Meningitis 15 0 15 mm-hO mm
Peritonitis 7 0 7 3 mm-8 mm
Osteomyeliti, 5 0 5 mm-8 mm
Bronchiolitis 1 0 1 1 mm
Pneumonia 18 1 17 1 mm-6 mm
URI 9 6 3 <lmm-lmm
Bronc}iitj, 7 4 3 <1 mm-i mm
Urinary tract iS 3 10 2mm-6 mm
infection
Diarrhea 15 11 14 <1 mm-S mm
Skin infection, 7 7 0 None
superficial
Cellulitis 4 0 4 2 mm-S mm
Abscess 2 0 1 3 mm-4 mm
bronchiolitis and pneumonia, all but one
had positive reactions, varying from 2 to 6
mm. The only patient with a lower
respira-tory tract infection who had a negative
reaction had pneumonia. At the time the
test was done she was already clinically
im-proving. In urinary tract infection, the
serum C-reactive protein varied from
nega-tive to 6 mm depending on the severity of
the infection. In diarrhea, the reactions
var-ied from negative to 5 mm depending upon
the severity of the condition. In superficial
skin infections there were negative
reac-tions, but in involvement of the deeper
tis-sues and in severe cases of cellulitis and
subcutaneous abscess formation positive
reactions varied from 2 mm to 5 mm.
There were 15 deaths (Table VII) among
the patients with infection. All were
autop-sied and were proven to have bacterial
in-fections. All had reactions of 2 mm or
greater.
Among the sick patients without
infec-tion, there were 12 deaths (Table VIII). All
but one had negative serum C-reactive
pro-teins. The one blood with the positive
reac-tion (6 mm) was from an infant with
pen-candial new growth (a rapidly growing
an-gioma). Of those with negative reactions, 6
had respiratory distress with pulmonary
hyaline membrane syndrome; one had
met-abolic acidosis of unknown etiology (all
cultures were negative for bacterial
agents); one had an intracranial
hemor-rhage with hemorrhagic pneumonitis; one
had congenital heart disease and also
multi-pie congenital anomalies; one had biliary
atresia, and one had Down’s syndrome with
A-V communis.
COMMENT
The absence of C-reactive protein in all
but one of the cord blood specimens in our
study is similar to other published
reports.35 Several investigators3’5 have
re-ported that 21% to 66% of women in labor
had positive serum C-reactive protein, while
all but one of the cord blood specimens of
their newborn infants had negative
reac-tions. This suggests that C-reactive protein
is not transmitted through the placenta
from the mother to the fetus.
The presence of serum C-reactive protein
in about 50% of the normal newborn infants
during the first week of life is similar to the
observation of Nemir et al. In both studies
the degree of positivity in the majority of
cases was only up to 1 mm. The cause of
this positive reaction in these normal
new-born infants was not analyzed. Nemir et al.4
suggested that this may be related to the
absorption of the necrotic tissue from the
umbilical stump which may serve as a
minor stimulus in the production of
C-reac-tive protein. However, Philipson et al. did
not think this is the cause because of the
high incidence of negative reactions during
the newborn period.
Very little is known about serum
C-reac-tive protein in infections during the first 6
months of life. Rozansky et al. reported the
presence of serum C-reactive protein in
amounts of 1+ to 4+ (equivalent to our
1 mm to 4 mm readings) in 6 infants with
in-fection in this age group. Philipson et al.
studied the occurrence of serum C-reactive
protein in infants whose clinical features
were suggestive of the presence of
C-reac-tive protein. Infection was one of the
cni-tenia in the selection of patients in their
study. Of the 42 infants under 6 months of
reac-5 wk
6 day
10day
‘2hr
‘2wk
5(lay
6 day
7 (lily
1 day
6 day
10 (lay
14 hr
9 day
4 day
‘21hr
WI”
\V/F
\V/M
TV/F
TV/F
TV/F
W/M
TV/M
\V/M
TV/F
W/M
TV/F
\V/M
TV/F
TV/M
6 mm
3 miii
6 ff111
5 111111
4 mm
‘2nmni
2 nini
4 nun
9 nun
3 111111
2 mm
4 mm
8him
4 fun
10 miii Septicemia, E. call
TABLE VII
DEATHS DUE TO INFECTION
Age Race/Sex Diagnosis C-RP
Septicopyemia with meningitis Septic emboli, liver, lungs
Septicemia (Aerobacter in blood and Spitz valve) Meningomyelocoele
Pyelonephritis, bilateral (Aerobacter aerogenes)
Uremia
Abscesses, thigh (Aerobacter aerogenes)
Peritonitis; volvulus, gangrenous Pneumonia, necrotizing
Pseudomnonas in blood, lungs, and peritoneal exudate
Pneumonia, congenital
Septicemia (Staph. anrens, coag.+) Omphalitis
Peritonitis; volvulus, gangrenous (Aerobacter+ Pseudomnona.s
+ Staph. aurens, coag.+)
Pneumonia, massive (Pseudomonas+ Aerobacter)
Septicemia (Aerobacter)
Pneumonia, E. coli
Intracranial hemorrhage
Septicemia with meningitis CE. mali)
Septicemia (Salmonella in blo (1and stool)
Septicemia with meningitis (E. coli)
Cellulitis, severe, with omphalities ((‘1. perfringens)
Peritonitis, secondary to ruptured omphalocoele
Peritonitis and meningitis (E. coli)
Septicemia with meningitis (Beta hemolytic streptococcus, probably not Group A)
Septicemia with meningitis (Listeria monocytogenes in spinal
fluid, blood, and skin lesion)
tions. Six had acute respiratory tract
infec-tion, 1 had acute urinary tract infection, 1
had megacolon with elevated
sedimenta-tion rate, and another had questionable
in-tracranial lesion with fever and some
men-ingeal involvement. In our study there is a
definite increase in the incidence of positive
reactors in our series of infants with
infec-tion during the first 6 months of life, more
so than that of the normal infants of the
same age group. Our findings suggest that
in infections during the first week of life a
reaction of 2 mm or greater may be
C-REACTIVE PROTEINS
TABLE VIII
DEATHS DUE TO ILLNESSES WITHOUT INFECTION
Age Race!.Se Diagnosis. C-RP
3 wk \V/M Biliary utresia
-1 mo \V/F Mongolian idiot with A-V communis
-15 hr W/M Pulmonary hyaline membrane disease
-I day V/F Pulmonary hyaline membrane disease
--I day V/F Pulmonary hyaline membrane disease
-2 hr W/F Pulmonary hyaline membrane disease
-23 hr W/F Pulmonary hyaline membrane disease
-2day W/M Pulmonary hyaline membrane disease
Rectal atresia
---8 day V/M Congenital heart disease with multiple congenital anomalies
-4 day W/M Intracranial hemorrhage with hemor-rhagic pneumonitis
-3 wk \V/M Metabolic acidosis, etiology unknown. All cultures negative for bacterial
agents
-21 mo %V/M Pericardial angioma with effusion 6 mm
any positive reaction showed a high degree
of correlation with the presence of
infec-tion. The greater the severity of the
infec-tion, the greater the intensity of the positive
reaction. We acknowledge, however, the
small numbers of young infants with
infec-tion on which the less than a week and the
1 week to less than a month statistics are
based. A larger series is needed to make a
definite conclusion of the foregoing
obser-vations.
There are limitations of the use of
C-reactive protein as the indicator of
infec-tion. As shown in our study, one-third of
tile cases of infections during the first 6
months of life would be missed if
C-reac-tive protein is used as an indicator. It is
also important to bear in mind the
non-specificity of the test. C-reactive protein
may be present not only in infection but
also in a wide variety of conditions as shown
in our study and in other reports.5 It is
ap-parent that serum C-reactive protein
deter-mination must be used in conjunction with
critical clinical judgment.
Serum C-reactive protein determination
requires 24 hours. In dealing with acutely
ill infants it may be necessary to initiate
therapy and not wait for the result.
In this study we did not determine when
the serum C-reactive protein appeared and
disappeared during the course of infection.
However, McCarty6 reported that it can
ap-pear quite rapidly after the onset of a
stim-ulus and also can disappear rapidly after
the subsidence of the stimulatory lesion. It
has been shown that C-reactive protein first
makes appearance in detectable amounts
about 12 hours after onset of stimulus.
Elimination of C-reactive protein may be
complete within 1 to 2 days after stimulus
is removed as in the case of successful
treat-ment of a bacterial infection.
SUMMARY
Serum C-reactive protein determinations
were done on 66 cord blood specimens and
on capillary blood specimens of 669
appar-ently normal infants and 266 infants ill with
known or suspected infection during the
first 6 months of life.
All but one of the cord blood specimens
were negative for C-reactive protein. The
incidence of positive reactors increased
soon after birth with 50% of the normal
newborns having positive reactions during
the first week of life. This rapidly decreased
after this period so that by 1 month to 6
months of age the incidence was only 2%.
The intensity of the positive reaction in the
majority was only up to 1 mm.
Two-thirds of the infants with infection
had positive reactions. The more severe the
infection the greater the intensity of the
positive reaction.
C-reactive protein was also present in a
variety of conditions besides infections.
Serum C-reactive protein determination
can be a valuable diagnostic aid in
infec-tions during the first 6 months of life when
the usual laboratory criteria for infections
are often not helpful. However, it has its
limitations. Like any other single laboratory
test, it must be used in conjunction with
critical clinical judgment.
REFERENCES
1. Morris, Hyman: The sedimentation rate in early infancy. Unpublished personal communica-tion.
infants
Birth Weight
(gm)
No Err/mange Err/mange Control
Male
Elhite
<1000
1001-1250
1251-1500
1301-1750
1751-2000
>2000
1
1 2
2 2
3
1 1
.5
4
1
Female <iooo
1001-1250
1251-1500
1501-1750 1751-2000
>2000
3
5 .5
1
1
6 4
2 1
.5
2
6
3
Non-li/mite
Male <1000
1001-1250 1 2 3
1251-1500 2 2 6
1301-1750 2 8 Ii
1731-2000 10 1 6
>2000 2 1 1
Female <1000
1001-1250 2
1251-1500 4 7
1501-1750 4 6 12
1751-2000 8 ii
>1000 2 2 2
50 50 87
The text of the article is correct as printed
and in accord with the conclusions.
Editor.
ARTICLES 277
a measure of the activity of the disease pro-cess in acute rheumatic fever. Amer. J. Med.,
8:445, 1950.
3. Rozansky, R., and Bercovici, B.: C-reactive
pro-tein during pregnancy and in cord blood.
Proc. Soc. Exp. Biol. Med.,
92:4,
1956.4. Nemir, Rosa Lee, Roberts, P. H., and
Barry-LeDeaux, S.: Observations of antistreptolysin-0, C-reactive protein and electrophoretic
pat-terns in maternal and neonatal sera. J.
Pediat., 51:493, 1957.
5. Philipson, L., and Tveteras, E.: C-reactive pro-tein in infancy: its appearance during the
first year of life, transplacental passage, and
electrophoretic pattern. Acta Paed., 46:1,
1957.
6. McCarty, M.: The C-reactive protein test.
Triangle, 4:142, 1960.
Errata
Attention has been drawn to two errors in
Table I on page 164 of the paper “Studies of
Non-Hemolytic Hyperbilirubinemia in
Prema-ture Infants I,” by Wishingrad, et a!.
(PlDI-ATRIS, 36:162, 1965).
The correct table, subsequently furnished
by the authors is:
TABLE I
DISTRIBUTION OF PATIENTS BETWEEN TIlE STUDY
