Introduction
:
The
aim
of
this
meta
-
analytic
review
was
to
help
establish
optimal
cut
-
off
levels
when
using
erythrocyte
sedimentation
rate
(ESR)
and
C
-
reactive
protein
(CRP)
in
the
diagnosis
of
diabetic
foot
osteomyelitis
(OM)
.
A
secondary
aim
was
to
determine
whether
these
simple
diagnostic
tests
demonstrate
more
of
a
“threshold
effect”
or
“dose
-
response”
when
discriminating
between
patients
with
and
without
OM
.
Methods
:
Six
eligible
articles
were
identified
through
a
search
of
Medline
and
EMBASE
electronic
databases
from
1966
to
2010
.
Summary
likelihood
ratios
for
predicting
the
presence
of
OM
in
the
case
of
both
a
positive
test
result
(LR+,
sensitivity/
1
-
specificity)
and
negative
test
result
(LR
-
,
1
-
sensitivity/specificity)
were
calculated
along
with
95
%
confidence
intervals
(CIs)
using
random
-
effects
models
for
several
commonly
reported
thresholds
for
ESR
and
CRP
.
Mantel
-
Haenszel
test
was
used
to
test
for
dose
-
response
as
thresholds
were
increased
given
a
positive
result
(LR+)
and
decreased
for
a
negative
result
(LR
-
)
.
Results/Conclusion
:
ESR
>
80
mm/h
proved
to
be
the
best
threshold
and
test
for
ruling
in
OM
(LR+
9
.
40
[
95
%
CI
0
.
65
-
135
)
.
Furthermore,
there
was
an
obvious
dose
-
response
with
increasing
ESR
levels,
and
a
three
-
fold
increase
in
the
likelihood
of
OM
as
ESR
levels
increased
from
60
mm/h
to
80
mm/h
(p
=
0
.
04
)
.
CRP
≤
3
.
2
mg/dl
proved
to
be
the
best
blood
test
for
ruling
out
OM
(LR
-
0
.
23
[
95
%
CI
0
.
17
-
0
.
52
]),
however,
unlike
ESR,
CRP
demonstrated
more
of
a
threshold
effect
in
the
diagnosis
of
OM
as
increasing
and
decreasing
levels
did
not
appear
to
alter
the
likelihood
of
having
underlying
OM
significantly
(p
>
0
.
05
)
.
Abstract:
Serum Inflammatory Markers
in
t
he
Diagnosis of
Diabetic
Foot Osteomyelitis
: A Meta
-
Analytic Review
Adam Fleischer, DPM, MPH, Maureen
Allanson
, BS, James
Wrobel
, DPM, MS
Department of Surgery, Advocate Illinois Masonic Medical Center
Introduction:
Diabetes
mellitus
(DM)
is
a
significant
public
health
concern,
with
an
estimated
23
.
6
million
people
affected
in
the
US
alone
.
The
US
spends
approx
.
$
174
billion,
or
~
1
out
of
every
5
healthcare
dollars,
on
patients
with
diabetes
annually
.
Foot
-
related
complications
in
the
form
of
ulceration
and
infection
are
the
leading
cause
of
hospitalization
and
lower
extremity
amputation
(LEA)
in
patients
with
diabetes,
costing
the
US
healthcare
system
$
43
,
000
to
$
63
,
000
per
event
.
Early
recognition
of
diabetic
OM
may
curtail
the
need
for
LEA,
however,
confirmatory
tests
such
as
biopsy
are
invasive
.
Diagnostic
tests
such
as
MRI
are
expensive
and
not
always
available
and
standard
radiographs
lack
sufficient
sensitivity
to
accurately
diagnose
early
OM
.
Therefore,
simple
laboratory
tests
of
common
serum
inflammatory
markers
(e
.
g
.
,
ESR,
CRP)
have
been
proposed
as
diagnostic
aids,
but
there
is
uncertainty
regarding
their
usefulness
in
DM
OM,
and
it
is
unclear
whether
or
not
these
tests
demonstrate
either
a
dose
response
or
threshold
effect
.
To
better
characterize
how
ESR
and
CRP
might
be
used
in
the
diagnosis
of
diabetic
foot
OM
.
Methods:
We
searched
MEDLINE
and
EMBASE
databases
with
the
following
search
terms
:
“diabetic”
and
“osteomyelitis”
or
“diabetic”
and
“ulcer”,
in
addition
to
each
of
the
following
words
:
C
-
reactive
protein
and
erythrocyte
sedimentation
rate
.
The
search
was
limited
to
studies
involving
adults
and
English
language
articles
from
the
period
1966
through
27
June
2010
.
We
identified
additional
articles
through
a
hand
search
of
references
from
retrieved
articles,
previous
reviews,
and
polling
experts
.
The
titles
and
abstracts
of
the
articles
retrieved
were
evaluated
to
determine
their
eligibility
for
our
review
.
Publications
in
abstract
and
letter
form
were
included
to
minimize
publication
bias
.
Conclusions:
1.
ESR
demonstrates
a
dose
-
response
likelihood
of
having
underlying
OM
with
increasing
levels
(p=
0
.
04
)
;
however
CRP
does
not
show
this
same
pattern
(
p=
0
.
266
)
.
2.
The
likelihood
of
having
OM
increased
three
-
fold
as
the
ESR
threshold
was
increased
from
70
mm/h
to
80
mm/h
.
3.
CRP,
on
the
other
hand,
demonstrates
more
of
a
threshold
effect
in
the
diagnosis
of
OM,
with
3
.
2
mg/dl
being
the
optimal
cut
-
point
.
4.
ESR
appears
to
be
a
specific
marker
for
diabetic
OM
,
with
increasingly
higher
LR+
values
at
higher
threshold
levels
(p<
0
.
05
)
.
An
elevated
ESR
above
80
mm/h
strongly
favors
the
diagnosis
of
OM
(LR+
9
.
40
)
.
5.
CRP,
conversely,
appears
to
be
a
sensitive
marker
for
diabetic
OM,
with
values
lower
than
3
.
2
effectively
ruling
out
underlying
OM
(LR
-
0
.
23
)
.
6.
Because
serum
inflammatory
markers,
by
themselves,
lack
accuracy,
we
believe
they
will
be
most
useful
in
modulating
our
pre
-
test
probability
for
OM
prior
to
considering
our
more
formal
diagnostic
(MRI,
radiographs)
or
confirmatory
tests
(biopsy/culture)
.
References:
Ertugrul, BM, Savk, O, Ozturk, MC, Oncu, S, Sakarya, S. The diagnosis of diabetic foot osteomyelitis: Examination findings an
d l
aboratory values. Med Sci Monit 15: 307
-
312, 2009.
Fleischer, AE, Didyk AA, Woods, JB, Burns, SE, Wrobel, JS, Armstrong, DG. Combined clinical and laboratory testing improves d
iag
nostic accuracy for osteomyelitis in the
diabetic foot. J Foot Ankle Surg 48:39
-
46, 2009.
Kaleta, JL, Fleischli, JW, Reilly, CH. The diagnosis of osteomyelitis in diabetes using erthorcyte sedimentation rate: A pilo
t s
tudy. J Am Pod Med Assoc. 91:445
-
450, 2001.
Malabu, UH, Al
-
Rubeaan, KA, Al
-
Derewish, M. Diabetic foot osteomyelitis: Usefulness of erythrocyte sedimentation rate in its dia
gnosis. West Afr J Med 26:113
-
116, 2007.
Newman, LG, Waller J, Palestro, CJ, Schwartz, M, Klein, MJ, Hermann, G, Harrington, E, Harrington, M, Roman, SH, Stagnaro
-
Green,
A. Unsuspected osteomyelitis in
diabetic foot ulcers: Diagnosis and monitoring by leukocyte scanning with indium in 111 oxyquinoline. J Am Med Soc 266:1246
-
1251
, 1991.
Rabjohn, L, Roberts, K, Troiano, M, Schoenhaus, H. Diagnostic and prognostic value of erythrocyte sedimentation rate in conti
guo
us osteomyelitis of the foot and ankle. J
Foot Ankle Surg. 46:230
-
237, 2007.
Purpose
Background
Search
strategy
Articles
were
included
for
review
if
they
fulfilled
all
of
the
following
criteria
:
They
were
original
studies
describing
CRP
or
ESR
in
the
diagnosis
of
lower
extremity
osteomyelitis
in
patients
with
DM
Data
could
be
extracted
into
2
x
2
tables
The
diagnostic
test
was
compared
with
a
reference
standard
.
In
studies
that
included
patients
with
and
without
DM,
only
those
patients
with
DM
were
included
in
the
analysis
.
Statistical
Analysis
Summary
likelihood
ratios
for
predicting
the
presence
of
OM
in
the
case
of
both
a
positive
test
result
and
negative
test
result,
as
well
as
sensitivities
and
specificities
were
calculated
using
random
-
effects
models
for
several
commonly
reported
thresholds
for
ESR
and
CRP
.
The
Mantel
-
Haenszel
test
for
trend
was
used
to
test
for
dose
-
response
as
thresholds
were
increased
given
a
positive
result
and
decreased
for
a
negative
result
.
P
values
less
than
0
.
5
were
considered
significant
.
All
analyses
were
performed
using
SAS
version
9
.
2
for
Windows
.
Results:
Our
original
search
yielded
152
potential
articles
of
which
19
were
selected
for
review
by
the
authors
.
Fourteen
articles
were
excluded
:
9
articles
did
not
use
ESR
or
CRP
in
the
diagnosis
of
osteomyelitis
and
the
data
could
not
be
extracted
in
the
remaining
5
.
Our
reference
search
provided
us
with
an
additional
35
articles
;
however
only
1
of
these
articles
fulfilled
all
of
the
inclusion
criteria
mentioned
previously
.
In
total,
six
articles
were
included
in
our
meta
-
analysis
(Figure
1
)
.
Figure
1
.
Search
strategy
All
six
articles
examined
ESR’s
relation
to
diabetic
osteomyelitis
however,
only
one
article,
Fleischer
et
al
2009
,
described
CRP
thresholds
.
The
articles
we
examined
were
of
fair
to
poor
quality
generally
.
Two
-
thirds
of
the
studies
were
prospective
.
None
of
the
article
displayed
level
one
evidence
and
only
two
studies
reported
consecutive
patient
enrollment
.
All
but
one
of
the
studies
used
bone
histopathology
to
diagnose
osteomyelitis
;
however,
Kaleta
et
al
and
Ertrugal
et
al
utilized
the
histopathology
gold
-
standard
inconsistently
at
about
55
%
of
the
time
.
There
were
a
total
of
305
patients
represented
in
this
meta
-
analysis
.
The
majority
of
these
people
were
inpatients
with
a
mean
prevalence
of
OM
of
59
%
.
Table 1.
Studies Describing CRP or ESR in the Diagnosis of
Lower Extremity Osteomyelitis in Patients with Diabetes
Mellitus
Source
Level of
Evidence*
Study
Type
Consecutive
Enrollment
Population
Age
Prevalence of
OM, %
Biopsy,
%
Method of Diagnosis of OM
Newman
et al 1991
II
Prospe
ctive
Yes
Inpatients
and
outpatients
with foot
ulcer
(n=35)
55.0
68†
100†
Culture and/or pathologic criteria
(osteonecrosis, marrow fibrosis,
and/or presence of inflammatory
cells)
Kaleta et
al 2001
IV
Retros
pective
No
Inpatients
with
osteomyeli
tis or
cellulitis
(n=29)
62.0
66
53
Pathology , positive results of at
least two imaging modalities (bone
scan, MRI, radiographs), or positive
probe to bone
Malabu et
al 2007
IV
Prospe
ctive
NS
Patients
with foot
ulcer
(n=43)
56.3
54
0
Positive results of two imaging
modalities (bone scan, MRI,
radiographs) or positive probe to
bone
Rabjohn
et al 2007
III
Prospe
ctive
NS
Inpatients
with
clinically
suspected
osteomyeli
tis (n=95)
61.0
69
100
Pathology or radiographs or
Technitium
-
99 three phase bone
scans
Ertugrul
et al 2009
II
Prospe
ctive
Yes
Inpatients
with
diabetic
foot lesions
(n=46)
64.0
52
54
Histopathology or microbiological
culture or T1 weighted MRI scan
Fleischer
et al 2009
III
Retros
pective
No
Inpatients
with a
single
forefoot
ulceration
(n=54)
61.5
63
100
Histopathology (focal necrosis or
intramedullary fibrosis with
infiltration of neutrophils)
Table 1
.
Abbreviations: CRP, C
-
reactive protein, ESR, Erythrocyte sedimentation rate, MRI, magnetic
resonance imaging, NS, Not specified, OM, osteomyelitis
*Level I: independent, blind evaluation of test with gold standard among a large sample of consecutive patients
with suspected target condition.. Level II: independent, blind evaluation of test with gold standard among a
small sample of consecutive patients with suspected target condition. Level III: nonindependent, blind
evaluation of test with gold standard among a nonconsecutive group of patients with suspected condition.
Level IV: nonindependent evaluation of test with standard of uncertain validity among a sample of patients
who have the target condition. Level V: nonindependent evaluation of test with standard of uncertain validity
among a sample of patients
† Calculations based on number of ulcers
ESR
>
80
mm/h
was
identified
as
the
single
most
specific
laboratory
test
for
diagnosing
OM
(spec=
94
.
2
%
)
.
There
was
an
obvious
dose
-
response
observed
for
the
likelihood
of
underlying
OM
with
increasing
ESR
thresholds,
and
a
three
-
fold
increase
in
the
likelihood
of
OM
as
ESR
threshold
was
increased
from
70
mm/h
to
80
mm/h
(
3
.
11
-
>
9
.
40
)
.
This
trend
was
statistically
significant
using
the
Mantel
-
Hanszel
test
with
a
p
value
of
0
.
04
(Table
2
)
.
Table 2. Summary Characteristics
for Erythrocyte
Sedimentation Rate for Diagnosing Osteomyelitis
ESR threshold
n
Sensitivity
Specificity
LR (+)*
LR (
-
)†
>60 mm/h
129
80.5 (74.0
-
85.8)
73.1 (63.4
-
80.9)
2.89 (0.38
-
21.5)
0.245 (0.24
-
2.56)
>70 mm/h
267
64.7 (60.6
-
68.0)
82.5 (75.3
-
88.2)
3.11 (1.21
-
7.99)
0.424 (0.178
-
1.01)
>80 mm/h
129
62.3 (56.8
-
64.9)
94.2 (86.1
-
98.0)
9.40 (
0.65
-
135)
0.365 (
0.03
-
5.26
)
Table 2.
Data in parentheses represent 95% confidence intervals. Abbreviations: LR (+), positive likelihood
ratio; LR (
-
), negative likelihood ratio; ESR, erythrocyte sedimentation rate
*Mantel Haenszel test for trend with increasing threshold levels = 4.041, p = 0.044
†Mantel Haenszel test for trend with decreasing threshold levels = 0.636, p = 0.425
Neither
increasing
nor
decreasing
levels
of
CRP
demonstrated
a
dose
response
for
diagnosing
OM
as
evident
by
the
nonsignifcant
Mantel
-
Haenszel
test
.
CRP
3
.
2
mg/dl
was
the
best
threshold
for
diagnosing
OM
with
the
highest
combined
total
or
sum
for
sensitivity
and
specificity
of
85
.
3
and
65
.
0
respectively
.
Table 3. Summary Characteristics for C
-
Reactive Protein for
Diagnosing Osteomyelitis
CRP threshold
n
Sensitivity
Specificity
LR (+)*
LR (
-
)†
2.3 mg/dl
54
88.0 (79.6
-
94.7)
40.0 (25.3
-
51.0)
1.47 (0.10
-
2.84)
0.29 (0.21
-
0.49)
3.2 mg/dl
54
85.3 (75.7
-
92.2)
65.0 (48.7
-
76.8)
2.44 (1.12
-
3.76)
0.23 (0.17
-
0.52)
8.4 mg/dl
54
55.9 (45.9
-
62.5)
80.0 (63.0
-
91.3)
2.79 (1.51
-
4.08)
0.55 (0.32
-
1.90)
Table 3.
Data in parentheses represent 95% confidence intervals
Abbreviations: LR (+) , positive likelihood ratio; LR (
-
), negative likelihood ratio; CRP, C
-
reactive protein
*Mantel Haenszel test for trend with increasing threshold levels = 1.236, p = 0.266
†Mantel Haenszel test for trend with decreasing threshold levels = 1.381, p = 0.240
As
CRP
threshold
(
green
arrow
)
for
establishing
OM
is
raised
from
2
.
3
to
3
.
2
to
8
.
4
,
the
likelihood
of
getting
a
true
positive
compared
to
a
false
positive
remains
essentially
the
same,
indicating
that
CRP
may
demonstrate
more
of
a
threshold
effect
for
diagnosing
underlying
OM
(Figure
2
)
.
However,
this
is
not
true
of
ESR
.
As
the
ESR
threshold
(
blue
arrow
)
for
diagnosing
OM
is
increased
from
60
to
70
to
80
,
the
likelihood
of
getting
a
false
positive
decreases
significantly
as
the
likelihood
of
getting
a
true
positive
remains
relatively
constant
.
This
trend
suggests
that
ESR
demonstrates
more
of
a
dose
response
likelihood
of
OM
with
increasing
levels
(Figure
3
)
.
Figure
2
.
Summary
receiver
operating
characteristic
curves
for
CRP
(from
Fleischer
et
al
.
2009
,
unpublished
figure,
n=
54
)
.
Figure
3
.
Summary
receiver
operating
characteristic
curves
for
ESR
(from
Fleischer
et
al
.
2009
,
unpublished
figure,
n=
54
)
.
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