The Utility of Serum d -Dimer for the Diagnosis of Periprosthetic Joint Infection in Revision Total Hip and Knee Arthroplasty

Journal Pre-proof The Utility Of Serum D-Dimer For The Diagnosis Of Periprosthetic Joint Infection In Revision Total Hip And Knee Arthroplasty Tejbir S. Pannu, MD, MS, Jesus M. Villa, MD, Preetesh D. Patel, MD, Aldo M. Riesgo, MD, Wael K. Barsoum, MD, Carlos A. Higuera, MD PII:

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DOI:

https://doi.org/10.1016/j.arth.2020.01.034

Reference:

YARTH 57742

To appear in:

The Journal of Arthroplasty

Received Date: 24 October 2019 Revised Date:

19 December 2019

Accepted Date: 14 January 2020

Please cite this article as: Pannu TS, Villa JM, Patel PD, Riesgo AM, Barsoum WK, Higuera CA, The Utility Of Serum D-Dimer For The Diagnosis Of Periprosthetic Joint Infection In Revision Total Hip And Knee Arthroplasty, The Journal of Arthroplasty (2020), doi: https://doi.org/10.1016/j.arth.2020.01.034. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.

THE UTILITY OF SERUM D-DIMER FOR THE DIAGNOSIS OF PERIPROSTHETIC JOINT INFECTION IN REVISION TOTAL HIP AND KNEE ARTHROPLASTY

Authors Tejbir S. Pannu MD, MS* [email protected] Jesus M. Villa, MD* [email protected] Preetesh D. Patel, MD* [email protected] Aldo M. Riesgo, MD* [email protected] Wael K. Barsoum, MD* [email protected] Carlos A. Higuera, MD* [email protected]

*Cleveland Clinic Florida, 2950 Cleveland Clinic Boulevard, Weston, FL- 33331

Corresponding Author Carlos A. Higuera, MD [email protected] Phone: (954) 659-5430 Cleveland Clinic Florida 2950 Cleveland Clinic Blvd. Weston, Florida, 33331

1 2 3

THE UTILITY OF SERUM D-DIMER FOR THE DIAGNOSIS OF PERIPROSTHETIC JOINT INFECTION IN REVISION TOTAL HIP AND KNEE ARTHROPLASTY

4 5 6

ABSTRACT

7 8

Introduction: There is scarce and contradicting evidence supporting the use of serum D-Dimer

9

for the diagnosis of periprosthetic-joint-infection (PJI) in revision total hip (THA) and knee

10

(TKA) arthroplasty. Therefore, the purpose of this study was to test the accuracy of serum D-

11

Dimer against the 2013 International-Consensus-Meeting (ICM) criteria.

12

Methods: A retrospective review was performed on a consecutive series of 172 revision

13

THA/TKA surgeries performed by three fellowship-trained surgeons at a single institution

14

(August 2017 to May 2019) and that had D-Dimer performed during their preoperative workup.

15

Out of this cohort, 111 (42 THA/69 TKA) cases had complete 2013-ICM criteria tests and were

16

included in the final analysis. Septic and aseptic revisions were categorized per 2013-ICM-

17

criteria (“gold standard”) and compared against serum D-Dimer using an established threshold

18

(850 ng/ml). Sensitivity, specificity, likelihood-ratios, and positive/negative predictive values

19

were determined. Independent t-tests, Fisher-exact tests, Chi-square tests, and receiver operating

20

characteristic (ROC)-curve analysis were performed.

21

Results: There was no statistically significant differences in baseline demographics between

22

septic and aseptic cases per 2013-ICM criteria. When compared to ICM-criteria, D-dimer

23

demonstrated high sensitivity (95.9%) and negative predictive value (90.9%) but low specificity

24

(32.3%), positive predictive value (52.8%), and overall, poor accuracy (61%) to diagnose PJI.

1

25

Positive likelihood ratio (LR) was 1.42 while negative LR was 0.13. The area under the curve

26

(AUC) was 0.742.

27

Conclusion: Serum D-Dimer has poor accuracy to discriminate between septic and aseptic cases

28

using a described threshold in the setting of revision total hip and knee arthroplasty.

29

30

KEYWORDS

31

Serum D-Dimer; Periprosthetic Joint Infection; PJI; Total Hip Arthroplasty; Total Knee

32

Arthroplasty

33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 2

51

INTRODUCTION

52 53

Periprosthetic joint infection (PJI) is a devastating complication that poses a huge burden on the

54

population and the health care system. The costs due to PJI are estimated to be more than $566

55

million dollars and are projected to exceed $1.62 billion by the year 2020 [1]. When compared to

56

the rest of the population, the quality of life in those patients who develop PJI is significantly

57

reduced [2]. Due to the magnitude of this problem, and in an effort to establish a standard

58

definition for the diagnosis of PJI, the Musculoskeletal Infection Society (MSIS) developed in

59

2011 [3] a set of criteria for PJI diagnosis, which was later modified and adopted by the

60

International Consensus Meeting (ICM) in 2013 [4]. Since then, the 2013 ICM criteria has been

61

the most commonly used definition to establish the diagnosis of PJI [4]. According to it, the

62

presence of two positive periprosthetic cultures with phenotypically identical organisms, or a

63

sinus tract communicating with the joint, or three positive criteria out of five minor criteria

64

confirm the diagnosis of PJI. The minor criteria are the following: (1) erythrocyte sedimentation

65

rate (ESR) >30mm/h and C-reactive protein (CRP) >10mg/L, (2) >3,000 WBCs/µl or positive

66

leukocyte esterase, (3) polymorphonuclear (PMN) % >80%, (4) one positive culture with

67

identified organism, and (5) >5 neutrophils per high power field (HPF) in 5 HPFs on the

68

histologic analysis [4]. Even though it is widely accepted by the orthopedic community, the 2013

69

ICM criteria has demonstrated a sensitivity of only 86.9% [5]. Consequently, it fails to diagnose

70

PJI in some cases. The gold standard test for the diagnosis of PJI remains elusive.

71

Serum D-dimer has gained attention in the orthopedic community for its possible role as an

72

inflammatory marker useful for the diagnosis of PJI [6]. Nevertheless, two recent investigations

73

reported results that are in disagreement with the ones of Shahi et al. and also showed that

74

fibrinogen might be a much better biomarker of infection [7,8]. In short, there is limited and 3

75

conflicting data supporting the use of serum D-Dimer for the diagnosis of PJI in revision total

76

hip (THA) and knee (TKA) arthroplasty. As a result, the objective of the current investigation is

77

to test the accuracy of serum D-Dimer against the 2013 ICM criteria for the diagnosis of

78

infection.

79

80

MATERIALS AND METHODS

81

After Institutional Review Board (IRB) approval, a retrospective review of electronic medical

82

records was performed on a consecutive series of 172 revision total hip arthroplasty (THA) and

83

total knee arthroplasty (TKA) patients (same number of cases) whose preoperative workup for

84

PJI included serum D-Dimer measurement. All revisions were performed between August 2017

85

and May 2019 by three fellowship trained surgeons at a single institution. Out of this cohort, 61

86

did not have a complete set of tests as required by the 2013 ICM criteria in order to establish or

87

refute infection. Consequently, these patients with incomplete laboratory tests were excluded. A

88

total of 111 cases (42 THAs and 69 TKAs) with complete 2013 ICM tests and D-Dimer were

89

included for statistical analyses.

90

The revisions were categorized as septic or aseptic according to the 2013 ICM criteria (modified-

91

MSIS) and to the serum D-Dimer test (the cut-off value used for that purpose was 850 ng/ml as

92

reported by Shahi et al.). Serum D-Dimer was processed at our institutional laboratory making

93

use of an “Automated immunoturbidimetric monoclonal antibody assay”. All septic revisions

94

underwent removal of the prosthesis and insertion of spacer as part of a two-stage exchange

95

arthroplasty while aseptic patients had single primary revision surgeries. Baseline demographics,

96

including

age,

gender

(male/female),

race

4

(white,

black,

other),

ethnicity

(non-

97

Hispanic/Hispanic), body mass index (BMI), comorbidity status [American Association of

98

Anesthesiology (ASA) grade] and smoking status (smoker/non-smoker) were noted and

99

compared between septic and aseptic cases as categorized by the 2013 ICM criteria.

100

Statistical Analysis

101

Continuous variables were described using means and standard deviations while categorical

102

variables were presented using numbers and frequencies. Independent t-tests, Fisher exact tests,

103

and Chi-square tests were used to compare patient characteristics (age, gender, race, ethnicity,

104

body mass index (BMI), ASA, and smoking status) of septic and aseptic cases per 2013 ICM

105

criteria. The sensitivity, specificity, likelihood ratios, positive and negative predictive values of

106

D-Dimer were determined against the 2013 ICM criteria which in our investigation was

107

considered as the “gold standard”. A receiver operating characteristic (ROC) curve analysis was

108

also performed to test the accuracy of D-Dimer. The optimal threshold of serum D-dimer for PJI

109

diagnosis was calculated using the Youden index (J-statistic = sensitivity + specificity – 1) based

110

on the coordinate points of the ROC-curve. To shed light on the results of the ROC-curve, the

111

test has a ‘low accuracy’ if the area under the cure (AUC) ranges from 0.5 to 0.7, it has a

112

‘moderate accuracy’ if the AUC ranges between 0.7 and 0.9, and it has a ‘high accuracy’ if the

113

AUC >0.9.

114

115

RESULTS

116

Baseline age, gender, race, ethnicity, BMI, ASA, and smoking status were not found

117

significantly different between septic and aseptic cases (Table 1). In the entire cohort analyzed,

118

44% of cases were categorized as septic based on the 2013 ICM criteria. In those revisions, a 5

119

wide diversity of organisms were cultured with Staphylococcus genus (S. aureus; S. epidermidis)

120

being the most commonly found organism followed by Pseudomonas aeruginosa and methicillin-

121

resistant Staphylococcus aureus (MRSA). The mean serum D-Dimer values in septic and aseptic

122

cases stratified based on the 2013 ICM criteria were 4,012 ng/ml and 2,092 ng/ml, respectively.

123

The mean serum D-Dimer values of septic and aseptic cases were found to be significantly

124

different (p value = 0.002; 95% CI, 705.9 – 3,134.8).

125

Performance of D-Dimer (using 850 ng/ml as a threshold) against the 2013 ICM criteria

126

To diagnose PJI, serum D-dimer demonstrated high sensitivity (95.9%) and negative predictive

127

value (90.9%) but low specificity (32.3%), positive predictive value (52.8%), and overall, low

128

accuracy (61%). Positive likelihood ratio (LR) was 1.42 while negative LR was 0.13 (Table 2).

129

Receiver-operator curve (ROC) analysis and cut-off value

130

The receiver-operator curve (ROC-curve) analysis demonstrated that the area under the curve

131

(AUC) was 0.742 meaning that the accuracy of serum D-dimer was moderate (Figure 1). Based

132

on the Youden index, the serum D-Dimer threshold for diagnosis of PJI was determined to be

133

2,300 ng/ml. When using this cut-off value, the serum D-dimer test demonstrated moderate

134

sensitivity 71.4% and moderate specificity of 74.2%, with overall improved accuracy (0.742) for

135

the diagnosis of PJI.

136

137

DISCUSSION

138

With the success of total hip and knee arthroplasty, the number of primary surgeries are

139

anticipated to increase 673% by the year 2030 [1,9]. As these numbers surge, so will the number

6

140

of periprosthetic joint infections. Thus, the need for an accurate PJI diagnosis is now more

141

relevant than ever. The determination of the “infection status” of a failed arthroplasty that is

142

about to undergo revision is a key step during the planning process. A comprehensive

143

preoperative clinical and laboratory workup is routinely performed for that purpose.

144

Unfortunately, there is no “gold standard” test for the diagnosis of infection. The 2013 ICM

145

definition (with a sensitivity of 86%) tends to miss many infections [5]. Notwithstanding, this

146

definition is the most accepted to diagnose infection for research and clinical purposes.

147

Several biomarkers have been found useful in confirming the diagnosis of PJI, with synovial

148

quantitative alpha-defensin showing the best performance [10]. Moreover, serum markers such

149

as CRP and ESR form the main stand in screening for PJI [11]. There is also new evidence

150

supporting the use of serum D-Dimer to diagnose infection [6]. The authors of the latter

151

investigation showed that this biomarker had high sensitivity and specificity (using 850 ng/ml as

152

the threshold). These findings spurred the introduction of D-Dimer along with alpha-defensin in

153

the newly proposed evidence-based definition of PJI [5]. This 2018 ICM definition showed a

154

higher sensitivity when compared to the widely used 2013 ICM criteria (97.7% vs. 86.9%) while

155

exhibiting a similar specificity. Nevertheless, the 2018 ICM PJI definition reached a low

156

consensus (68%) [12].

157

Contrary to the findings of Shahi et al., two recent investigations did not find that D-Dimer was a

158

useful test for the diagnosis of PJI [7,8]. In light of the conflicting reports, we sought in the

159

current investigation to assess the diagnostic accuracy of the serum D-Dimer when compared

160

against the 2013 ICM criteria for the diagnosis of periprosthetic joint infection before revision

161

total hip and knee arthroplasty.

7

162

Our study should be viewed in light of certain limitations. It has a retrospective study design

163

which makes it prone to bias. However, this limitation is minimized by the fact that all cases

164

analyzed were part of a consecutive series of revisions performed in a standard fashion by three

165

fellowship trained adult reconstruction surgeons at a single institution. We also acknowledge that

166

the current study lacks data concerning the incidence of venous thromboembolism (VTE) or

167

other conditions that may alter serum D-Dimer levels. However, we evaluated a consecutive

168

series of patients, which from the practical point of view, replicates clinical practice. A marker of

169

infection (i.e., serum D-Dimer) that is only useful in a narrow spectrum of the patients (i.e., no

170

cigarette smoking, no trauma, no malignancy, no acute coronary syndromes, no stroke, no

171

peripheral artery disease, no chronic inflammatory conditions, no VTE, or any other

172

hematological or coagulation disorders, etc.) could not easily be applied in routine clinical

173

practice. Another limitation is that we compared serum D-Dimer against the 2013 ICM criteria

174

(the “gold standard” in this investigation) in the know that this definition was not a true “gold

175

standard” diagnostic test because its sensitivity and specificity are imperfect. Nevertheless, the

176

2013 ICM definition is widely accepted and that is why we considered it a reasonable

177

comparative standard. In order to address these limitations in future research studies, multicenter

178

collaborations with a satisfactory number of cases with draining sinus tract or two positive

179

cultures (establishing an irrefutable diagnosis of PJI) can be of utmost value as a comparative

180

gold standard to assess the accuracy of future PJI diagnostic tests. Taking into account signs and

181

symptoms during the evaluation of history and physical examination in any future PJI definition

182

could also be valuable.

183

We found that serum D-Dimer demonstrated good sensitivity (95.9%) but poor specificity

184

(32.3%). When above the threshold of 850 ng/mL, D-Dimer showed a slight increase in the

8

185

probability of infection (positive likelihood ratio) but when below of it, this biomarker exhibited

186

a marked decrease in the probability of existing PJI (negative likelihood ratio). With an area

187

under the curve (AUC) of 0.742 in the ROC-curve analysis, D-Dimer showed moderate accuracy

188

to discriminate between septic and aseptic hip and knee cases. The mean serum D-Dimer value

189

of septic cases (4,012 ng/ml) was almost twice the one of aseptic cases (2,092 ng/ml). Although

190

both values were significantly different, these were above the threshold currently considered to

191

set apart septic from aseptic cases (850 ng/ml). Based on our data, an improved serum D-Dimer

192

threshold for PJI diagnosis was calculated to be 2,300 ng/ml. At this cut-off point, serum D-

193

Dimer showed moderate sensitivity (71.4%) and improved specificity (74.2%). Both values,

194

much lower than previously reported by Shahi et al. These conflicting results offer an

195

opportunity to reassess the threshold and consequently the value of serum D-Dimer for the

196

diagnosis of PJI. Further investigation is warranted. Our results agree with the findings of a

197

recent study which evaluated plasma fibrinogen and D-Dimer for the diagnosis of PJI [8]. The

198

AUC for plasma D-Dimer in that investigation was 0.657 which was significantly poorer than

199

the AUC of plasma fibrinogen (0.852). That study concluded that there is a limited value for the

200

use of plasma D-Dimer for the diagnosis of infection [8]. It is important to note that Li et al.

201

speculated that the use of plasma D-Dimer (instead of serum D-Dimer) as well as differences in

202

race and/or ethnicity in their cohort of patients could explain the divergent results when

203

compared to the findings of Shahi et al [8]. Another investigation, also evaluating plasma D-

204

Dimer, but with a threshold of 1.02 mg/L FEU to confirm or refute infection, demonstrated poor

205

sensitivity (68.29%) and specificity (50.70%) [7].

206

Our findings diverge from the results reported by Shahi et al., who while establishing 850 ng/ml

207

as the predictive D-Dimer cut-off value to differentiate septic from aseptic cases, reported

9

208

excellent sensitivity (89%) and specificity (93%) [6]. In the current investigation, we speculate

209

that our dissimilar findings could be due to differences in the methodology employed to measure

210

serum D-Dimer. We were unable to delve into this as Shahi et al. did not mention in their report

211

the exact serum D-Dimer laboratory method used to obtain the values. It could also be possible

212

that the lack of reproducibility of results regarding the use of D-Dimer is related to the high

213

variability of techniques available to measure D-Dimer. Another reason might be that the

214

proposed threshold is not accurate. In view of this, we ran an ROC curve analysis comparing

215

serum D-Dimer levels to 2013 ICM criteria and, making use of the Youden Index (Sensitivity +

216

Specificity – 1), obtained a new cut-off value for PJI diagnosis with improved overall AUC

217

(0.742).

218

In conclusion, when compared to the widely used 2013 ICM criteria, serum D-Dimer (using an

219

established threshold of 850 ng/ml) has a poor accuracy to discriminate between septic and

220

aseptic cases in the setting of revision total hip and knee arthroplasty. However, the use of a

221

different threshold may improve the operative characteristics of the test to diagnose PJI.

222

Therefore, prospective multicenter studies are needed to establish such thresholds and unfold

223

better reproducibility of the test.

224 225

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Test Is Promising for the Diagnosis of Periprosthetic Joint Infection and Timing of

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Li R, Shao H-Y, Hao L-B, Yu B-Z, Qu P-F, Zhou Y-X, et al. Plasma Fibrinogen Exhibits

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Better Performance Than Plasma D-Dimer in the Diagnosis of Periprosthetic Joint

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Day JS, Lau E, Ong KL, Williams GR, Ramsey ML, Kurtz SM. Prevalence and

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Shoulder Elb Surg 2019;19:1115–20. doi:10.1016/j.jse.2010.02.009.

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Saleh A, Ramanathan D, Siqueira MBP, Klika AK, Barsoum WK, Higuera Rueda CA.

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FIGURE LEGENDS

270 271

Figure 1. Receiver operating characteristic curve analysis for serum D-dimer when compared to 2013 ICM (modified-MSIS) criteria. (AUC – area under the curve)

272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 13

299

TABLE LEGENDS

300 301

Table 1. Baseline demographics of patients who underwent septic or aseptic revisions (according to the 2013 ICM criteria).

302 303 304 305

Table 2. Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios of serum D-dimer when compared to 2013 International Consensus Meeting (ICM) criteria for patients with revision due to aseptic loosening or suspected periprosthetic joint infection.

306

14

Table 1. Baseline demographics of patients who underwent septic or aseptic revisions (according to the 2013 ICM criteria).

Age (years)

2013 ICM (-) (n=62)

2013 ICM (+) (n=49)

p-value

68 ± 10

70 ± 10

0.299

Gender Female

35 (56.5%)

27 (55.1%)

Male

27 (43.5% )

22 (44.9%)

0.887

Race White

48 (77.4%)

39 (79.6%)

Black

11 (17.7%)

7 (14.3%)

Other

3 (4.8%)

3 (6.1%)

Non-Hispanic

55 (88.7%)

47 (95.9%)

Hispanic

7 (11.3%)

2 (4.1%)

30.5 ± 6.9

30.5 ± 7.3

1

2 (3.3%)

0 (0%)

2

34 (55.7%)

20 (40.8%)

3

25 (41%)

28 (57.1%)

4

0 (0%)

1 (2%)

3 (4.9%)

2 (4.1%)

58 (95.1%)

47 (95.9%)

0.860

Ethnicity 0.167 BMI Kg/m2

0.302

ASA

0.135

Smoking Status Smoker

0.834 Non-smoker

SD - Standard deviation; ICM: International Consensus Meeting (ICM); ASA – American Society of Anesthesiologists

Table 2. Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios of serum D-dimer when compared to 2013 International Consensus Meeting (ICM) criteria for patients with revision due to aseptic loosening or suspected periprosthetic joint infection.

2013 ICM (-)

2013 ICM (+)

Total

D-dimer (-)

20

2

22

D-dimer (+)

42

47

89

Total

62

49

Accuracy = 61% Sensitivity = 95.9% Specificity = 32.3% Positive predictive value = 52.8% Negative predictive value = 90.9% Positive Likelihood Ratio = 1.42 Negative Likelihood Ratio = 0.13