1. Level of Evidence: Level II Clin Orthop Relat Res 2008 Journal meeting 2008-10-08 Summarized R4 黃贊文 Supervised Dr. 沈世勛 Diagnosis of Infected Total Knee

2. The role and efficacy of serological tests and synovial fluid analysis To determine the false negative incidence of intraoperative culture The role that prophylactic antibiotics given prior to revision surgery may have on culture results. To explore the clinical fate of patients with a false positive unexpected intraoperative culture

3. Periprosthetic joint Infection Accurate and early diagnosis is the first step in effectively managing patients with PJI. At the present time diagnosis remains dependent on clinical judgment and reliance on standard clinical tests

4. Reasons of difficulty in diagnosing periprothetic joint infection The clinical presentation of PJI can be innocuous and mimic other conditions. The radiographic workup in the diagnosis of PJI is rarely informative and cannot distinguish between septic and aseptic failures. No single test with absolute accuracy for diagnosis of PJI.  Typically the diagnosis will be based on a combination of findings.

5. Reasons of difficulty in diagnosing periprothetic joint infection Although reports regarding sensitivity and specify of numerous diagnostic tests in the literature abound, the interpretation of the available data has been hampered by the low sample size of these studies. The cutoff values for the fluid cell count and neutrophil differential are not agreed upon.

6. Patients and Methods

7. Inclusion criteria 2000 to 2005, three institutions. Patient who needed a revision TKR for component loosening  889 patients with a mean age of 67 years (range, 43–94 years). Patients were diagnosed with periprosthetic infection if they fulfilled one of the following criteria: (1) an abscess or sinus tract was found communicating with the joint space (2) positive preoperative aspiration culture on solid media (3) ≧ 2 positive intraoperative cultures (4) 1 positive culture on solid media + the presence of gross intracapsular purulence or abnormal histology

8. Definition of tests Histologically positive: Histologically positive: 5 PMN /HPF ≧ 5 PMN /HPF Serological tests Serological tests A CRP value > 10 mg/L. A CRP value > 10 mg/L. A ESR value > 30 mm/hr A ESR value > 30 mm/hr Bacteriological exam : Bacteriological exam : Intraoperative culture Preoperative aspirate Elevated Serological test ESR/CRPWBC/DC False negative-+++/- False positives+---

9. Results

10. Result- CRP Infection Non-infection Infection Non-infection Number of patients 116 (39.2%) 180 (60.8%) CRP (mg/L) 110 7 ESR ( mm/hr) 29 85 22 P<0.001 P<0.001

11. Result - joint fluid analysis (A) The cutoff value for optimal accuracy in diagnosis of PJI was 1100 cells/lL for fluid leukocyte count. (B) The cutoff value for optimal accuracy for fluid neutrophil differential was 64%. PMN > 1100 cells/lL positive predictive Neutrophil differential > 64% value 100% PMN < 1100 cells/lL negaitive predictive Neutrophil differential < 64% value 99.6% Receiver-operating-characteristic (ROC) curve

12. Result - introperative tissue cultures Specificity Sensitivity positive negative predictive value predictive values Organisms 98% 30% 89% 70% ≧ 5 neutrophils 100% 50% 100% 79% Organisms ≧ 5 neutrophils 100% 43-64% 100% 82%

13. Result - introperative tissue culture 29 cases were false positive 5 were treated with an extended course of intravenous antibiotics 24 received no further treatment.  None of these 29 patients manifested any sign of infection at a minimum followup of 24 months (average, 46 months; range, 24–74 months). 12 patients were periprosthetic infection  11 patients were treated with a course of antibiotics. 2 patients became reinfected within 1 year.  The remaining 10 patients had no further sequelae. Intraoperative culture Preoperative aspirate Elevated Serological test ESR/CRPWBC/DC Infection (12)++++/- False positives (29)+---

14. Result - introperative tissue culture 171 patients with positive preoperative aspirate with or without prophylactic antibiotics < 1 hour culture negative 72 received prophylactic antibiotics 9 (12.5%) 99 without prophylactic antibiotics 8 (8.1%) p = 0.34

15. Discussion

16. Diagnostic Tools of Periprosthetic joint Infection History, PE History, PE Serologic tests Serologic tests - WBC, differential count, CRP,ESR - IL-6, procalcitonin, TNF-α Arthrocentesis Arthrocentesis - Bacteriological analysis - Histological Analysis Imagine Modalities Imagine Modalities - Plain X-ray - Plain X-ray - Bone Scan - Bone Scan - Gallium Scan - Gallium Scan - Indium-111-labeled scan - Indium-111-labeled scan Molecular analysis Molecular analysis - -Polymerase Chain Reaction (PCR) Culture (Gold Standard) Culture (Gold Standard)

17. Serologic tests ESRCRP Sensitivity93%91% Specificity83%86% Accuracy86%88% Prospective 1997and 2001 Number of patients/knee 145/151 Male / Female 71 / 74 CRP > 13.5 mg/L ESR > 22.5 mm/h

18. Retrospective 2000 and 2005 Number of patients/knee 296/296 Male / Female 125 / 171 Age (years) 66 CRP > 10 mg/L ESR > 30 mm/h

19. CRP and ESR Advantage - sensitive - readily available - cost-effective - most useful when they are monitored serially Disadvantage  A different levels of significance attached to CRP and ESR as a diagnostic tool in the literatures.  does not identify the micro-organism  does not provide the information necessary to develop a specific therapeutic antibiotic regimen. ~Virolainen P. Scand J Surg 2002;91:178-81. ~Greidanus NV. J Bone Joint Surg [Am] 2007;89-A:1409-16. ~Austin MS. J Arthroplasty 2008;23:65-8. ~Gollwitzer H. Orthopade 2006;35:904-6 (in German).

20. Serologic tests IL-6 (>12 pg/ml) Procalcitonin (>0.3 ng/ml) TNF-  (>40 ng/ml) Sensitivity95%33%43% Specificity87%98%94% ~F. Bottner et al. JBJS-B, 2007; 89:94

21. Joint Fluid Analysis Invasive procedure Culture Smear (Gram stain) Routine (Histological exam)  Precise identification of bacteria and their antibiotic resistance patterns  many authors recommend routine aspiration before a revision, even when there is no indication of an infection. ~Pellegrini VD Jr.Instr Course Lect 1997;46:215-19. ~Simmons TD. Am J Knee Surg 1996;9:99-106. ~Tsukayama DT.J Bone Joint Surg-A 2003;85-A(Suppl 1):75-80. ~Saleh KJ. J Bone Joint Surg [Am] 2003;85-A(Suppl 1):21-5.

22. Joint Fluid Analysis -Definition of positive of tests Histologically positive: Histologically positive: At least 5 neutrophilic polymorph leucocytes per high-power field (× 400) were identified in at least one of ten such fields. At least 5 neutrophilic polymorph leucocytes per high-power field (× 400) were identified in at least one of ten such fields. ~ Pandey R. J Clin Pathol 1999;52:118-23 ~ Mirra JM. Clin Orthop 1976;117:221-40. ~ Mirra JM. Clin Orthop 1982;170:175-83. ~ Feldman DS. J Bone Joint Surg [Am] 1995;77-A:1807-13. ~ Lonner JH. J Bone Joint Surg [Am] 1996;78-A:1553-8. Bacteriologically positive : Bacteriologically positive : Same bacterium was incubated for 14 days and identified in at least Same bacterium was incubated for 14 days and identified in at least 2 samples. 2 samples.  The length of the incubation period is important for identifying the micro-organism in aspirated fluid or biopsies micro-organism in aspirated fluid or biopsies ~Ince A. Clin Infect Dis 2004;39:1599-603. ~Friesecke C. Orthopade 2006;35:940-5. ~Bori G. J Bone Joint Surg-A 2007;89-A:1232-7.

23. Antibiotics free period Culture results from an aspiration may also be influenced by the administration of antibiotics to the patient At least 14 days, and if possible 4 weeks If the patient develops symptoms of systemic infection during the antibiotic free period, the TKR should be revised without delay. If the patient develops symptoms of systemic infection during the antibiotic free period, the TKR should be revised without delay.  an antibiotic-loaded spacer should be used in addition to broad-spectrum  an antibiotic-loaded spacer should be used in addition to broad-spectrum antibiotic therapy. antibiotic therapy. ~Levitsky KA. J Arthroplasty 1991;6:237-44. ~Barrack RL. Clin Orthop 1997;345:8-16. ~Duff GP. Clin Orthop 1996;331:132-9. ~Mont MA. J Bone Joint Surg [Am] 2000;82-A:1552-7 ~Burnett RS. Clin Orthop 2007;464:164-78. ~Fehring TK. Clin Orthop 1998;356:34-8. ~Barrack RL. Clin Orthop Relat Res 1997:8.

24. Joint Fluid Analysis Joint Fluid Analysis -A synovial fluid leukocyte count It is useful for the diagnosis of infection in TKA. Cutoffs for the diagnosis of Periprosthetic infection   Leukocyte counts > 1700/μL - 2500 /μL   Neutrophils > 60 - 73% ~ Kersey R. J Arthroplasty 2000;15:301. ~ Mason JB. J Arthroplasty 2003;18:1038. ~ Trampuz A. Am J Med 2004;117:556. ~ Parvizi J. J Bone Joint Surg Am 2006;88(Suppl 4):138.

25. Joint Fluid Analysis The value of this investigation remains controversial.  contamination of the aspirated fluid  bacteria that are difficult to grow in culture (ex: anaerobes and Gram(-) organisms)  Nonwithdrawal of antibiotic therapy prior to aspiration. ~Levitsky KA. J Arthroplasty 1991;6:237-44. ~Barrack RL. Clin Orthop 1997;345:8-16. ~Barrack RL. Orthopedics 1997;20:862-4. ~Saleh KJ. J Bone Joint Surg [Am] 2003;85-A(Suppl 1):21-5.

26. Joint Fluid Analysis Retrospective 2000 and 2005 Number of patients/knee 429/429 Male / Female 206 / 223 Age (years) 67 (43-94) WBC >1100 cells/10 -3 cm 3 +PMN >64%  98.6%

27. Histology (pre-op) JBJS-B, 2008; 90:874 July 2004 and September 2007 Patients / knee 144/145 Male / Female 63 / 81 Age (years) 68.4 (30-87) Duration after arthroplasty 38.2 months Follow-up (months) 23.4 (9-40) Primary diagnosis Osteoarthritis 129 Rheumatoid arthritis 16

28. Histology (intra-op) JBJS-A. 2007;89:1232 The probability of infection is high when at least 5 neutrophils /HPF It is not possible to rule out infection when the number of neutrophils is less than five.

29. Conclusion Simple serological tests, namely ESR and CRP, are excellent screening tools and we believe they should be obtained in every patient with a painful TKA. High predictive rate of PJI under CRP > 10 mg/L. serological tests CRP > 10 mg/L. ESR > 30 mm/hr ESR > 30 mm/hr WBC >1100 cells/10-3cm3 Joint fluid analysis WBC >1100 cells/10-3cm3 PMN >64% PMN >64%  For ambiguous cases these fast and simple intraoperative test have a valuable role in reaching a diagnosis In patients had infecting organism isolated preoperatively  that administration of prophylactic antibiotic did not interfere with isolation of an infecting organism. (>90%) Intraoperative cultures cannot and should not be used as gold standards for diagnosis of PJI as there is a relatively high percentage of both false- negative and false-positive cases.

30. Thanks for attention!