C-Reactive

Edward
From

Protein

L. Kaplan,

M.D.,

the Departments

STREPTOCOCCAL

Pharyngitis

and Lewis W. Wannamaker,

of Pediatrics

ABSTRACT.
This study was designed
to explore
whether
the
test for C-reactive
protein
(CRP)
is useful
in differentiating
bona fide streptococcal
infection
from
the symptomatic
carrier
at the time of the acute
visit to the physician.
Serial
blood samples
from 157 children
with symptomatic
pharyngitis and a positive
culture
for group
A streptococci
were
analyzed
for the presence
or absence
of CRP.
These
data
were compared
with the patients
antibody
responses
to two
streptococcal
extracellular
antigens
(antistreptolysin
0 and
antistreptococcal
deoxyribonuclease
B). Seventy-eight
percent of patients
with serologically
confirmed
streptococcal
pharngitis
had
a positive
CRP
test at the initial
visit.
Conversely,
if the CRP test was negative
at the acute
visit,
only about
25% later
showed
an antibody
response.
This
latter finding
held regardless
of the degree
of positivity
of the
initial
culture,
the presence
of exudate
or adenitis,
or the
presence
of a temperature
greater
than
38.3 C (101 F) or
coryza.
These data suggest
that the CRP test may be helpful
to the clinician,
especially
if this abnormal
protein
is absent
at the time
of the acute
visit.
Pediatrics
60:28-32,
1977,
STREPTOCOCCAL
PHARYNGITIS,
ANTISTREPTOLYSIN
0, ANTISTREPTOCOCCAL
DEOXYRIBONUCLEASE
B, C-REAcrIvE
PROTEIN,

in Streptococcal

CARRIER.

and Microbiology,

indicated

(Tnicersity

that

pharyngitis

M.D.

and

of
a

studies

(CRP)

and

a positive

culture

for

group

A strepto-

cocci
into
those
with
bona
fide streptococcal
infection
and those who are streptococcal
carriers
with symptoms
due to some
other
cause.2
This
differentiation
is especially
important
because
the
risk of developing
acute
rheumatic
fever appears
to be low in the chronic
carrier
of group
A
$-hemolytic
streptococci.
In addition,
the longstanding
carrier
appears
to be less of an epidemiologic
threat,
i.e., he or she is less likely
to
spread
the organism
to contacts.4
Previous
studies
reported
from
this laboratory
28

PEDIATRICS

Vol.

60

No.

1 July

with

symptomatic

culture

for

group

further

revealed

that

among

clinical

may

be

positive

with

this

illness,8#{176} but

to

our knowledge
this laboratory
test has not been
correlated
with
antibody
responses
to streptococcal
extracellular
antigens.
Realizing
that

acute

gitis

children
positive

findings,
the presence
of anterior
cervical
adenitis
was most often associated
with bona
fide streptococcal
infection.5
Among
laboratory
studies,
the peripheral
WBC
count6
and the ESRT have
been
reported
to be
elevated
in patients
with streptococcal
pharyngitis. Several
investigators
have commented,
almost
anecdotally,
that the test for C-reactive
protein

ness

and
intensive
search,
methods
have
not been
physician
can consistently
children
with
pharyn-

Minneapolis

$-hemolytic
streptococci,
only
approximately
half
had
serologically
confirmed
streptococcal
infection
as demonstrated
by a rise in antibodies
to streptococcal
extracellular
antigens.5
These

acute-phase
reactants
cators
of inflammation,

Despite
a continuing
clinical
and laboratory
identified
by which
the
and reliably
differentiate

of Minnesota,

clinical
coccal

of the

CRP

are
we

determination

illness
in predicting
and bacteriological
infection
would

rather
nonspecific
evaluated
the
at the

time

mdiusefulof the

which
children
with
findings
of streptodevelop
an
antibody

(Received
November
22, 1976; revision
accepted
for publication
February
3, 1977.)
Supported
by U.S. Public
Health
Service
research
grant
HL
19307-01
and
conducted
under
the
sponsorship
of the
Commission
on Streptococcal
and Staphylococcal
Diseases,
Armed
Forces
Epideniiological
Board,
and with the sponsorship and support
of the U.S. Army
Medical
Research
and
Development
Command
under
research
contract
DADA-1770-C-0081.
Dr. \Vannamaker
is a Career
Investigator
of the American
Heart Association.
ADDRESS
FOR REPRINTS:
(ELK.)
Department
of Pediatrics,
Box 94, University
of Minnesota,
Minneapolis,
MN
55455.

1977

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Antibody Rise (69)

No Rise (88)
p< .01

FIG. 1. Diagram
A streptococci

showing
percent
of 157 patients
with pharyngitis
who developed
antibody
response
and proportion
protein
in their sera at acute
visit (see

response.
The results
of the CRP test were correlated
with
the subsequent
antibody
response
to
two
streptococcal
extracellular
antigens,
antistreptolysin
0 (ASO) and antistreptococcal
deoxyribonuclease
B (anti-DNase
B).

MATERIALS

AND METHODS

The patients
eligible
for admission
to this study
were
children
15 years
of age or younger
who
presented
to the emergency
room
of a general
hospital
with uncomplicated
pharyngitis.
At the
time
of the initial
visit,
cultures
were
obtained
from the anterior
nares and the throat,
and serum
samples

were

obtained.

The

patients

were

seen

again 24 hours later and for convalescent

visits at
three
and six weeks
following
the initial
visit. At
each convalescent
visit, in addition
to obtaining
a
history,
a physical
examination
including
a
cardiac
examination
and blood
pressure
determination
was
performed.
Urinalyses
were
done.
Details
of the study
population,
laboratory
tests,
and
therapy
have
been
described
previously.5
Sera were stored
at -15 C. All serum
samples
for
each patient
were
run simultaneously.
CRP
determinations
were
performed
using
commercially
available
reagents
(Difco,
Detroit)
and the accompanying
protocol,
which
is a modi-

fication

and

of

and positive
culture
of those who had
text).

the

technique

for group
C-reactive

described

by

Anderson

McCarty.

RESULTS
Serial blood
samples
(acute
visit, three
weeks,
six weeks)
for CRP determination
were
available
from 157 children
with symptomatic
pharyngitis
or tonsillitis
and a positive
culture
for group
A
/3-hemolytic

streptococci.

The results
of the CRP determinations
reported
here refer only to sera obtained
at the acute
visit.
Although
convalescent
sera (three
weeks
and six
weeks)
were
also tested
for the presence
of this
protein,
they
were
rarely
positive.
Eleven
(less
than
10%) of the convalescent
serum
samples
collected
at the three-week
visit were
positive
and a similar
number
were
positive
at six weeks.
In no instances
were
serum
samples
from
the
same

patient

positive

at both

three

and

six weeks.

In six cases the CRP test remained

weakly
positive at the three-week
visit after being
positive
at
the initial
visit.
Review
of these
few patients
clinical
findings
revealed
nothing
distinctive
about
them
or their
clinical
courses.
In the group
of 157 patients
reported
here,
69
(44%) demonstrated
a significant
rise in ASO and!
or anti-DNase
B titer
(Fig.
1). Of these
69
patients,
54 (78%) had a positive
CRP test at the
ARTICLES

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29

P1

Positive CRP (lOU

CRP (56)

Negative

Antibody
No53%
43%rise

p<.0l
2. Diagram
showing
percent
of 157 patients
with pharyngitis
A streptococci
who had C-reactive
protein
in their sera at acute
without
positive
C-reactive
protein
who
developed
antibody
text).
FIG.

initial

visit.

patients
initial

(64%)
had a positive
CRP
visit.
Of those
with
a positive

53%

As

seen

subsequently

in

Figure

2,

101

demonstrated

of

the

157

test at the
CRP
test,

a significant

rise

in ASO and/or
anti-DNase
B. In contrast,
only
about
one quarter
(15/56)
of those with a negative
CRP
test had a significant
rise in streptococcal
antil)ody
titers.
We examined
several
clinical
signs and symptoms

in these

patients

and

of the initial
cultures
or absence
of these
correlated
with
the
These

the

degree

of positivity

to determine
if the presence
specific
findings
could
be
CRP
determination
at the

acute

visit.

(The

totals

for each

results

group

157

patients

since

specific

are

shown

do not

in the

always

observations

Table.

add
were

up to
not

recorded
for some
patients.)
Positive
cultures
were
divided
into those
with
50 or more colonies
of hemolytic
streptococci
on
the initial
culture
plate (> 2 + culture)
and those
with fewer
than 50 colonies
(2 + or less). Patients
with
strongly
positive
cultures
more
frequently
had a positive
CRP test (72%) than did those
with
weakly
positive
cultures
(49%). It is also true that
those
with strongly
positive
cultures
and a positive
CRP
test
were
somewhat
more
likely
to
develop
an antibody
response
(58%)
than
were

30

CRP IN STREPTOCOCCAL

and positive
culture
for group
visit. Percent
of those with and
response
is also shown
(see

those

with
less than
50 colonies
and a positive
test (40%). Conversely,
a larger
percentage
of patients
with a weakly
positive
culture
had a
negative
CRP test (51%) than
did those
with
50
colonies
or greater
on the initial
plate
(28%).
In
both
of the latter
groups
with
a negative
CRP
test, only about
one patient
in four developed
an
CRP

antibody

rise.

Anterior
cervical
lymphadenitis
(tender
nodes)
was also evaluated
for correlation
with a positive
CRP
test and an antibody
response
(Table).
Of
those
with
adenitis
(71 patients),
about
three
fourths
had a positive
CRP
test at the initial
visit;
of those
who
did not demonstrate
adenitis
(84
patients),
only about
one half had a positive
CRP
test. However,
patients
with
adenitis
and a positive CRP
test were
only slightly
more
likely
to
develop
an antibody
response
(59%)
than
were
those
without
adenitis
but with
a positive
CRP
test
(49%).
As might
be suspected,
a larger
percentage
(46%) of patients
without
adenitis
had
a negative
CRP
test
than
did
patients
with
adenitis
(24%). Again,
about
75% of those
evaluated who had a negative
CRP
test did not later
experience
an antibody
response.
The presence
of
adenitis
seemed
to make
no difference.
The data for patients
with and without
pharyn-

PHARYNGITIS

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OF CRP

CoiussiTIoN

DETERMINATION

WITH

CLINICAL

SIGNS

AND

SYMPTOMS

AND

INITIAL

CULTURES

No.
With

Degree

>

(%)

of

No.

Patients

Positive

( %)

Subtotal

of

Antibody +

Antibody

Total No.
of Patients

Patients

Negative

With

CRP

CRP

Subtotal

Antibody +

Antibody

44 (58)
10 (40)

32 (42)
15 (60)

76 (72)
25 (49)

8 (27)
7 (27)

22 (73)
19 (73)

30 (28)
26 (51)

106
51

32 (59)
22 (49)

22 (41)
23 (51)

54 (76)
45 (54)

5 (29)
10 (26)

12 (71)
29 (74)

17 (24)
39 (46)

71
84

38 (51)

36 (49)

74 (75)

16 (59)

11 (41)

27 (47)

6 (24)
9 (29)

19 (76)
22 (71)

25 (25)
31 (53)

99
58

19 (53)
31 (51)

17 (47)
30 (49)

36 (57)
61 (69)

5 (19)
9 (33)

22 (81)
18 (67)

27 (43)
27 (31)

63
88

24 (51)
27 (54)

23 (49)
23 (46)

47 (80)
50 (54)

5 (42)
10 (24)

7 (58)
32 (76)

12 (20)
42 (46)

59
92

of positivity

2+
2 +

Adenitis

Present
Absent
Exudate

Present
Absent

Coryza
Present
Absent

Temperature
<

38.3
38.3

C
C

geal or tonsillar
exudate
at the acute
visit are
similar
to the adenitis
data (Table).
Patients
with
a positive
culture
but a negative
CRP
test-no
matter
whether
exudate
was observed-usually
(almost
75%)
did
not
show
an antibody
rise,
suggesting

the

possible

value

of a negative

test.

Many
clinicians
do not feel that
coryza
is a
reliable
indicator
of streptococcal
pharyngitis
in
children.
A positive
CRP test was found
slightly
more
often
in the absence
of a history
of coryza
(69%) than when
it was present
(57%). A negative
CRP test was more
often seen in the presence
of
coryza
(43%) than when
it was not present
(3 1%).
There
proved
to be
no
difference
in
the
percentage
of patients
showing
a positive
CRP
test with an antibody
rise whether
or not coryza
was present.
Eighty

percent

of patients

with

a temperature

of 38.3 C (101 F) or greater

had a positive
CRP
test at the initial
visit; about
one half of those with
a temperature
of less than
38.3 C had a positive CRP test. The presence
of a temperature
of
38.3 C or greater
in those who had a positive
CRP
test at the initial
visit did not seem
to influence
the number
who would
later
show
an antibody
response.

DISCUSSION
The
would
physician
truly

vidual

potential
be at the
in

infected
with

value
of the CRP determination
time of the acute
visit to assist
differentiating

with
streptococci
a positive
culture

the

child

from
who

or

symptomatic
carrier.
patient,
as we have
infection
is probably
A Streptococcus.5
Like other
acute-phase
nonspecific
indicator
protein
has been found
infectious

adult

the mdiis only

a

latter
the
group

reactants,
the CRP is a
of
inflammation.
This
in human
serum
in myriad

noninfectious

states

ranging

from

patients
with tumors
to those who have received
an injection
of benzathine
penicillin.-2
It has
been
used
extensively
in following
the clinical
course
of patients
with
rheumatic
fever
because
the protein
is not normally
found
in human
serum
and the test may therefore
be easier
to interpret
than the ESR.
A review
of the literature
suggests
that CRP is
not infrequently
present
in serum
of patients
with
pharyngitis
from
whom
hemolytic
streptococci
are recovered.#{176} However,
earlier
studies
did not
attempt
to correlate
the CRP
test with
streptococcal
antibody
data.
Since
only
half of these
patients
with positive
throat
cultures
have
serologically
confirmed
infection,5-
we evaluated
the
CRP test as a possible
means
of differentiating
the
truly

infected

individual

carrier.
Of those
69 patients
tion (recovery
of the
rise),

the

and

In the case
of this
previously
suggested,
not related
to the

78%

had

a positive

from

the

symptomatic

who had bona

fide infecorganism
plus an antibody
CRP

test

at

the

time

of

the acute visit (Fig. 1). Conversely,

if the CRP test
was negative
at the initial
visit (Fig. 2), only about
one
patient
in four
developed
an
antibody
response
to either
streptolysin
0 and/or
deoxyriARTICLES

Downloaded from by guest on November 10, 2016

31

bonuclease
frequently

B. This
positive

streptococcal

impression
that
in serologically

pharyngitis

is strengthened

fact that patients

with a negative
seldom
show
a rise in antibody
suggest

that

this

test

the
test
confirmed

may

be

by

is
the

initial
CRP test
titer.
These
data

helpful

primarily

in

patients
with no CRP in their sera.
In a previous
report,
our data
suggested
that
there was little correlation
between
the degree
of
positivity
of the initial
culture
and the antibody
response.5
It is of some interest,
however,
that one
is more
likely
to have
a positive
CRP
test with
a
strongly
positive
culture
than
when
only a few
colonies
of ,8-hemolytic
streptococci
can
be
isolated.
An intriguing
correlation
was found
between
the presence
of CRP
in the acute
sera and the
clinical
signs and symptoms
that were
evaluated
(adenitis, exudate,
fever,
coryza).
The data
from
this study
suggest
that
no matter
whether
the
finding
is present
or absent,
if the CRP
test is
initially
negative,
there
is only
a 25% to 30%
chance
of the patient
having
bona
fide streptococcal
infection
(proven
by a significant
antibody
response).
The
CRP
test falls short
of being
a perfect
predictor
of which
patients
with pharyngitis
and
a positive
culture
will
develop
an antibody
response.
However,
the data do strongly
suggest
that
this laboratory
test may be helpful
to the
clinician,
especially
if the CRP determination
is
negative
at the initial
visit.

before

of acute
rheumatic
fever.
Yale
1961.
4. Wannamaker
LW:
Epidemiology
of
streptococcal
diseases,
in McCarty
M (ed): Streptococcal
Infections. New York, Columbia
University
Press,
1954,
p 164.
5. Kaplan
EL, Top FH Jr, Dudding
BA, Wannamaker
LW:

6.

7.

8.

9.

10.

11.

12.

13.

14.

REFERENCES
1. Wannamaker
diagnosis

LW:

Perplexity

of streptococcal

and

precision

pharyngitis.

in
Am

Child

the

J Dis

124:352,
1972.
2. Kaplan
EL: Unresolved
problems
in the diagnosis
and
epidemiology
of streptococcal
infections,
in Wannamaker
LW,
Matsen
JM (eds):
Streptococci
and
Streptococcal
Diseases:
Recognition,
Understanding, and Management.
New York, Academic
Press,
1972, p 558.
3. Rammelkamp
CH Jr, Stolzer
BL: The
latent
period

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15.

the

onset

Biol Med

34:226,

Diagnosis

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streptococcal

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The

prob-

lem of differentiating
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carrier
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Siegel
AC, Johnson
EE,
Stollerman
GH:
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rheumatic
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N Engl J Med 265:559,
1961.
Shapera
RM, Matsen
JM: Nitroblue
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51:284,
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RF, Swift HF, Wilson
AT: Bacteriologic
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streptococci
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Anderson
HC, McCarty
M: Determination
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A: Behavior
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HF: Effect
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UE, Whitehouse
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Br J Obstet
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KG,
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LA:
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ACKNOWLEDGMENT
The authors
for technical

express
assistance

PHARYNGITIS

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their appreciation
to Miriam
during
these studies.

Horneff

C-Reactive Protein in Streptococcal Pharyngitis

Edward L. Kaplan and Lewis W. Wannamaker
Pediatrics 1977;60;28
Updated Information &
Services

including high resolution figures, can be found at:

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or in its entirety can be found online at:
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007.
Copyright 1977 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005.
Online ISSN: 1098-4275.

Downloaded from by guest on November 10, 2016

C-Reactive Protein in Streptococcal Pharyngitis

Edward L. Kaplan and Lewis W. Wannamaker
Pediatrics 1977;60;28

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
/content/60/1/28

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked
by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,
Illinois, 60007. Copyright 1977 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: 0031-4005. Online ISSN: 1098-4275.

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