Interleukin-6 and other inflammatory markers in diagnosis of periprosthetic joint infection (PJI) 4 th International Conference/Orthopedics & Rheumatology Baltimore, Maryland, USA October 27 th, 2015 Adham Elsharkawi Elgeidi, MD Abdelrahman Elganainy, MD Noha Abou Elkhier, MD Shirien Rakha, MD Mansoura, EGYPT

No Conflict of interest

BackgroundBackground Aim of the studyAim of the study Patients & MethodsPatients & Methods - Criteria for definitive diagnosis of PJI - Criteria for definitive diagnosis of PJI ResultsResults DiscussionDiscussion - Limitations - Limitations ConclusionsConclusions

Background

PJI is one of most common indications for PJI is one of most common indications for revision hip and knee arthroplasties. revision hip and knee arthroplasties. In revision arthroplasty, distinction bet In revision arthroplasty, distinction bet septic and aseptic failure is critical → septic and aseptic failure is critical → Rx of failure secondary to PJI is different. Rx of failure secondary to PJI is different. Background

Several serum inflammatory markers → Dx of Several serum inflammatory markers → Dx of suspected PJI. suspected PJI. IL-6 is a cytokine produced by activated IL-6 is a cytokine produced by activated macrophages, monocytes and T cells in macrophages, monocytes and T cells in context of inflammatory response. context of inflammatory response. IL-6 as a dx marker is still under investigation IL-6 as a dx marker is still under investigation & is not used routinely. & is not used routinely. Background

Validate usefulness of IL-6 & other inflammatory markers (CRP, ESR, and WCC) in dx of PJI Aim of the study

Patients and methods

40 hip / knee replacement Patients for 40 hip / knee replacement Patients for 2-stage revision surgery ( ). 2-stage revision surgery ( ). 21 ♂ & 19♀. 21 ♂ & 19♀. Age: 38–72 years (58.4 years ). Age: 38–72 years (58.4 years ). No arthroplasty was sonicated. No arthroplasty was sonicated. Prospective study

Exclusion criteria 1.Chronic inflam. conditions (e.g. RA). 2.Malignancy. 3.Antibiotic Rx prior to surgery.

Blood samples obtained within 2 hrs before surgery. Blood samples obtained within 2 hrs before surgery. Collected into two separate tubes. Collected into two separate tubes. One: a serum separator tested for CRP and IL-6. One: a serum separator tested for CRP and IL-6. The other : with sodium citrate for ESR and WCC. The other : with sodium citrate for ESR and WCC. Blood test

Intra-op 6 deep tissue samples collected for: 1.Histopathological evaluation (formalin preserved, paraffin embedded sections). 2. Conventional microbiologic culture (sterile surgical container ). Tissue Samples

Definitive Diagnosis of PJI (1) Visible purulence surrounding prosthesis. (2) Sinus tract communicating to implant. (3) Growth of bacteria on culture: a- ≥ 2 cultures that yield same organism. a- ≥ 2 cultures that yield same organism. b- 1 culture with a virulent microorganism b- 1 culture with a virulent microorganism (e.g. Staph aureus). (e.g. Staph aureus). (4) Histopathological Examination: a- acute inflammation (≥ 5 PMN / HPF) a- acute inflammation (≥ 5 PMN / HPF) b. combined with a positive culture. b. combined with a positive culture.

Results

Results 40 patients.40 patients. 11 (27.5 %): proved to be infected (PJI).11 (27.5 %): proved to be infected (PJI). 29 (72.5 %): aseptic failure of prosthesis.29 (72.5 %): aseptic failure of prosthesis.

Results Isolated bacteria included:Isolated bacteria included: 1.Gram positive cocci: a.staphy aureus (n=5) a.staphy aureus (n=5) b.coagulase-negative staph (n=3) b.coagulase-negative staph (n=3) c.enterococci (n=1) c.enterococci (n=1) 2.Gram negative bacilli: a.escherichia coli (n=1) a.escherichia coli (n=1) b.pseudomonas aeuroginosa (n=1) b.pseudomonas aeuroginosa (n=1)

Table 1: Demographic data for the study population Characteristic Infected (n=11) Aseptic (n=29) Age (years) 59.6± ±7.8 Gender Male 4 (36.4 %) 17 (58.6 %) Male 4 (36.4 %) 17 (58.6 %) Female 7 (63.6 %) 12 (41.4 %) Female 7 (63.6 %) 12 (41.4 %) Joint type Knee 4 (36.4 %) 10 (34.5 %) Knee 4 (36.4 %) 10 (34.5 %) Hip 7 (63.6 %) 19 (65.5 %) Hip 7 (63.6 %) 19 (65.5 %) Variables are expressed as mean ± SD, or numbers (percentage)

Table 2: Analysis of inflammatory markers in patients with infected and aseptic revision arthroplasty Inflammatory marker All procedures (hip+knee) Infected Aseptic P value Infected Aseptic P value ESR (mm/hour) Mean SD WCC (cell×10 9L) Mean SD CRP (mg/L) Mean SD IL-6 (pg/L) Mean SD

Table 3: sensitivity, specificity, PPV, NPV, & accuracy of inflammatory markers Test Cut-off Sensit (%) Specif (%) PPV (%) NPV (%) Accuracy (%) ESR (mm/hour) CRP (mg/L) WCC (cell/ 10 9 /L ) IL-6 (pg/mL) IL-6 + CRP

Discussion

Dx of PJI remains a real challenge. Dx of PJI remains a real challenge. Standard lab used as first line tests to determine PJI Standard lab used as first line tests to determine PJI ie ESR,WCC, and CRP, are not consistently reliable. ie ESR,WCC, and CRP, are not consistently reliable. Cultures of wound drainage and sinus tracts do not Cultures of wound drainage and sinus tracts do not truly reflect organisms deep in joint, due to truly reflect organisms deep in joint, due to likelihood of contamination by other skin flora. likelihood of contamination by other skin flora. Joint aspirate is useful for determining deep Joint aspirate is useful for determining deep infection. Sometimes, it cannot be easily obtained or infection. Sometimes, it cannot be easily obtained or enough fluid is aspirated. enough fluid is aspirated. Discussion

In this study, we evaluated utility of pre-op ESR, In this study, we evaluated utility of pre-op ESR, WCC, serum CRP, and IL-6 as markers for PJI. WCC, serum CRP, and IL-6 as markers for PJI. ESR has little value in diagnosis of PJI since its ESR has little value in diagnosis of PJI since its sensitivity (81.8%) and specificity(82.8%) are low. sensitivity (81.8%) and specificity(82.8%) are low. WCC sensitivity of 90.9 % and specificity of 75.9 % WCC sensitivity of 90.9 % and specificity of 75.9 % IL-6 sensitivity (100 %) is similar to CRP, its IL-6 sensitivity (100 %) is similar to CRP, its specificity (90.9 vs 86.2 %) and accuracy (92.5 vs specificity (90.9 vs 86.2 %) and accuracy (92.5 vs 87.5 %) are higher %) are higher. Discussion

Advantage of IL-6: exhibits more rapid ↑and quicker ↓ to Advantage of IL-6: exhibits more rapid ↑and quicker ↓ to normal vs CRP or ESR which are ↑ up to 3 wks post-op. normal vs CRP or ESR which are ↑ up to 3 wks post-op. IL-6 level is a superior indicator of post-op. inflam. response IL-6 level is a superior indicator of post-op. inflam. response and to monitor infected patient’s response to Rx (1-3). and to monitor infected patient’s response to Rx (1-3). 1.Odak S, McNicholas M (2012) Diagnosis and management of infection after total knee arthroplasty. Orthop Trauma 26(2):80–85 2.Bottner F, Wegner A, Winkelmann W, Becker K, Erren M, Gotze C (2007) Interleukin- 6, procalcitonin, TNF-α markers of periprosthetic infection following total joint replacement. J Bone Joint Surg Br 89-B:94–99 3.Wirtz DC, Heller KD, Miltner O, Zilkens KW, Wolff JM (2000) Interleukin-6: a potential inflammatory marker after total joint replacement. Int Orthop 24:194–196 Discussion

Limitations 1.Small number of included patients: 40 patients. 1.Not serially monitor IL-6 & markers post-op. 2.Intra-op. tissue samples chosen is not infected.

Conclusions

Conclusions IL-6 is reliable marker for PJI, as it disting. between patients with infection and aseptic failure of prosthesis.IL-6 is reliable marker for PJI, as it disting. between patients with infection and aseptic failure of prosthesis. IL-6 >10.4 pg/ml and CRP >18 mg/L → identify all patients with PJIIL-6 >10.4 pg/ml and CRP >18 mg/L → identify all patients with PJI (sensitivity 100 %, NPV 100 %). (sensitivity 100 %, NPV 100 %). CRP + IL-6 is an excellent screening test to rapidly rule out deep infection of the implant.CRP + IL-6 is an excellent screening test to rapidly rule out deep infection of the implant.

ﺍﻠﻧﻯ ﺮﺑﻛﻣ ﺃﻋﺑﺪﻮﺍ ﻟﻧﺎﺱ ﺍ ﻴﺄﻴﻬﺎ ﻗﺑﻟﻛﻣ ﻣﻦ ﻴﻦ ﻮﺍﻠﻧ ﺧﻟﻗﻛﻣ ﺗﺗﻗﻮﻦ ﻠﻌﻠﻛﻣ (٢۰ ﺍﻟﺑﻗﺮﺓ ) O mankind! Worship your lord (Allah) who created you and those before you so that you may become Al-Muttaqun (the pious and righteous persons who fear Allah much and love Allah much, ( The Noble Qur`an, The Cow,20) بسم الله الرحمن الرحيم In the name of Allah, In the name of Allah, the Beneficent, the Merciful Thank You Mansoura, EGYPT 2015