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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 1976 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: 0031-4005. Online ISSN: 1098-4275.
The Hematology
of Bacterial
in Premature
Infants
A. Zipursky,
F.R.C.P.(C)
the
From
Departments
Hamilton,
ABSTRACT.
A series
of
premature
M.D., F.R.C.P.(C),
ontario,
infants
of
Pediatrics
Qualitative
toxic
was
studied
changes
the sepsis-proven
provided
valuable
infections.
Thrombocytopenia
occurred
proven
group
or destniction
In
such
and seemed
of platelets
cases,
resulted
it was
from
platelets
a direct
and/or
NEUTROPHILS,
neutrophils
(DOhle
bodies,
frequently
in
the
sepsis-
evidence
and
minimal
in
of
intravascular
concluded
effect
of
endothelium.
NEONATAL
coagulation
was
that thrombocytopenia
had
the bacteria
or its products
on
Pediatrics,
57:839-853,
1976,
SEPSIS,
and
Clinical
THROMBOCYTOPENIA.
the
Forty-nine
Regional
McMaster
cases
the
We
have
reported
infants
in
previously
which
we
and
and G. I. Akenzua,
Biostatistics,
McMaster
M.B.,
University,
our
studies
demonstrated
of
the
MATERIAL
premature
Neonatal
AND
METHODS
infants
were
studied
at
Intensive
Care
Unit,
University
Medical
Centre.
All
cases
hill-term
Epidemiology
CLINICAL
Subjects
for
and vacuolization)
were more frequent
in
group
and, together
with the band count,
techniques
for the diagnosis
of bacterial
granulation,
Canada
the presence
of bacterial
infection.
On the basis of clinical
evidence
and bacteriological
studies,
they were divided
into
three
groups
in which
sepsis
was considered
to be proven,
possible,
or unlikely.
Band neutrophil
counts
were elevated
niost frequently
in the sepsis-proven
group
and the elevation occurred
usually
within
24 hours
of onset
of signs of
disease.
Infections
fluid,
or peritoneal
fluid
was
positive
in 12
for bacteria.
In one case, lung aspirate
source
of the bacteria.
In two cases,
abscesses
and
bacterial
July
29;
otitis
media
were
was
lung
found
postmortem.
importance
of nonsegmented
(band)
neutrophil
diagnosis
of infections.
In the present
study,
we have
examined
the
pattern
of hematological
changes
associated
with
counts
in
sepsis
in
of life.
the
premature
We
believe
infants
that
during
these
for earlier,
and
rial infections
more accurate,
and for greater
the
processes
pathologic
the
observations
involved.
first
month
provide
diagnosis
of bacteunderstanding
of
(Received
November
3,
ADDRESS
rics,
West,
FOR
McMaster
Hamilton,
revision
accepted
for
publication
1975.)
REPRINTS:
University
Ontario
(AZ.)
Department
Medical
Centre,
L8S4J9,
Canada.
1200
of PediatMain
Street
839
TABLE
CLINIcAL
FEATURES
OF
INFANTS
\VITH
CoNFIiuIEI
INFECTION
(SEPSI5-PIIoVEN)
.s7eitrophils
(per
Baiul
Ge.sta(wk)
Birthweight
(gui)
Age at
Onset
(days)
tiOH
,-
iiiiii)
Peak
Signs
Culture
Site
Outcome
Organism
Peak
(((1
S(g?lun
-,
(t1
Peak
Day
Peak
Dat,
36
2,1(X)
Shock
Blood
11. influenzae
Died day 0
-,
29
1,190
Apnea
CSF
E. coil
Alive
8,200
11
15,600
11
:1
34
1,39()
Vomiting
Peritoneum
K. aerogenes
Alive
6,100
11
13,300
11
27
1,090
Apnea
Blood
K. aerogenes
Alive
6,200
15,200
26
1,19()
Apnea
Otitis
media,
lung al)scess
18,600
28
1 ,320
Vomiting
Peritoneuin
F.
1,480
18
Apnea
Blood
S.
E.
100
Died
day
15
2,600
coil
Died
day
:3,500
epi(lerlni(lis
Alive
7,100
19
coli
Alive
3,600
weichii
Died
4,100
5,600
18,400
700
6,2(X)
2,2(X)
7,3(X)
(postmortem)
35
2,113
Fever
CSF,
30
1,640
Apnea
Blood
C.
lOt
34
1,990
Apnea,
jaundice
Blood
F. coil
Alive
31
1,370
Respiratory
Blood
E.
coli
Alive
P.
morganii
Died
--
-ii-
blood
day
7,200
12,900
19
18,200
4,300
distress
12
28
1,000
Respiratory
distress
Lung
13
35
2,680
Respiratory
distress
Blood
14
24
682
Apnea
Middle
aspirate
ear
Streptococcus
(B)
Alive
Streptococcus
(B)
Died
day
day
2,500
14,700
5,2(X)
28,3(X)
aspirate,
lung
abscess
(postmortem)
15
31
2,030
See
Figure
4.
tSee
Figure
5.
(2)
Infants
with
suggestive
(sepsis-possible)
clinical
tion
(16
course
and
skin
aspirate2)
I)lOod
(3)
was
sepsis
CSF
with
no
(32
was
clinical
the
and
Infants
to
laboratory
cases,
of bacterial
infec-
urine
X-ray,
in
the
diagnosis.
were
of
these
there
was
evidence
no
to
17,5(X)
which
was
not
significantly
2 or 3 (1,467
563
gm and
603 gm respectively).
All infants
in group
1 received
but one of group
2 (No. 28, who
However,
day of life)
negative.
infants
either
definitive
received
in group
instances,
(sep-
although
support
200
1,865
gastric
infection
cases,
Alive
1,551
gIn (SD 533)
different
from
groups
the
chest
cultures
In
S. epidernidis
of infection
these
cells
evidence
49):
suspected,
or
In
(e.g.,
pus
supported
cultures
sis-unlikely)
31):
data
culture,
Blood
evidence
to
suggestive
laboratory
culture,
Abdominal
distension
antibiotics;
3 also
antibiotics
cloxacillin,
ten
received
used
antibiotics;
died on the
were
dicloxacillin,
all
third
out
of the
18
antibiotics.
In
all
gentamycin
plus
or penicillin.
Methods
the
Most
samples
were
taken
as capillary
blood
from heel punctures,
occasionally
venous
samples
(in EDTA)
were
studied.
Standard
hematologic
techniques
were employed
for cell counting
using
did
not
(30.0
a Model
prepared
diagnosis.
The
840
differ
3.0
birthweight
significantly
and
from
groups
or
Dacie
S Coulter
using
the
and
Lewis,
Counter.
Blood
glass
spreader,
which
resulted
smears
described
in square-ended
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HEMATOLOGY
OF BACTERIAL
INFECTIONS
were
by
TABLE
CLINIcAL
FEATURES
OF
INFANTS
WITH
II
SUGGESTIVE
EVIDENCE
OF
INFECTION
(SEPSIS-POSSIBLE)
(per
Neutrophils
,_-----------_..
Segmented
Band
Ca.sc
Gestation
(ivk)
16
34
Birth-
Age
weight
Onset
(gin)
(days)
2,210
,_-.-------.----.
at
Peak
Signs
Lethargy,
Skin
diarrhea
17
30
1,430
pus
Respiratory
in
covered
with
at birth
X-ray
distress,
18
Outcome
Remarks
pus
of
chest
Peak
cii mm)
Peak
Day
Peak
Day
Alive
1,100
7,200
Alive
6,400
27,300
pneumonia
larynx
907
Lethargy
1,990
Lethargy
Alive
Urine
culture:
coil (100,000
colonies/mI)
Alive
500
5,700
1,900
12
11,700
12
19
33
20
27
808
Apnea
Alive
800
14,300
21
35
1,616
Respiratory
Alive
400
3,100
Alive
200
5,600
41,200
E.
distress
22
32
2,035
Respiratory
distress
23
29
1,160
Covered
PUS
24
34
25
26
26
34
with
Alive
12,200
I)irth
at
Lethargy
CSF: pleocytosis,
no culture
Alive
300
5,200
760
Lethargy
Neutrophils
gastric
(2)
Alive
1,800
12
10,500
12
2,041
15
Lethargy
X-ray
2,170
of
in
aspirate
2,100
Alive
100
15
Alive
700
11,100
13,300
chest
20
pneumonia
27
26
765
Jaundice
Pits
in
trachea
( Pseudomonas)
28
1,535
31
Hydronephrosis
Died
day 3
3,500
( postmortem)
29
27
21
1,100
Apnea
CSF:
pleocytosis,
culture
30
26
850
Respiratory
distress
31
31
2,100
Jaundice
Died
Netitrophils
gastric
(2)
smears
were
in which
excellent
cell
over
distribution
a large
area.
stained
ulocyte
with
May
Grunwald-Giemsa
counts
were
done
using
cresyl
blue
Platelet
or
counts
new
were
contrast
microscopy.
Coagulation
studies
techniques
developed
described
elsewhere.
The
ate
and
hematological
classify
and
morphology
The
smears
were
in
stains.
under
performed
by
our
laboratory
techniques
neutrophils
blue
manually,
and
used
bands
phase
microand
to enumerhave
been
200
23
3,500
21
in
day
1,500
9,100
12,000
Alive
100
previously.
In
aspirate
described
were
stain.
Reticeither
brilliant
methylene
done
Alive
negative
that
study,
a band
was
defined
as a neutrophil
in which
the width
of the
narrowest
segment
of the nucleus
was
not less
than one third the broadest
segment.
The normal
values
for band
and
neutrophil
counts
were
derived
from
studies
of
who were
followed
serially
180
premature
during
the
first
infants
month
of life.3
Blood
smears,
stained
with
May
GrUnwaldGiemsa
stain,
were
examined
for D#{246}hlebodies,
toxic
granulation,
and vacuoles
(Fig.
1). DOhle
bodies
are aggregates
of rough
endoplasmic
retic-
841
FIG.
1. A, A band
one
large
neutrophil
DOhle
segmented
showing
body
neutrophil
Platelet
stage
size
was
x
an
area
of
no
significant
of
platelets
either
Ilucleus.
granulation.
C,
determined
with
was
blood
the
use
of an
using
where
distributed
difference
found
at
in
erythrocytes
evenly.
on
in blood
smears
or EDTA.
heparin
A hand
were
determined
platelets
studied
smear
were
B,
standardized
Diameters
on 100
the
platelets
and
the
vacuolization.
This
micrometer.
800 magnification
and
toxic
with
micrometer.
granulation
above
showing
neutrophil
ocular
normal
(arrow)
There
was
measurements
anticoagulated
by
RESULTS
The
and
normal
month
band
which
Giemsa
were
stains
assessed
stain
neutrophils
were
vacuolization
neutrophils
2+
=
25%
4 +
as
2 +
0
=
tamed
tion
ulation
ules.
842
blue
in
75%. Toxic
normal
basis
0 =
3+
or
percentage
1 + = <
of
phils
were
top).
The
51%
3 +
cells,
and
with
the
nucleus
to 75%,
and
was quantitated
1 +
4 +
25%,
slight,
of neutrophils
convery
heavy
granulagross
toxic
gran-
obscured
by
toxic
gran-
The
within
after
with
levels
hours
In
were
the
In the
frequently
were
of
nine
already
clinical
other
appearance
of
IV).
Furthermore,
clinical
clinical
the
signs
peak
of
band
(Fig.
all
24
counts
hours
infection
counts
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HEMATOLOGY
OF BACTERIAL
INFECTIONS at Indonesia:AAP Sponsored on August 27, 2014
of
band
hours
(Table
24
2,
cases
signs
within
band
during
neutro-
studied,
of infection
groups,
elevated
in
13 cases
elevated
onset
two
of
group.
15 cases
reached
onset
of the
one
all
is discussed
band
of
in
hence,
as
values
1 1 out
first
normal
difference
infections,
in
the
age;
included
normal
proven
peak
48
counts
the
the
2. In
significant
were
of
elevated
infection.
in Figure
no
(band)
during
to gestational
infants
D#{246}hlebodies,
50%
granules,
premature
nonsegmented
counts
find
relative
for
granulation,
IlloSt
could
of the
none,
granulation
approximately
Gr#{252}nwald-
hundred
neutrophils
magnification.
The
quantitated
>
May
we
counts
analysis
elsewhere
.
In infants
1). Two
x 1,250
on the
involved;
to 50%,
dark
in
light
(Fig.
at
for
neutrophil
group,
ulum
values
segmented
IV).
were
less
after
the
(Table
in
the
TABLE
CLINICAL
FEATURES
OF
INFANTS
No
WITH
III
DEFINITIVE
EVIDEIICE
OF
INFECTION
(SEPSIS-UNLIKELY)
(per
Neutrophils
Birth-
Age
,-------------------.
at
tion
weight
Onset
Case
(tvk)
(gui)
(days)
32
34
1,931
Peak
Outcome
mm)
,---------.-
Band
Gesta-
cii
Segmented
Peak
Peak
Day
2,000
13,900
Alive
1,700
10,400
Alive
200
4,900
6,200
400
5,700
Alive
1,400
10,700
Jaundice
Alive
1,500
16
9,800
Signs
Remarks
Respiratory
No evidence
distress
sepsis
of
Died
day 4
Peak
Day
at
autopsy
33
36
1,740
Respiratory
distress
34
35
2,150
Petechiae
35
36
2,260
NDS#{176}
36
27
1,535
NDS
37
32
1,440
38
34
2,360
39
36
2,860
NDS
40
33
1,140
NDS
Alive
Alive
Jaundice
Alive
Apnea
Alive
1,000
Alive
Fetal
growth
Alive
retardation
41
32
2,030
Respiratory
distress
42
26
1,021
16
43
35
2,950
Poor weight
gain
Alive
500
5,300
44
30
1,220
Respiratory
distress
Alive
1,400
4,500
45
27
730
Respiratory
distress
3,800
4,100
Intraventricular
hemorrhage
Died
day
16
46
36
2,040
Jaundice
Alive
800
8,200
47
34
2,040
Vomiting
Alive
100
3,300
48
33
1,830
NDS
Asphyxia
Alive
1
9,500
2,300
36
NDS
No
distinct
majority
of
abnormally
(Fig.
2, top).
Shock
illness
in
but
these
throughout
In contrast
following
neutrophil
(Table
IV),
of
infants
high
of bands
signs
onset
counts
often
if at all (Fig.
infants
groups
the
to the
the
Died
the
general
were
period
not
of study
early
appearance
of sepsis,
segmented
did not
2, bottom).
condition
rise
until
later
the
rise
in neutrophil
count
in
possible
and unlikely
sepsis was less
at 24 hours
(Table
IV)
or any
time
frequent
(Fig.
2,
bottom).
infection
onset
drop
of
in
In some
cases,
was associated
neutrophil
counts
10 (Fig.
During
change
bodies,
ulation.
cases
as in case
4).
infection,
in
apparent
a dramatic
1 (Table
the neutrophils
in appearance
vacuoles,
and,
Some
of these
shown
the
with
I) and
were
case
noted
day
1
sepsis
2,900
as a possibility.
attempted
to
quantitate
the
morphological
changes
in neutrophils
using
the
classification
described
above.
We have found
that the neutrophils of adults
and normal
newborns
are usually
0 or occasionally
1+
In the sepsis-unlikely
group,
there
were
no
cases
in which
DOhle bodies
or toxic granulation
were
above
1+
prior
to the
onset
of signs
suggestive
of infection
(Fig.
5 and 7). In case 44,
the neutrophils
were
graded
as 2 + for D#{246}hle
bodies
in one
post
sample.
In a few cases,
vacuolization
was increased
(Fig. 6). However,
in
the sepsis-proven
cases,
the D#{246}hlebodies
and
vacuolization
were
more
frequent
after
the
appearance
of signs of infection
(Fig. 5 and 6); the
changes
in toxic
granulation
were
less
pronounced.
The changes
in the sepsis-possible
group
As expected,
groups
with
suggested
to
in that
one
found
D#{246}hle
less consistently,
toxic
granchanges
are typified
by the
other
two
843
Figures
and
4.
We
have
were
intermediate
between
the
E
E
U
C,
0
I-
U)
-J
I-
UU
LU
z
0
14
7
DAY
OF
21
28
21
28
LIFE
cv,
E
E
40
35
Cv,
0
Ix
30
Cl)
-a
I
25
0.
0
20
ID
LU
15
10
LU
I-
LU
LU
U)
14
DAY
FIG.
2. Peak
signs
in
area
represents
from
studies
band
proven
counts
Sepsis
the
of
180
(top)
(square),
range
and
peak
possible
for
premature
normals
infants
OF
neutrophil
sepsis
who
counts
(circle)
(excluding
and
the
were
LIFE
(bottom)
after the onset of clinical
unlikely
sepsis (triangle)
cases. Shaded
highest
followed
5%).
serially
These
during
values
the
were
first
obtained
month
of
life.
844
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HEMATOLOGY
INFECTIONS
C,)
E
E
CASE #7
C,)
x
C)
U)
E
E
C)
E
E
C)
0
7.5-
(I)
a.
6.5-
o.--o
7.0-
Neutrophils
o-o
.--.Bonds
U)
I-.
U
L---#{243}
Platelets
6.0-
I-
5.5-
5.0-
20-
500-
4.5-
18-
450-
4.0-
16-
400-
3.5-
14-
350-
3.0-
12-
300-
2.5-
10-
250-
2.0-
8-
200-
1.5 -
6-
150-
1.0-
4.
100-
.5-
2-
50-
0-
0-
0-
POST
PRE
C)
-a
a.
0%
ONSET
OF
SYMPTOMS
4+oD#{244}hIeBody
. Vacuolization
3+-
2+1+0
I TFT1I
12
13
14
T1ft
15
16
17
18
DAY
It should
possible
neutrophils
be noted
OF
32
20
21
22232425
LIFE
weeks.
Well
until
infusion.
Staphylococcus
blood
stream.
Recovery
18 days
of age
epidermidis
occurred
with
therapy.
prior
groups.
age
t
19
evident
laboratory
the onset
infection.
evidence
of clinical
845
TABLE
NEUTROPHIL
BAND
AND
STUDIED
24
WITHIN
IV
COUNTS
HOURS
IN PREMATURE
OF
Table V. There
it can be seen that
seven of the 15
proven
sepsis
patients
developed
thrombocytopenia
in the first week
after
the onset
of disease
compared
to one of the 16 sepsis-possible
and one
of the 18 sepsis-unlikely
patients.
The thrombocytopenia
could
be quite
severe,
as shown
in Figure
3 and 4. All patients
with
thrombocytopenia
in the sepsis-proven
group
fell
below
70,000/cu
mm
and
five patients
below
30,000/cu
mm. The average
duration
of thrombocytopenia
was 6.6 days with
a range
of 3 to 17
INFANTS
APPEARANCE
OF
SIGNS
OF
INFECTION
No. With
increased
Sepsis
No.
Bands
Neutrophils
13
11
10
9
4
2
3
3
0
Proven
Possible
Unlikely
Statistical
Bands
Proven
Proven
Possible
No. With
increased
Analysis
vs. unlikely
vs. unlikely
<
P0
.05
(S)
.001 (HS)
>
.05
(NS)
vs. possible
vs. unlikely
>
.05
(NS)
possible
.vs.
<
days.
Neutrophils
Proven
Proven
Possible
vs.
<
unlikely
.05
>
thromboplastin
(S)
.05
HS
significant;
highly
significant;
NS
not signifi-
cant.
TABLE
THROMBOCYTOPENIA
IN
INFANTS
INFECTION
IN
WAS
WHOM
BACTERIAL
SUSPECTED
Platelet
No. With
Thrombo-
No.
Studied
Sepsis
op#{176}
Countst
No.
100,000
<
/cu
No.
mm
Done
Proven
15
Possible
16
46
Unlikely
18
50
Statistical
Infants
with
Proven
Proven
42
vs.
vs.
#{176}Thrombocytopenia
counts
of
<
<
unlikely
during
the
first
t During
tNS
is defined
seven
mm
days
after
(NS)
.05
>
(5)
.05
(NS)
mm
unlikely
100,000/cu
.05
>
Platelet
counts
100,000/cu
Proven
vs. possible
Proven
vs. unlikely
Possible
Analysis
vs. possible
vs. unlikely
Possible
83
thrombocytopenia
as
two
<
.001
(HS)
<
.05
(HS)
>
.05
(NS)
consecutive
(confirmed
onset
by
of signs
HS
platelet
blood
of
smear)
infection.
highly
signifi-
cant.
Thrombocytopenia
frequently
course
of infection.
This
is
representative
cases (Fig. 3 and
have
found
thrombocytopenia
infants
846
following
the
onset
developed
in the
seen
in the
two
4). In addition,
we
in several
other
of sepsis
thrombin
clotting
time,
and
05
time,
factors
(NS)
as shown
in
low
3t)
is similar
to
that
reported
by
others.3
In several
infants
with
thrombocytopenia,
platelets
were sized during
the period
of thrombocytopenia.
In all cases,
large
platelets
were
seen during
this time (Table
VII and Fig. 8). In
addition,
in all these
patients,
there
appeared
during
the period
of thrombocytopenia,
large
platelets
with
unusually
abundant
cytoplasm
as
shown
in Figure
8.
The
hematological
changes
associated
with
sepsis occurring
in cases 7 and 10 are illustrated
in
Figures 3 and 4. In these cases, one can follow the
sequence
of changes
which
occur.
In case
7,
clinical
signs of infection
appeared
suddenly
on
the 18th day of life, presumably
due to infusion
of
contaminated
intravenous
solution.
Fortunately,
a blood
count
was taken
prior to this episode
and
six hours
later.
The
acute
rise in band
count
without
elevation
of neutrophil
count
is seen. The
next
day,
neutrophilia
was
noted
along
with
distinct
changes
in neutrophil
morphology,
with
the appearance
of DOhle bodies
and an increase
in
vacuolization.
Toxic
granulation
did not increase
Downloaded OF
fromBACTERIAL
pediatrics.aappublications.org
at Indonesia:AAP Sponsored on August 27, 2014
HEMATOLOGY
INFECTIONS
CASE
C)
#10
C)
E
E
E
E
C)
C)
E
E
C)
PRE
x
1)
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a-
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-a
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(Esti
I-
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-a
a-
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18-
450-
4.0-
16-
400-
3.5-
14-
350-
3.0-
12-
300-
2.5-
10-
250-
2.0-
8-
200-
1.5-
6-
150-
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100-
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OF
SYMPTOMS
11
4+
3+
D#{243}hle Body
Vacuoluzation
2+
1+
0
1
DAY
Fic.
4.
suddenly
Case
10.
became
Birthweight
lethargic
was
and
had
Recovery
1,990
several
occurred
gm
and
apneic
with
gestational
episodes.
antibiotic
OF
age
Blood
36
LIFE
weeks.
culture
grew
At
3 days
Escherichia
of
age
coli.
therapy.
ARTICLES
847
TABLE
TABLE
PLATELET
DIAMETERS
IN
VI
Adults
Mean
SD
Newborns
No.
AND
Tha meters
,
Group
MEGATHROMBOCYTES#{176}
NEWBORNS
IN
VII
NEWBORNS
\VITH
SEPSIS
AND
THROMBOCYTOPENIA
ADULTS
Megathromhocyt(s
(IL)
(%)
.VO.Of
Oto
1.Oto
2.Oto
0.9
1.9
2.9
Group
3.0w
3.9
>
4.0
Adults
Normal
Case7
14
1.1%
1.5%
63%
15%
32%
13%
3.5%
1.8%
0.4%
0.5%
Case
Sampies
14
11
6t
9t
6t
newborns
4
Case3
11
Mean
1.0%
68%
29%
1.5%
0.5%
SD
1.5%
11%
9%
2.0%
0.5%
3.9
2.0
17
34
14
0.5 to 5.5
0 to 7
1to25
13 to 48
lltol7
3IL#{149}
#{176}Diaineter
t These
Range
Mean
represent
all
samples
studied
during
the
period
thrombocytopenia.
period
of thrombocytopenia,
megathrombocytes
were
noted
as were
the unique
type
of platelet
described
above
(Fig.
8). This
case,
therefore,
presented
most of the hematological
features
that
significantly.
The fall in platelet
count
was noted
24 hours
after onset
of signs and progressed
over
the next three
days, returning
to normal
only on
the sixth day after
onset
of sepsis.
During
this
4-
3>-
0
0
2-
LU
1
I
:0
0
1-
00
.
0
.
.
.
#{149}#{149}
#{149}
-000cKXJ0000
Pre
5. DOhIe
studied
848
body
(sepsis-proven,
average
index
before
SSSSSS
Pre
PROVEN
FIG.
#{149}
#{149}sm
0
000000cIxxDo
Post
Post
POSSI
and
after
onset
BLE
of signs
sepsis-possible,
sepsis-unlikely).
DOhle body intensity
(see text)
Pre
UNLIKELY
of illness
The
per 200
Post
in the
DOhle
three
body
neutrophils
groups
index
of subjects
represents
scanned.
HEMATOLOGY
BACTERIAL
INFECTIONS at Indonesia:AAP Sponsored on August 27, 2014
Downloaded fromOF
pediatrics.aappublications.org
the
of
4-
3-
0
I
I
I
-I
#{149}s=
00
II
II
I
I
>
00
6. Netitrophil
of
index
Post
or-cy
Post
index
before
(sepsis-proven,
average
and
after
sepsis-possible,
frequency
of
vacuolization
111111
Pre
POSSIBLE
studied
the
II
Pre
vacuolization
subjects
represents
II
II
I
I
I
000000000
PROVEN
Fic.
0000000
Pre
rOt,p5
III
II
III
Post
UNLIKELY
onset
of signs
of illness
sepsis-unlikely).
(see
text)
The
per
200
in
the
three
vacuolization
neutrophils
scanned.
we
have
severe
come
Case
as well,
the
to
bacterial
10 showed
very
several
additional
onset
was
of sepsis
taken
at
mated
onset
of
newborn
infant.
similar
changes
but had,
features.
Once
again,
dramatic
time.
and
The
first
in retrospect,
counts
were
normal
Thrombocytopenia
from
the
blood
of
sepsis.
It
mm
ten
30,000/cu
penia
as characteristic
in the
blood
work
change
was
seemed
to have
the
previous
day.
Approximately
ten
later,
a subsequent
count
showed
an
in bands.
At
that
time,
qualitative
in the
neutrophils
were
also
evident.
Platelet
sepsis.
was
that
which,
neutropenia
started
hours
increase
changes
recognize
infection
persisted
for
prior
was
smear)
was
documented
hours
five
to the
evident
at the
later.
onset
as
being
Thrombocyto-
days.
DISCUSSION
The
infants
patients
hospitalized
in
this
study
at a regional
of
(as estiapparent
were
premature
neonatal
inten-
of the
hematologic
studies.
In addition,
we
defined
a group
in which
sepsis
was
deemed
possible
in our opinion
and finally
a group
in
which
it was considered
unlikely.
We also examined
a normal
series of premature
infants.
In this series,
to be reported
elsewhere,3
we excluded
those with serious
disease
and were
able to define a normal
group
for study during
the
first
month
of life.
Against
this background
of
normal
values,
it can be seen that
infants
with
proven
sepsis had high band counts
after the onset
of sepsis
(Fig.
2). These
were
found
more
frequently
in this group
than in the possible
or
unlikely
groups.
Furthermore
(Tables
I and IV)
the elevation
in band count
occurred
early in this
group,
usually
within
24 hours
of onset
of signs.
ARTICLES
Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on August
27, 2014
849
4-
3I
II
20
1-
I
I
00
0
II
0
0
0
II
0
III
00000000
Pre
000000000
Post
Toxic
index
before
and after
(sepsis-proven,
sepsis-possible,
the average
degree
of granulation
represents
The
and
neutrophil
IV); however,
majority
count
itself
rose
as seen in Figure
of infants
with
proven
later
(Tables
I
2, bottom,
the
sepsis
eventually
developed
an elevation
in neutrophil
count.
The
character
and
timing
of band
and
segmented
neutrophil
response
to infection
is typified
in case
7 (Fig. 3). In this case, the infection
resulted
from
infusion
of
Accordingly,
be determined
contaminated
intravenous
in band
counts
delayed
rise
was
evident
fluids.
of infection
could
speed
of response
as was
the
subsequent
We conclude,
therefore,
that
an elevation
of
the band
neutrophil
count
above
the
normal
range
(Figure
2, top) is a valuable
laboratory
sign
in premature
infants
in whom
sepsis is suspected.
It is, of course,
only a laboratory
test and one that
is not
perfect
infections
response
neutropenia
850
in
since,
can
band
may
as
shown
occur
with
neutrophils.
be
the
first
in
Pre
Figure
2,
no evidence
UNLIKELY
of sepsis,
as shown
(Fig. 4).
The
fact
that
sepsis
showed
speaks
for
tion
of
the
cases
band
presence
I) and
case
of
of infection
and
sepsis-unlikely
segmented
group
may
counts
in these
cases.
group
infants
eleva-
neutrophils
also
10
possible
neutrophil
for assignment
to a possible
suggest
that
many
of these
have infection.
The occasional
band
of
some
1 (Table
elevated
the
The criteria
(Table
II)
indeed
did
in case
in
represent
the
uncon-
infections.
As in full-term
infants,
total neutrophil
counts
are of limited
value
for the diagnosis
of infection
since
elevation
Thus,
in the
is
cases
found
neutrophil
or rose only later
often
and
sepsis,
inconsistent.
we
counts
in the
which
disease
remained
(Tables
also
observed
that
top,
Furthermore,
counts
were
sign
unlikely
disease.
group,
often
Neutrophilia
we
late
of proven
of a
Furthermore,
hematological
Post
firmed
in neutrophils.
severe
Post
POSSIBLE
granulation
studied
==s:rn
0L50
SISI
Pre
PROVEN
Fac. 7.
subjects
sometimes
elevated
before
in the
in
frequently
normal,
I and IV).
neutrophil
the
sepsis-
the onset
of clinical
absence
of an increase
HEMATOLOGY
OF pediatrics.aappublications.org
BACTERIAL
INFECTIONS
Downloaded from
at Indonesia:AAP Sponsored on August 27, 2014
in band
count
may
there
is no evidence
result
of
stress
or
must
conclude,
is not a reliable
occur
in
of infection,
other
nonspecific
that
therefore,
or
patients
in
presumably
sensitive
whom
the
causes.
One
neutrophilia
test
of
itself
infections
in
newborns.
in
Cases
7 and
association
change
in
10 also
the
as
Toxic
changes
has
unusual
and
infection
and
toxic
seems
of
with
been
to
are
represent
the
normal
described
they
of infection.
D#{246}hlebodies
are
smear
of normal
of blood
smears
with
not
the
increased
granules
found
DOhle
bodies.
that
D#{246}hlebodies
in
own
indicate
2%
by us in the
of
blood
in a review
women,
found
It is of interest
the
but
leukopoiesis
that
most
pregnant
women
to 10% of neutrophils.
that
of
number
of these
production
stress
adults.
Abernathy,
of 500
normal
he found
studies
the
during
found
elsewhere,
represent
neutrophils
the
and
of
along
with
granulation.
It is unlikely
that
the actual
increases.
The
significance
presumably
study
to
that,
significant
vacuolization
are
aggregates
reticulum
intensity
neutrophils.
of granules
is
neutrophils
a response
vacuolization
granulation
staining
clearly
there
D#{246}hle bodies,
D#{246}hle bodies
endoplasmic
usually
neutrophil
none
sepsis,
circulating
appearance
of
toxic
granules.
rough
demonstrated
with
neutrophils
in his
had
Our
of
FIG. 8. Platelets
platelets.
B,
platelet
with
period
A,
Normal
appearing
recovery
of infection.
ARTICLES
Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on August 27, 2014
851
normal
infants
bodies.
DOhle
the
proven
nuniber
occasionally
bodies
sepsis
rose
may
were
group
after
group
granulation
groups.
In
suggestion
that
frequently
after
higher
Similarly,
after
the
changes
were
DOhle
29%,
and
the
were
and
seen
than
possible
more
before.
were
seen
groups
studied
the
bacteremia.
amounts
and
of the
of
that
group,
of toxic
granula-
vacuolization
patients
in
studied
in
toxic
feature.
iably
her
study
of
granulation
as
present
always
during
sepsis
newborn
8, suggest
increased
Zieve
et al.
between
the
and bacterial
presence
infections.
of
are
consistent
although
we
vacuolated
relationship
vacuolated
They
found
neutrophils
that
in
neutrophils,
found
that
from
1% to
1 19 had
the
vacuo50%
of the
longer.
there
with
often
relate
to the
Also,
was
as
those
the
use
infection.
these
However,
they
toxic
between
particularly
in
where
seven
15 infants
HEMATOLOGY
and
cytopenia
the
that
associated
the
in
with
total
on
frequently
were
OF BACTERIAL
found
of
there
produc-
megathrombocytes
increased
platelet
recently
in our
in
sepsis.
the
cases
by
these
during
diameters.
platelets
periods
During
bone
produc(mega-
of increased
the
period
megathrombocytes
all
patients
that
platelet
patients.
poiesis
from
megakaryocyte
net-Gajdos
the
The
qualitative
numbers,
studied
not
clear.
coagulation
VII),
was increased
estimation
of
thrombo-
assessment
of marrow
as performed
by Bondifficult
and of ques-
infections
is
of
were
(Table
production
group
intravascular
numbers
platelet
large
their
scanning
platelet
that
production.
in
by
estimating
appear
from
base
of decreased
estimated
observed
concluded
resulted
They
finding
We
a series
thrombo-
They
had
as assessed
been
suggesting
reported
developed
in this
to be
In
megathrombo-
et a!. is very
tionable
value in our view. This may
for the difference
in our conclusions
Bonnet-Gajdos
et a!.
The
cause
of thrombocytopenia
of
band
of platelet
development
that
time
production.
aspirates.
found
laboratory
sepsis-proven
size
production.
of
who
with
platelet
conclusions
platelet
indices
increased
They
that platelet
thrombocytopenia
the
precludes
absolute
infection.
was seen
et
infants
newborn
thrombocytes)
qualitative
additional
series,
of the
of five
the
frequently
in
The
overlap,
clinical
onset
the
numbers
thrombocytopenia,
that
of
since
(Fig.
3
Bonnet-Gajdos
It has
granulation,
also
together
evidence
of bacterial
Thrombocytopenia
and
between
is great
as
provide
numbers
cause
series
took an average
3 to 17).
platelet
production
increased
since
during
periods
of
tion
for
later
tests
had
of
overlap
occurring
of
tion
appear
the
was
often
out that
this
limited
VII), suggesting
to
the
to be higher
in neutrophils
occur
more
with
infections
than
others.
between
values
prior
to
and
(Table
marrow
infected
and other
groups
and
before
and after
onset
samples.
It is our impression,
therefore,
changes
infants
however,
increased
cytes
was
for platelet
following
During
et
noted
considerable
appeared
this
The
present
interpretation
so rapidly
relatively
does
increase
thrombocytopenia.
the
that
that
thrombocytopenia
cases
and pointed
and capacity
of megakaryocytes
tended
in gram-
have
resulted
from
and/or
sequestration.
that
in these
122
of Zieve
and
failure
findings
both
infections.
shortened
Furthermore,
they
promptly
after
institu12 to 24 hours).
Our
found
neutrophils
seen
shown
are not
close
total
neutrophil
population.
felt that
they
disappeared
tion of antibiotics
(within
studies
never
Our
findings,
toxic
granules
in infection.
showed
a very
with
vacuolated
evidence
of sepsis.
They
lated
neutrophils
varied
852
important
was invar-
a change
babies.
that
patients
counts,
an
occurred
our patients,
thrombocytopenia
of 6.6 days to recover
(range,
Our findings
suggest
that
infection,
in healthy
in Figure
last
neonatal
described
a series
of cases
in association
with sepsis in
He noted,
as we have (Table
gram-negative
was
may
respective-
than
Cohen
and Gardner
reported
a series
of adults
with thrombocytopenia
secondary
to gram-negative bacterial
infection.3
They
felt that platelet
reserves
described
a!.,
and
in
less
thrombocytopenia
positive
also
noted
prolonged
75%,
ly.
Xanthou,2
thrombocytopenia
in five cases
of the thrombocytopenia.
cases
would
support
that
thrombocytopenia
developed
but
neutrophils
In
The
severe,
was
Corrigan4
recently
of thrombocytopenia
children
and infants.
survival
great.
al.
bodies,
29%
was
of infection
of vacuolization
not
in
in the unlikely
in the possible
and
group,
there
is no
granulation
adult patients
with
they found abnormal
tion,
seen
bodies
thrombocytopenic.
some
instances
30,000/
cu mm
I), that
proven
et
Steigbigel
in
unusual
latter
onset
levels
in the
rise was
no DOhle
frequent
the
toxic
onset
often
of
was
proven
DOhle
more
onset
tion
(Fig.
5). No significant
possible
group
and almost
seen
in the unlikely
group.
Toxic
contain
found
Although
(DIC)
be the reason
and those of
in
bacterial
disseminated
has been
INFECTIONS
invoked
as a cause,
there
is much
evidence
against
it.
7 and 10, the evidence
of consumpcoagulopathy
was minimal.
Corrigan
recent-
Thus,
in cases
tive
ly published
associated
evidence
was
of DIG
minimal
It is very
or
nonexistent.
that
process.
damaging
cells.
adhere
circulating
on
on
8.
to have
are
9.
found
to
Endotoxin
platelets
aggregates
was
endothelial
endothelium.
effect
platelet
appears
cells
N Engl
7.
affected
and,
have
in
been
fact,
10.
found
during
endotoxemia
in experimental
animals.9
It may
be that,
in some
cases,
the primary
platelet
effect
is followed
by, or causes,
intravascular
coagulation.
Thus,
in cases 7 and 10, there
were mild, but significant,
depressions
of factor
5
levels
as well
as slight
increases
in fibrin
split
products.
Furthermore,
Corrigan
also found
some
evidence
of intravascular
coagulation
in association with the thrombocytopenia
of sepsis.4
It is possible
also
that
coagulation
may
be
initiated
directly
by activation
of Hageman
factor,
either
through
contact
with
damaged
endothelium2#{176} or directly
by endotoxin
activaMason
and Colman
have studied
a series of
12.
13.
14.
15.
16.
cases
of
found
DIG
due
to
gram-negative
factor
12
the
mechanism,
septicemia
levels
17.
significantly
re-
Whatever
thrombocytopenia
we
which
conclude
frequently
that
compli-
cates
severe
bacterial
infections
may
be associated
with no, or little,
evidence
of DIC.
In conclusion,
it can be said that in premature
infants
with
bacterial
changes
of band
topenia
and segmented
neutrophils.
frequently
develops
as
of
all
the
there
striking
recognition
in
infections
of
derable
help in the
of bacterial
infections
number
these
and
often
is
of
2.
Yeung
3.
Dacie
4.
5.
CY,
Tam
A: Gastric
R, Zipursky
diagnosis
20.
21.
22.
index
of megakaryocyte
meganumber.
Med
I, Kutti
1974.
Abernathy
MR: DOhle bodies
associated
with uncomplicated
pregnancy.
Blood 27:380,
1966.
Xanthou
M: Leukocyte
blood
picture
in ill newborn
babies.
Arch Dis Child
47:741,
1972.
Zieve PD, Haghshenass
M, Blanks M, Krevans
J: Vacuolization
of the
neutrophils.
Arch
Intern
Med
118:356,
1966.
Corrigan
JJ Jr: Thrombocytopenia:
A laboratory
sign of
septicemia
in infants
and children.
J Pediatr
85:219,
1974.
Cohen
P, Gardner
FH: Thrombocytopenia
as a laboratory sign and complication
of gram-negative
bacteremic
infections.
Arch Intern
Med 117:113,
1966.
Karpatkm
S, Garg
5K: The megathrombocyte
as an
index of platelet
production.
Br J Hematol
26:307,
1974.
Bonnet-Gajdos
M, Navarro
J, Roy C: Insufficance
tran-
et erythroblastes
an cours
chez le nourrisson.
Noiv
Rev Fr Hematol
14:471,
1974.
McGrath
JM, Stewart
GJ: The effects
of endotoxin
on
vascular
endothelium.
J Exp Med 129:833,
1969.
Maca RD, Fry GL, Hoak JC: New method
for detection
and quantitation
of circulating
platelet
aggregates.
Microvasc
Res 4:453, 1972.
Wilner
GD,
Nossel
HL,
LeRoy
EC:
Activation
of
Hageman
factor
by collagen.
J Clin Invest 47:2608,
1968.
Morrison
DC,
Cochrane
CG:
Direct
evidence
for
Hageman
factor
(factor
XII) activation
by bacterial
lipopolysaccharides
(endotoxins).
J Exp
Med
140:797,
1974.
Mason JW, Colman
RW: The role of Hageman
factor
in
disseminated
intravascular
coagulation
induced
by
septicemia,
neoplasia
or liver
disease.
Thromb
Diath
Hemorrh
26:325,
1971.
A: Neutrophil
of
neonatal
infec-
ACKNOWLEDGMENT
1974.
aspirate
19.
consi-
and understanding
newborn.
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and
the
changes
diagnosis
in the
are
as an
sitoire en megakaryocytes
dinfections
bacteriennes
22
the
infants.
Unpublished
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5: Use of the
284:11,
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of
thrombokinetics
to bone
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GE, Athens
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Zipursky
A, Brown
EJ: The ingestion
of IgC sensitized
erythrocytes
by
abnormal
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and
of premature
5K, Amorosi
thrombocyte
evidence
are
vascular
other
damaged
a direct
the
platelets
Endotoxin
and
to the
has
the
effect
Platelets
also
in others
likely
by the septic
a direct
whereas
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We would
like to thank
Mrs. Phyllis
Silke for typing
the
manuscript
and Mrs. Wendy
Yacura
for clerical
assistance.
Also, we are grateful
for the technical
assistance
of Benjamin
Zipursky.
Elizabeth
J. Brown provided
valuable
advice.
We would
like to acknowledge
the tremendous
assistance
and encouragement
given to us by Dr. J. Sinclair
and his staff
in the McMaster
Neonatal
Intensive
Care Unit.
ARTICLES
853
Citations
Reprints
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 1976 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005.
Online ISSN: 1098-4275.