Interleukin-6 and other Interleukin-6 and other inflammatory markers in inflammatory markers in

diagnosisdiagnosisof periprosthetic joint of periprosthetic joint

infection (PJI)infection (PJI)44thth International Conference/Orthopedics & Rheumatology International Conference/Orthopedics & Rheumatology

Baltimore, Maryland, USABaltimore, Maryland, USAOctober 27October 27thth, 2015, 2015

Adham Elsharkawi Elgeidi, MDAdham Elsharkawi Elgeidi, MDAbdelrahman Elganainy, MDAbdelrahman Elganainy, MD

Noha Abou Elkhier, MDNoha Abou Elkhier, MDShirien Rakha, MDShirien Rakha, MD

Mansoura, EGYPTMansoura, EGYPT

No Conflict of interest 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

BackgroundBackground

• 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 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 Background

Validate usefulness of IL-6 & other Validate usefulness of IL-6 & other inflammatory markers (CRP, ESR, and WCC) inflammatory markers (CRP, ESR, and WCC)

in dx of PJIin dx of PJI

AimAim of the study of the study

Patients and methodsPatients and methods

• 40 hip / knee replacement Patients for 40 hip / knee replacement Patients for 2-stage revision surgery2-stage revision surgery (2011-2013(2011-2013).). • 21 ♂ & 19♀.21 ♂ & 19♀.

• Age: Age: 38–72 years (58.4 years )38–72 years (58.4 years )..

• No arthroplasty was sonicated.No arthroplasty was sonicated.

Hips26

TKA 14

Prospective studyProspective study

Exclusion criteriaExclusion criteria

1.1.Chronic inflam. conditions (e.g. RA).Chronic inflam. conditions (e.g. RA).

2.2.Malignancy.Malignancy.

3.3.Antibiotic Rx prior to surgery.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 testBlood test

Intra-op Intra-op 6 deep tissue samples 6 deep tissue samples collected for:collected for:

1.1.Histopathological evaluation (formalin Histopathological evaluation (formalin preserved, paraffin embedded sections).preserved, paraffin embedded sections).

2. Conventional microbiologic culture (sterile 2. Conventional microbiologic culture (sterile surgical container ).surgical container ).

Tissue SamplesTissue Samples

Definitive Diagnosis of PJIDefinitive Diagnosis of PJI

(1) Visible purulence surrounding prosthesis. (1) Visible purulence surrounding prosthesis. (2) Sinus tract communicating to implant. (2) Sinus tract communicating to implant. (3) Growth of bacteria on culture:(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:(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.

ResultsResults

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 Results

• Isolated bacteria included:Isolated bacteria included:

1.1. Gram positive cocci: Gram positive cocci:

a.staphy aureus (n=5)a.staphy aureus (n=5)

b.coagulase-negative b.coagulase-negative staph (n=3)staph (n=3)

c.enterococci (n=1)c.enterococci (n=1)

2.2. Gram negative bacilli: 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 Table 1: Demographic data for the study populationstudy population

Characteristic Infected (n=11) Aseptic (n=29) Characteristic Infected (n=11) Aseptic (n=29) AgeAge (years) 59.6±6.1 57.9±7.8 (years) 59.6±6.1 57.9±7.8 GenderGender 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 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)Variables are expressed as mean ± SD, or numbers (percentage)

Table 2: Analysis of inflammatory Table 2: Analysis of inflammatory markers in patients with infected and markers in patients with infected and

aseptic revision arthroplastyaseptic revision arthroplastyInflammatory marker All procedures (hip+knee)Inflammatory marker All procedures (hip+knee) Infected Aseptic Infected Aseptic P valueP valueESR ESR (mm/hour)(mm/hour)Mean 85.9 28.3 0.0001Mean 85.9 28.3 0.0001SD 33.9 20.5SD 33.9 20.5WCC WCC (cell×10(cell×10 9 9L)L)Mean 12.3 7.7 0.0001Mean 12.3 7.7 0.0001SD 2.9 1.7SD 2.9 1.7CRP CRP (mg/L)(mg/L)Mean 80.7 11.7 0.004Mean 80.7 11.7 0.004SD 61.9 13.1SD 61.9 13.1IL-6 IL-6 (pg/L)(pg/L)Mean 64.6 5.9 0.0001Mean 64.6 5.9 0.0001SD 34.1 3.1SD 34.1 3.1

Table 3: sensitivity, specificity, PPV, NPV, Table 3: sensitivity, specificity, PPV, NPV, & accuracy of inflammatory markers& accuracy of inflammatory markers

Test Cut-off Sensit (%) Specif (%) PPV (%) NPV (%) Accuracy (%)Test Cut-off Sensit (%) Specif (%) PPV (%) NPV (%) Accuracy (%)

ESRESR (mm/hour) (mm/hour) 45.0 81.8 82.8 64.3 92.3 82.545.0 81.8 82.8 64.3 92.3 82.5

CRPCRP (mg/L) (mg/L) 18.0 18.0 100.0100.0 86.2 68.8 86.2 68.8 100.0100.0 87.5 87.5

WCCWCC (cell/ (cell/1010 9 9 /L/L) ) 9.2 90.9 75.9 58.8 95.6 80.09.2 90.9 75.9 58.8 95.6 80.0

IL-6IL-6 (pg/mL) (pg/mL) 10.4 10.4 100.0 100.0 90.9 79.0 90.9 79.0 100.0100.0 92.5 92.5

IL-6 + CRP IL-6 + CRP 100.0 99.0 92.0 100.0 97.5100.0 99.0 92.0 100.0 97.5

DiscussionDiscussion

• 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 ie ESR,WCC, and CRP, ESR,WCC, and CRP, are not consistently reliable.are not consistently reliable.• CulturesCultures of wound drainage and sinus tracts do not 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 Joint aspirate is useful for determining deep 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.

DiscussionDiscussion

• 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.

• ESRESR has little value in diagnosis of PJI since its 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 WCC sensitivity of 90.9 % and specificity of 75.9 % sensitivity of 90.9 % and specificity of 75.9 % • IL-6IL-6 sensitivity (100 %) is similar to sensitivity (100 %) is similar to CRPCRP, its, 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.87.5 %) are higher.

DiscussionDiscussion

• Advantage of IL-6: exhibits more rapid Advantage of IL-6: exhibits more rapid ↑↑and quicker and quicker ↓↓ to to normal vs CRP or ESR which are normal vs CRP or ESR which are ↑ ↑ up to 3 wks post-op.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 and to monitor infected patient’s response to Rx (1-3).(1-3).

1.Odak S, McNicholas M (2012) 1.Odak S, McNicholas M (2012) Diagnosis and management of infection after total Diagnosis and management of infection after total knee arthroplasty. knee arthroplasty. Orthop Trauma 26(2):80–85Orthop Trauma 26(2):80–852.Bottner F, Wegner A, Winkelmann W, Becker K, Erren M, Gotze C 2.Bottner F, Wegner A, Winkelmann W, Becker K, Erren M, Gotze C (2007) (2007) Interleukin-6, procalcitonin, TNF-Interleukin-6, procalcitonin, TNF-α α markers of periprosthetic infection following total markers of periprosthetic infection following total joint replacementjoint replacement. J Bone Joint Surg Br 89-B:94–99. J Bone Joint Surg Br 89-B:94–993.Wirtz DC, Heller KD, Miltner O, Zilkens KW, Wolff JM (2000) 3.Wirtz DC, Heller KD, Miltner O, Zilkens KW, Wolff JM (2000) Interleukin-6: a Interleukin-6: a potential inflammatory marker after total joint replacement. potential inflammatory marker after total joint replacement. Int Orthop 24:194–196Int Orthop 24:194–196

DiscussionDiscussion

LimitationsLimitations

1.1. Small number of included patients: 40 patients.Small number of included patients: 40 patients.

1.1. Not serially monitor IL-6 & markers post-op.Not serially monitor IL-6 & markers post-op.

2.2. Intra-op. tissue samples chosen is not infected.Intra-op. tissue samples chosen is not infected.

ConclusionsConclusions

ConclusionsConclusions

• IL-6 is reliable marker for PJIIL-6 is reliable marker for PJI, as it disting. between patients with , as it disting. between patients with infection and aseptic failure of prosthesis.infection and aseptic failure of prosthesis.

• IL-6 IL-6 >>10.4 10.4 pg/ml and pg/ml and CRP CRP >>18 18 mg/L → identify all patients with mg/L → identify all patients with PJI PJI

(sensitivity 100 %, NPV 100 %).(sensitivity 100 %, NPV 100 %).

• CRP + IL-6 is an excellent screening test CRP + IL-6 is an excellent screening test to rapidly rule out deep to rapidly rule out deep infection of the implant.infection of the implant.

يأيها ا لناس أعبدوا ربكم النى خلقكم والن ين من قبلكم

لعلكم تتقون (البقرة ٢۰)

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)

الرحيم الرحمن الله الرحيم بسم الرحمن الله بسم In the name of Allah , In the name of Allah ,

the Beneficent, the Mercifulthe Beneficent, the Merciful

Thank Thank YouYou

Mansoura, EGYPT Mansoura, EGYPT

20152015