C-reactive protein and diabetic foot ulcer infections: A meta-analysis

Abstract

Background
Accurate identification of diabetic foot ulcer infection (IDFU) through inflammatory markers is still a challenge in clinical practice.

Objectives
This meta-analysis aims to investigates whether there is a significant indigenous association between CRP level and diabetic foot ulcer infection.

Methods
The studies on the diagnosis of IDFU by inflammatory marker C-reactive protein published before November 2021 in PubMed, Web of Science, Embase, and Cochrane Library were searched. Since the included seven studies were cohort studies and cross-sectional studies, the quality evaluation was founded on the standard of Newcastle-Ottawa Scale (NOS), which was convenient and straightforward. The stata 15.0 software (Cambridge, UK) was used for statistical analysis of data collected for analysis.

Results
Finally, we included seven articles and investigated 592 patients, including 362 patients with IDFU and 230 patients without diabetic foot ulcer infection (NIDFU). Seven studies assessed the results of CRP, with significant heterogeneity among included studies (χ² = 18.93, P = 0.004; I² = 68.3%). Therefore, the combined effect adopts the random effect model, and the combined impact of standardized mean difference is 0.81 (95% CI 0.49–1.12; z = 4.99, p = 0.000). The funnel plot showed no significant asymmetry, and Egger's Test (z = 0.30, P = 0.764) and Begg's Test (t = −0.50, p = 0.637) showed no publication bias. Sensitivity analysis shows that the results are robust. Through subgroup analysis, we find that regional and CRP types are both sources of high heterogeneity. Meanwhile, the meta-regression results of the random effect model showed that HbA1c (P = 0.021), BMI (P = 0.029), and creatinine levels (P = 0.003) had significant effects on the heterogeneity of the relationship between IDFU, and serum CRP levels.

Discussion
Meta-analysis showed a clear association between C-reactive protein and IDFU. Understanding the pathophysiology of IDFU and rapid identification of risk factors for reducing patient burdens, amputation, and mortality are essential.

Full text

C-reactive protein and diabetic foot ulcer infections: A meta-analysis
Wan-Qing Zhang
a
, Wen Tang
a
, Shi-Qi Hu
a
, Xue-Lei Fu
a
, Hua Wu
a
, Wang-Qin Shen
a
,
*
,
Hong-Lin Chen
b
,
**
a
School of Medicine, Nantong University, Nantong, China
b
School of Public Health, Nantong University, Nantong, China
ARTICLE INFO
Keywords:
Diabetic foot ulcer infections
C-reactive protein
Meta-analysis
ABSTRACT
Background: Accurate identication of diabetic foot ulcer infection (IDFU) through inammatory markers is still
a challenge in clinical practice.
Objectives: This meta-analysis aims to investigates whether there is a signicant indigenous association between
CRP level and diabetic foot ulcer infection.
Methods: The studies on the diagnosis of IDFU by inammatory marker C-reactive protein published before
November 2021 in PubMed, Web of Science, Embase, and Cochrane Library were searched. Since the included
seven studies were cohort studies and cross-sectional studies, the quality evaluation was founded on the standard
of Newcastle-Ottawa Scale (NOS), which was convenient and straightforward. The stata 15.0 software (Cam-
bridge, UK) was used for statistical analysis of data collected for analysis.
Results: Finally, we included seven articles and investigated 592 patients, including 362 patients with IDFU and
230 patients without diabetic foot ulcer infection (NIDFU). Seven studies assessed the results of CRP, with sig-
nicant heterogeneity among included studies (
χ
2
=18.93, P =0.004; I
2
=68.3%). Therefore, the combined
effect adopts the random effect model, and the combined impact of standardized mean difference is 0.81 (95% CI
0.49–1.12; z =4.99, p =0.000). The funnel plot showed no signicant asymmetry, and Egger’s Test (z =0.30, P
=0.764) and Begg’s Test (t = − 0.50, p =0.637) showed no publication bias. Sensitivity analysis shows that the
results are robust. Through subgroup analysis, we nd that regional and CRP types are both sources of high
heterogeneity. Meanwhile, the meta-regression results of the random effect model showed that HbA1c (P =
0.021), BMI (P =0.029), and creatinine levels (P =0.003) had signicant effects on the heterogeneity of the
relationship between IDFU, and serum CRP levels.
Discussion: Meta-analysis showed a clear association between C-reactive protein and IDFU. Understanding the
pathophysiology of IDFU and rapid identication of risk factors for reducing patient burdens, amputation, and
mortality are essential.
1. Introduction
Diabetes mellitus (DM) is one of the fastest-growing public health
challenges of the 21st century. By 2045, 700 million adults are expected
to be affected by diabetes, seriously damaging people’s lives and health.
[1] DM complications continue to increase worldwide, diabetic foot
ulcer (DFU)has become one of the most challenging situations in daily
clinical practice. DFU patients face a high risk of amputation and death
once they are diagnosed with the infection. [2] Diabetic foot ulcer
infection (IDFU) is a familiar cause of diabetes-related hospitalization,
accounting for about 25% of the hospitalized patients with diabetes, and
the increase in medical costs brings a heavy burden to families. [3–6]
Infection is a process in which pathogenic microorganisms interact
with organisms, tissues, or cells. The invasion of pathogenic microor-
ganisms into the host and reproduction in the host tissue can induce
inammatory reactions. [7] However, the diagnosis of IDFU is not
simple and clear. [8] Biomarker detection is a rapid, effective and
low-cost method for diagnosing diseases. The American Society of In-
fectious Diseases (IDSA) and the International Working Group on Dia-
betic Foot (IWGDF) stressed that the diagnosis of infection should not
only rely on microbial analysis, but also focus on clinical standard test
standards. [9,10] In the 2019 guidelines, microbiological assessment of
* Corresponding author. School of Medicine, Nantong University, 19#Qixiu Road, Nantong, Jiangsu, 226000, China.
** Corresponding author. School of Public Health, Nantong University, 9#Seyuan Road, Nantong, Jiangsu, 226000, China.
E-mail addresses: 29572378@qq.com (W.-Q. Shen), honglinyjs@126.com (H.-L. Chen).
Contents lists available at ScienceDirect
Journal of Tissue Viability
journal homepage: www.elsevier.com/locate/jtv
https://doi.org/10.1016/j.jtv.2022.05.001
Received 23 November 2021; Received in revised form 22 January 2022; Accepted 3 May 2022
Journal of Tissue Viability 31 (2022) 537–543
Available online 7 May 2022
0965-206X/© 2022 Tissue Viability Society / Society of Tissue Viability. Published by Elsevier Ltd. All rights reserved.

Journal of Tissue Viability 31 (2022) 537–543
538
infection is an important recommendation module to identify the clas-
sication of infection and reduce the serious consequences of early
treatment for IDFU. [11,12]
The diagnosis of IDFU is mainly through the examination of valuable
inammatory biomarkers in the blood, such as C-reactive protein (CRP),
procalcitonin (PCT), erythrocyte sedimentation rate (ESR), and white
blood cell count (WBC). Recently, serum PCT is becoming a promising
biomarker in the study of IDFU. Studies have shown that serum PCT
levels indicate whether diabetic foot is infected. [13–15] In addition, the
diagnostic accuracy of serum PCT for bacterial infection was higher than
that of WBC and serum CRP levels. [16,17] Traditional inammatory
markers for diagnosis of infection, such as ESR and CRP, have increased
in almost all inammatory responses. However, one study showed that
high-sensitivity CRP (hs-CRP) was considered to be the most valuable
biomarker for IDFU. [18] CRP is an acute-phase response protein. [19]
When patients with IDFU, under the regulation of interleukin-6 (IL-6),
interleukin-1 (IL-1), and other cytokines, CRP is produced by hepato-
cytes in time, and rapidly increases, [20,21] and even can be increased
to 1000 times the normal value at the site of infection, which is a hot
spot for research on biomarkers of inammation or infection. [22] Some
cis-acting elements can also induce liver-specic expression of CRP. [23]
Studies have shown that plasma CRP levels can accurately distinguish
between clinically uninfected ulcers and mild or moderate infected ul-
cers, and may predict the existence of osteomyelitis. [24] Therefore, this
study aims to summarize the relationship between serum CRP levels and
IDFU by meta-analysis. By identifying changes in levels of inammatory
markers, interventions are implemented as early as possible to reduce
the risk of complications, amputation, and even death in patients with
DFU.
Inammatory markers (CRP) associated with the diagnosis of IDFU
have been identied in previous reports. However, serum CRP levels in
patients with IDFU have only been evaluated in limited studies. How-
ever, there is no systematic evaluation at present. Therefore, this meta-
analysis aims to investigates whether there is a signicant indigenous
association between CRP level and IDFU.
2. Methods
This meta-analysis was reported according to the Preferred Report-
ing Items for Systematic Reviews and Meta-analyses (PRISMA) guide-
lines. [25,26]
2.1. The inclusion and exclusion criteria of the literature
Inclusion criteria: (a) study design cross-sectional or cohort study;
(b) to analyze the relationship between IDFU and inammatory bio-
markers; (c) complete data for extraction or calculation.
Exclusion criteria: (a) studies without the full text; (b) the repeated
publication or study with obvious bias; (c) no relevant outcome data.
2.2. Information sources, search strategy, and selection process
PubMed, Web of Science, Embase, and Cochrane Library, were
searched for studies published before November 2021. The search
strategy in the PubMed database is as follows: ("foot diabetic" OR "dia-
betic feet" OR "feet diabetic" OR "foot ulcer diabetic" OR "Diabetic Foot")
AND ("infections" OR "Infection and Infestation" OR "Infestation and
Infection" OR "Infections and Infestations" OR "Infestations and In-
fections" OR "Infection") AND ("c reactive protein" OR "c reactive pro-
tein" OR "hsCRP" OR "high sensitivity c reactive protein" OR "high
sensitivity c reactive protein" OR "hs-CRP"). After searching the four
databases, the titles and abstracts were reviewed, and studies considered
eligible for inclusion were further assessed through full-text reading to
nalize the included articles. To avoid the possibility of missing the
published literature, the reference list of the retrieved articles was also
reviewed. The two reviewers (A, B) independently screened the
literature in the database, extracted the data, and cross-checked them. If
there was any disagreement, the third author was asked to resolve it
together.
2.3. Data extraction
We use standardized data collection protocols to extract all the data
that are worth analyzing in the literature. The two authors mentioned
above independently extracted data from the nal consensus screening
literature. For primary research studies, the following data were
extracted: author, year, country, design, sample size, duration of dis-
ease, BMI, CRP assay, CRP classication, HbA1c, blood glucose, creati-
nine, and CRP levels of IDFU and NIDFU.
2.4. Quality assessment
Two independent researchers analyzed the data collected from all
the articles. Since the included seven studies were cohort studies and
cross-sectional studies, the quality evaluation was founded on the
standard of Newcastle-Ottawa Scale (NOS), which was convenient and
straightforward. The NOS scale consists of three main modules: object
selection, comparability, and exposure/outcome, four stars, two stars,
and three stars, respectively. The scale uses ve-pointed stars to repre-
sent the score, and the total score is nine stars. The score is proportional
to the research quality, and inversely proportional to the bias risk. The
researchers compared their results to reach a consensus on the literature
ultimately included in the review sample.
2.5. Statistical analysis
The stata 15.0 software (Cambridge, UK) was used for statistical
analysis of data collected for analysis. First, we drew a forest map to
show the relationship between IDFU and serum CRP levels. The het-
erogeneity was assessed by forest map results. If I
2
>50%, select the
random-effect model for reporting; if I
2
<50%, select the xed-effect
model. Publication bias was assessed using funnel plots and Egger’s
Test and Begg’s Test. In addition, sensitivity analysis is used to evaluate
whether the uncertainty assumptions of data and methods affect the
robustness of the merging results. If there is still a high degree of het-
erogeneity, subgroup analysis will be used to analyze the clinical het-
erogeneity and methodological heterogeneity, and meta-regression will
be used to explore the relationship between research characteristics and
research results, to identify the sources of heterogeneity in the included
literature. In our analysis, two-sided P <0.050 was considered statisti-
cally signicant.
3. Results
3.1. Search results
Through the search strategy (Fig. 1), 697 studies were retrieved from
the online database, and three studies were retrieved through other
ways. After removing 100 repetitive articles by endnote software, 600
titles and abstracts were selected. After reviewing the title and abstract,
49 full-text literatures were assessed according to the inclusion and
exclusion criteria. Finally, seven articles were selected for the nal meta-
analysis. The ow chart of the document retrieval is shown in Fig. 1.
3.2. Characteristics of included studies
The seven nal meta-analysis articles are all English Language arti-
cles. A total of 592 patients were investigated, including 362 patients
with IDFU and 230 patients with NIDFU. Seven studies reported their
gender distribution. Among 592 subjects, 359 (60.64%) were males.
Among the seven studies included, four studies analyzed the serum CRP
level, and three studies investigated hs-CRP. CRP detection method, one
W.-Q. Zhang et al.

Journal of Tissue Viability 31 (2022) 537–543
539
study using Immuno-nephelometry assay, two studies using Nephelo-
metric assay, one study using Immunoturbidimetric assay, the other two
studies were detected in the hospital biochemistry laboratory. The
characteristics of the other included studies are shown in Table 1.
3.3. Quality evaluation of included studies
According to the Newcastle-Ottawa Scale (NOS), the bias risk of
included studies was evaluated. The results of bias risk assessment
included in cohort studies and cross-sectional studies are shown in
Table 2. All the studies responded well under the evaluation of the NOS.
According to the score, seven studies were low risk. In all, the risk of bias
of the included studies was moderate.
3.4. Results of meta-analysis
We summarized and analyzed the relationship between serum CRP
levels of patients in the NIDFU group and the IDFU group. Seven studies
assessed the results of CRP, with signicant heterogeneity among
included studies (
χ
2
=18.93, P =0.004; I
2
=68.3%). Therefore, the
combined effect adopts the random effect model, and the combined
effect of standardized mean difference is 0.81 (95% CI 0.49–1.12; z =
4.99, p =0.000) (Fig. 2). This indicates that there is a signicant positive
correlation between IDFU and a high level of serum CRP. The funnel plot
showed no signicant asymmetry, and Egger ’s Test (z =0.30, P =
0.764) and Begg ’s Test (t = − 0.50, p =0.637) showed no publication
bias (Fig. 3). Sensitivity analysis shows that the results are robust. Each
Fig. 1. Flow diagram of the trial selection for the meta-analysis.
W.-Q. Zhang et al.

Journal of Tissue Viability 31 (2022) 537–543
540
time one study was omitted for analysis, the summary results were not
signicantly affected by any single study (Fig. 4).
The results of regional subgroup analysis show that the summary
standardized mean difference (SMD) was 0.827 (95% CI 0.386–1.268) in
Asia; in Europe, the summary SMD was 0.748 (95% CI 0.387–1.110)
Subgroup meta-analysis results by the study were designed as follows: in
cohort studies, the summary SMD was 0.948 (95% CI 0.550–1.346); and
in cross-sectional studies, the summary SMD was 0.697 (95% CI
0.203–1.191). Subgroup analysis was performed according to CRP
types, CRP the summary SMD was 0.778 (95% CI 0.349–1.207); hs-CRP,
the summary SMD was 0.807 (95% CI 0.289–1.383) (Fig. 5). Group
analysis according to the characteristics of the study (Table 3).
The meta-regression results of the random effect model showed that
HbA1c (P =0.021), BMI (P =0.029), and creatinine levels (P =0.003)
had signicant effects on the heterogeneity of the relationship between
diabetic foot ulcer infection and serum CRP levels. Other results of meta-
regression showed that average age (P =0.076), sex ratio (P =0.198),
duration of diabetes (P =0.748), and blood glucose (P =0.735) were not
sources of high heterogeneity.
4. Discussion
We systematically reviewed the published epidemiological studies
on the relationship between inammatory markers (CRP) and diabetic
foot ulcer infection. In this meta-analysis, we found that the summary
SMD of serum CRP in the IDFU group was 0.81 (95% CI 0.49–1.12, z =
4.99, p =0.000) compared with that in the NIDFU group. This meta-
analysis conrmed the strong association between diabetic foot ulcer
infection and serum CRP levels.
We found that the serum CRP value in the IDFU group was signi-
cantly higher than that in the NIDFU group. CRP can produce immune
effect by combining the bacterial cell wall, cell membrane, and phos-
phatidylcholine (PC) on phosphorus lipoprotein that invades the wound
of diabetic foot ulcer. CRP can recognize foreign substances and activate
C3 complement invertase through classical pathways to regulate com-
plement. In addition, CRP combined with FcR in phagocytes also has
extensive anti-inammatory effects. Binding with platelet activating
factor (PAF) to reduce inammatory response. Binding with chromo-
somes to eliminate cell DNA in necrotic tissues.
According to the subgroup analysis, there may be difference between
serum CRP levels and diabetic foot ulcer infection in each continent,
with Asia leading the comparison. It is reasonable that Asia is the most
prominent, because Asia is considered to be the center of the diabetes
epidemic, accounting for about 60% of the world. [27] Due to the
different economic level and people ’ s way of life, regional restrictions
may be one reason for the great difference. In the future, more studies
are needed to further explore the levels of inammatory markers in
Table 1
Characteristics of included studies and CRP (mg/L) levels in IDFU group and NIDFU group.
Author, year Country Design Sample
size(M/F)
Age
(Year)
Duration of
disease
(years)
BMI
(kg/
m
2
)
CRP assay CRP
classication
HbA1c
(%)
Blood
glucose
(mg/dl)
creatinine
(mg/dl)
CRP
cut-
off
IDFU NIDFU
N ‾x ±s N ‾x ±s
Jeandrot, A,2008
[15]
France Prospective 93(56/
37)
68.70
±39.16
19.88 ±
21.83
NR Immuno-
nephelometry
CRP 7.22 ±
3.31
NR NR 17 70 121.9 ±
231.02
23 8.58 ±
14.85
Jonaidi Jafari,
N,2014 [29]
Iran Retrospective 60(31/
29)
58.15
±10.11
14.5 ±7.63 NR NR CRP 7.65 ±
2.24
NR NR 7.1 30 46.50 ±
46.50
30 9.20 ±
5.30
Umapathy,
D,2018 [30]
India Cross-
sectional
110(65/
45)
59.32
±8.55
NR 26.7 ±
4.54
Nephelometric CRP 9.7 ±
2.56
197.25 ±
96.43
1.21 ±0.38 NR 76 45.58 ±
71.8
34 25.10
±43.03
Dhamodharan,
U,2018 [31]
India cross-
sectional
44(22/
22)
57.75
±9.03
NR 26.48
±4.37
Nephelometric hs-CRP 9.94 ±
1.87
164.58 ±
51.51
1.2 ±0.54 3.12 24 41.26 ±
63.75
20 28.75
±44.12
Zakariah, N,
A,2020 [32]
Malaysia Cross-
sectional
128(82/
46)
61 ±
9.72
NR NR Immunoturbidimetric hs-CRP 8.05 ±
2.84
NR NR 3.47 73 11.62 ±
11.22
55 1.09 ±
1.28
Aslan, S,2020
[33]
Turkey Prospective 81(46/
35)
60.08
±11.32
27.9 ±
40.02
NR NR CRP 8.93 ±
2.17
188.59 ±
90.23
1.35 ±1.26 1.64 48 8.69 ±
8.3
33 1.1 ±
1.1
Todorova, A.
S,2021 [34]
Bulgaria Cross-
sectional
76(57/
19)
60.04
±10.48
16.20 ±
9.47
30.08
±6.12
Immunoturbidimetric hs-CRP 9.30 ±
2.18
NR NR 5.57 41 37.7 ±
47.5
35 5.07 ±
3.67
Table 2
Newcastle-Ottawa scale was used to evaluate the quality of the included studies.
Study Selection
(Stars
awarded)
Comparability
(Stars awarded)
Outcome
ascertainment
(Stars awarded)
Bias risk
(Total
stars
awarded)
Jeandrot,
A,2008
3 2 3 Low (8)
Jonaidi Jafari,
N,2014
3 0 3 Low (6)
Umapathy,
D,2018
3 1 3 Low (7)
Dhamodharan,
U,2018
3 1 3 Low (7)
Zakariah, N,
A,2020
3 1 3 Low (7)
Aslan, S,2020 3 2 3 Low (8)
Todorova, A.
S,2021
3 2 3 Low (8)
W.-Q. Zhang et al.

Journal of Tissue Viability 31 (2022) 537–543
541
patients with diabetic foot ulcer infection in different continents of the
world. In addition, the levels of serum CRP and hs-CRP were detected in
the included seven articles. High-sensitivity CRP is not a new CRP, but is
named according to the higher sensitivity of the detection methodology
in the low concentration range (1–10 mg/L). It has high accuracy in the
range of low concentration CRP (1–10 mg/L), and can detect the
sensitivity of the limit concentration of 0.15 mg/L. [28] This may also be
one of the sources of high heterogeneity.
In our included studies, it is a very important issue to distinguish
whether diabetic foot ulcers are infected by CRP cut-off values. Among
the seven studies, ve studies showed the optimal cut-off values of
infection in DFU, which were 7.1 mg/dL, 3.12 pg/mL, 3.47 mg/dL, 1.64
mg/L, and 5.57 mg/L, respectively. In one study, for better management
of DFU, the optimal cut-off value of CRP for distinguishing grade 1 from
Fig. 2. Forest plot of serum C-reactive protein (CRP) levels in NIDFU and IDFU patients.
Fig. 3. Publication bias analysis of the meta-analysis.
W.-Q. Zhang et al.

Journal of Tissue Viability 31 (2022) 537–543
542
grade 2 DFU was 17 mg/L. One study did not give the optimal cut-off
value of CRP. It is hoped that there will be more studies on the cut-off
value of the best inammatory markers (such as CRP) to diagnose
whether DFU are infected, so as to take the best measures to manage
such patients.
This meta-analysis has certain limitations, mainly including the
following aspects. Firstly, signicant heterogeneity was found in the
included studies. Second, different detection methods were used to
detect the level of serum CRP in the included studies. Third, due to the
limited number of studies in serum CRP and IDFU, lack of literature, it is
impossible to conduct extensive and rigorous analysis, and the accuracy
of overall effect estimation is also reduced.
In conclusion, our meta-analysis showed a strong correlation be-
tween IDFU and serum CRP level.
5. Conclusion
With the continuous upward trend of diabetic patients worldwide,
the risk of IDFU is also gradually increasing. People’s economic burden
is getting heavier and heavier, and the risk of amputation and death
increases. Accurate identication and distinction of different types of
IDFU are still a challenge in clinical practice. Understanding the path-
ophysiology of IDFU and rapid identication of risk factors is crucial. It
Fig. 4. Sensitivity analysis of the meta-analysis.
Fig. 5. Subgroup analysis of serum CRP levels in patients with NIDFU and IDFU.
Table 3
Subgroup analyses according to study characteristics.
SMD 95% CI Heterogeneity p Value
Study of continents
Asia 0.827 0.386–1.268 77.2% 0.002
Europe 0.748 0.387–1.110 13.1% 0.283
CRP Classication
CRP 0.778 0.349–1.207 69.4% 0.020
hs CRP 0.807 0.289–1.383 74.5% 0.020
Design
cohort study 0.948 0.550–1.346 47.2% 0.150
Cross-sectional study 0.697 0.203–1.191 78.7% 0.003
W.-Q. Zhang et al.

Journal of Tissue Viability 31 (2022) 537–543
543
is hoped that a more comprehensive assessment will be made of each
patient with diabetic foot infection who has received the same clinical
and laboratory tests. In addition to determining the relationship be-
tween CRP level and IDFU, future studies may also comprehensively
consider other covariates that affect CRP level.
Ethical approval
None needed as this is a review of existing studies.
Funding
None.
Declaration of competing interest
None.
Acknowledgments
We thank the editor and anonymous reviewers for several insightful
comments that signicantly improved the paper.
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