THE DIAGNOSIS OF PERIPROSTHETIC JOINT INFECTIONS …...potential periprosthetic joint infection, it...
Transcript of THE DIAGNOSIS OF PERIPROSTHETIC JOINT INFECTIONS …...potential periprosthetic joint infection, it...
THE DIAGNOSIS OF PERIPROSTHETIC JOINT
INFECTIONS OF THE HIP AND KNEE
GUIDELINE AND EVIDENCE REPORT Adopted by the American Academy of Orthopaedic Surgeons
Board of Directors June 18, 2010
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Disclaimer This Clinical Practice Guideline was developed by an AAOS physician volunteer Work Group based on a systematic review of the current scientific and clinical information and accepted approaches to treatment and/or diagnosis. This Clinical Practice Guideline is not intended to be a fixed protocol, as some patients may require more or less treatment or different means of diagnosis. Clinical patients may not necessarily be the same as those found in a clinical trial. Patient care and treatment should always be based on a clinician’s independent medical judgment, given the individual patient’s clinical circumstances. Disclosure Requirement In accordance with AAOS policy, all individuals whose names appear as authors or contributors to Clinical Practice Guideline filed a disclosure statement as part of the submission process. All panel members provided full disclosure of potential conflicts of interest prior to voting on the recommendations contained within this Clinical Practice Guidelines. Funding Source This Clinical Practice Guideline was funded exclusively by the American Academy of Orthopaedic Surgeons who received no funding from outside commercial sources to support the development of this document. FDA Clearance Some drugs or medical devices referenced or described in this Clinical Practice Guideline may not have been cleared by the Food and Drug Administration (FDA) or may have been cleared for a specific use only. The FDA has stated that it is the responsibility of the physician to determine the FDA clearance status of each drug or device he or she wishes to use in clinical practice. Copyright All rights reserved. No part of this Clinical Practice Guideline may be reproduced, stored in a retrieval system, or transmitted, in any form, or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission from the AAOS. Published 2010 by the American Academy of Orthopaedic Surgeons 6300 North River Road Rosemont, IL 60018 First Edition Copyright 2010 by the American Academy of Orthopaedic Surgeons
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Summary of Recommendations The following is a summary of the recommendations in the AAOS’ clinical practice guideline, The Diagnosis of Periprosthetic Joint Infections of the Hip and Knee. This summary does not contain rationales that explain how and why these recommendations were developed nor does it contain the evidence supporting these recommendations. All readers of this summary are strongly encouraged to consult the full guideline and evidence report for this information. We are confident that those who read the full guideline and evidence report will note that the recommendations were developed using systematic evidence-based processes designed to combat bias, enhance transparency, and promote reproducibility.
This summary of recommendations is not intended to stand alone. Clinical decisions should be made in light of all circumstances presented by the patient. Procedures applicable to the individual patient rely on mutual communication between patient, physician, and other healthcare practitioners.
1. In the absence of reliable evidence about risk stratification of patients with a potential periprosthetic joint infection, it is the opinion of the work group that testing strategies be planned according to whether there is a higher or lower probability that a patient has a hip or knee periprosthetic infection.
Strength of Recommendation: Consensus Note: Please see page 17 of this document for a definition of “higher and lower probability”.
2. We recommend erythrocyte sedimentation rate and C-reactive protein testing
for patients assessed for periprosthetic joint infection. Strength of Recommendation: Strong
3. We recommend joint aspiration of patients being assessed for periprosthetic
knee infections who have abnormal erythrocyte sedimentation rate AND/OR C-reactive protein results. We recommend that the aspirated fluid be sent for microbiologic culture, synovial fluid white blood cell count and differential.
Strength of Recommendation: Strong
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4. We recommend a selective approach to aspiration of the hip based on the patient’s probability of periprosthetic joint infection and the results of the erythrocyte sedimentation rate (ESR) AND C-reactive protein (CRP). We recommend that the aspirated fluid be sent for microbiologic culture, synovial fluid white blood cell count and differential.
Selection of Patients for Hip Aspiration Probability of
Infection ESR and CRP
Results Planned Reoperation
Status Recommended Test
Higher + + or + − Planned or not planned Aspiration
Lower + + or + − Planned Aspiration or Frozen Section
Lower + + Not planned Aspiration
Lower + − Not planned Please see Recommendation 6
Higher or Lower − − Planned or not planned No further testing Key for ESR and CRP results + + = ESR and CRP test results are abnormal + − = either ESR or CRP test result is abnormal − − = ESR and CRP test results are normal
Strength of Recommendation: Strong
5. We suggest a repeat hip aspiration when there is a discrepancy between the probability of periprosthetic joint infection and the initial aspiration culture result.
Strength of Recommendation: Moderate
6. In the absence of reliable evidence, it is the opinion of the work group that
patients judged to be at lower probability for periprostheic hip infection and without planned reoperation who have abnormal erythrocyte sedimentation rates OR abnormal C-reactive protein levels be re-evaluated within three months. We are unable to recommend specific diagnostic tests at the time of this follow-up.
Strength of Recommendation: Consensus
7. In the absence of reliable evidence, it is the opinion of the work group that a
repeat knee aspiration be performed when there is a discrepancy between the probability of periprosthetic joint infection and the initial aspiration culture result.
Strength of Recommendation: Consensus
8. We suggest patients be off of antibiotics for a minimum of 2 weeks prior to obtaining intra-articular culture.
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Strength of Recommendation: Moderate
9. Nuclear imaging (Labeled leukocyte imaging combined with bone or bone
marrow imaging, FDG-PET imaging, Gallium imaging, or labeled leukocyte imaging) is an option in patients in whom diagnosis of periprosthetic joint infection has not been established and are not scheduled for reoperation.
Strength of Recommendation: Weak
10. We are unable to recommend for or against computed tomography (CT) or magnetic resonance imaging (MRI) as a diagnostic test for periprosthetic joint infection.
Strength of Recommendation: Inconclusive
11. We recommend against the use of intraoperative Gram stain to rule out
periprosthetic joint infection. Strength of Recommendation: Strong
12. We recommend the use of frozen sections of peri-implant tissues in patients
who are undergoing reoperation for whom the diagnosis of periprosthetic joint infection has not been established or excluded.
Strength of Recommendation: Strong
13. We recommend that multiple cultures be obtained at the time of reoperation in
patients being assessed for periprosthetic joint infection. Strength of Recommendation: Strong
14. We recommend against initiating antibiotic treatment in patients with suspected
periprosthetic joint infection until after cultures from the joint have been obtained.
Strength of Recommendation: Strong
15. We suggest that prophylactic preoperative antibiotics not be withheld in patients
at lower probability for periprosthetic joint infection and those with an established diagnosis of periprosthetic joint infection who are undergoing reoperation.
Strength of Recommendation: Moderate
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Work Group Craig Della Valle MD, Chair Rush University Medical Center 1611 W Harrison St # 300 Chicago, IL 60612-4861 Javad Parvizi, MD, Vice-Chair Rothman Institute 925 Chestnut St - 5th Fl Philadelphia, PA 19107 Thomas W Bauer, MD PhD Cleveland Clinic Foundation Department of Pathology 9500 Euclid Ave Desk L25 Cleveland, OH 44195 Paul E DiCesare, MD UC Davis Medical Center Department of Orthopaedic Surgery 4860 Y St Ste 3800 Sacramento, CA 95817 Richard Parker Evans, MD University of Arkansas for Medical Sciences Department of Orthopedics 4301 W Markham, #531 Little Rock, AR 72205 John Segreti, MD Rush University Medical Center 600 S Paulina St. Ste 143 Chicago, Il 60612 Mark Spangehl, MD Mayo Clinic 5777 East Mayo Blvd Phoenix, AZ 85054
Guidelines and Technology Oversight Chair: William C. Watters III MD 6624 Fannin #2600 Houston, TX 77030 Evidence Based Practice Committee Chair: Michael Keith, MD 2500 Metro Health Drive Cleveland, OH 44109-1900 AAOS Staff: Charles M. Turkelson, PhD Director of Research and Scientific Affairs 6300 N River Road Rosemont, IL 60018 Janet L. Wies MPH AAOS Clinical Practice Guideline Mgr Patrick Sluka MPH AAOS Research Analyst Kristin Hitchcock, MSI AAOS Medical Librarian Special Acknowledgements Sara Anderson MPH Kevin Boyer Laura Raymond, MA
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Peer Review Participation in the AAOS peer review process does not constitute an endorsement of this guideline by the participating organization.
The following organizations participated in peer review of this clinical practice guideline and gave explicit consent to be listed in this document:
American Association of Hip and Knee Surgeons
European Bone and Joint Infection Society
Knee Society
Musculoskeletal Infection Society
Society of Nuclear Medicine
Participation in the AAOS peer review process does not constitute an endorsement of this guideline by the participating organization.
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Table of Contents
SUMMARY OF RECOMMENDATIONS ..............................................................III
WORK GROUP .................................................................................................. VI
PEER REVIEW.................................................................................................. VII
TABLE OF CONTENTS ................................................................................... VIII
LIST OF FIGURES ............................................................................................ XII
LIST OF TABLES............................................................................................. XIII
I. INTRODUCTION ...........................................................................................1
Overview ....................................................................................................................................................... 1
Goals and Rationale ..................................................................................................................................... 1
Intended Users .............................................................................................................................................. 1
Patient Population ........................................................................................................................................ 2
Etiology.......................................................................................................................................................... 2
Incidence ....................................................................................................................................................... 2
Burden of Disease ......................................................................................................................................... 2
Risk Factors .................................................................................................................................................. 2
Emotional and Physical Impact................................................................................................................... 2
Potential Benefits and Harms...................................................................................................................... 2
II. METHODS.....................................................................................................3
Formulating Preliminary Recommendations............................................................................................. 3
Study Selection Criteria ............................................................................................................................... 3 Inclusion of studies with mixed patient populations.................................................................................. 4 Best Available Evidence............................................................................................................................ 4
Literature Searches ...................................................................................................................................... 4
Data Extraction............................................................................................................................................. 5
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Judging the Quality of Evidence ................................................................................................................. 5 Diagnostic Studies ..................................................................................................................................... 5 Prognostic Studies ..................................................................................................................................... 7
Defining the Strength of the Recommendations ........................................................................................ 7
Consensus Development............................................................................................................................... 8
Statistical Methods ....................................................................................................................................... 9
Peer Review................................................................................................................................................... 9
Public Commentary.................................................................................................................................... 10
The AAOS Guideline Approval Process................................................................................................... 10
Revision Plans ............................................................................................................................................. 10
Guideline Dissemination Plans .................................................................................................................. 10
III. ALGORITHMS.........................................................................................12
IV. RECOMMENDATIONS AND SUPPORTING DATA ...............................15
Recommendation 1 ..................................................................................................................................... 15 Summary of Evidence.............................................................................................................................. 18 Excluded Articles..................................................................................................................................... 21 Study Quality........................................................................................................................................... 34 Study Results ........................................................................................................................................... 40
Recommendation 2 ..................................................................................................................................... 44 Summary of Evidence.............................................................................................................................. 46 Excluded Articles..................................................................................................................................... 47 Study Quality........................................................................................................................................... 51 Study Results ........................................................................................................................................... 56
Recommendation 3 ..................................................................................................................................... 74 Summary of Evidence.............................................................................................................................. 75 Excluded Articles..................................................................................................................................... 76 Study Quality........................................................................................................................................... 77 Study Results ........................................................................................................................................... 78
Recommendation 4 ..................................................................................................................................... 85 Summary of Evidence.............................................................................................................................. 86 Excluded Articles..................................................................................................................................... 87 Study Quality........................................................................................................................................... 90 Study Results ........................................................................................................................................... 92
Recommendation 5 ................................................................................................................................... 101 Excluded Articles................................................................................................................................... 102 Study Quality......................................................................................................................................... 103 Study Results ......................................................................................................................................... 103
Recommendation 6 ................................................................................................................................... 104
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Recommendation 7 ................................................................................................................................... 106 Excluded Articles................................................................................................................................... 106
Recommendation 8 ................................................................................................................................... 107 Excluded Articles................................................................................................................................... 108 Study Quality......................................................................................................................................... 109 Study Results ......................................................................................................................................... 109
Recommendation 9 ................................................................................................................................... 110 Summary of Evidence............................................................................................................................ 113 Excluded Articles................................................................................................................................... 114 Study Quality......................................................................................................................................... 123 Study Results ......................................................................................................................................... 128
Recommendation 10 ................................................................................................................................. 146 Summary of Evidence............................................................................................................................ 146 Excluded Articles................................................................................................................................... 147 Study Quality......................................................................................................................................... 148 Study Results ......................................................................................................................................... 150
Recommendation 11 ................................................................................................................................. 153 Summary of Evidence............................................................................................................................ 153 Excluded Articles................................................................................................................................... 154 Study Quality......................................................................................................................................... 155 Study Results ......................................................................................................................................... 156
Recommendation 12 ................................................................................................................................. 159 Summary of Evidence............................................................................................................................ 160 Excluded Articles................................................................................................................................... 161 Study Quality......................................................................................................................................... 163 Study Results ......................................................................................................................................... 165
Recommendation 13 ................................................................................................................................. 171 Summary of Evidence............................................................................................................................ 171 Excluded Articles................................................................................................................................... 173 Study Quality......................................................................................................................................... 176 Study Results ......................................................................................................................................... 178
Recommendation 14 ................................................................................................................................. 189 Excluded Articles................................................................................................................................... 190 Study Quality......................................................................................................................................... 191 Study Results ......................................................................................................................................... 192
Recommendation 15 ................................................................................................................................. 193 Excluded Articles................................................................................................................................... 194 Study Quality......................................................................................................................................... 197 Study Results ......................................................................................................................................... 199
Future Research ....................................................................................................................................... 201
V. APPENDIXES............................................................................................203
Appendix I................................................................................................................................................. 204 Work Group........................................................................................................................................... 204
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Appendix II ............................................................................................................................................... 205 AAOS Bodies That Approved This Clinical Practice Guideline ........................................................... 205 Documentation of Approval .................................................................................................................. 206
Appendix III.............................................................................................................................................. 207 Study Attrition Flowchart ...................................................................................................................... 207
Appendix IV.............................................................................................................................................. 208 Literature Searches ................................................................................................................................ 208
Appendix V ............................................................................................................................................... 211 Data Extraction Elements ...................................................................................................................... 211
Appendix VI.............................................................................................................................................. 212 Judging the Quality of Diagnostic Studies............................................................................................. 212 Judging the Quality of Prognostic Studies............................................................................................. 213 Judging the Quality of Treatment Studies ............................................................................................. 213
Appendix VII ............................................................................................................................................ 214 Form for Assigning Strength of Recommendation (Interventions) ....................................................... 214
Appendix VIII........................................................................................................................................... 216 Voting by the Nominal Group Technique ............................................................................................. 216 Opinion-Based Recommendations ........................................................................................................ 216
Appendix IX.............................................................................................................................................. 219 Structured Peer Review Form................................................................................................................ 219
Appendix X ............................................................................................................................................... 222 Peer Review Panel ................................................................................................................................. 222 Public Commentary ............................................................................................................................... 223
Appendix XI.............................................................................................................................................. 224 Interpreting the Forest Plots................................................................................................................... 224
Appendix XII ............................................................................................................................................ 225 Conflict of Interest................................................................................................................................. 225
Appendix XIII........................................................................................................................................... 227 References ............................................................................................................................................. 227 Articles Excluded from the Systematic Review(s) ................................................................................ 237
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List of Figures Algorithm for Patients with Higher Probability of Hip or Knee Periprosthetic Joint
Infection ................................................................................................................ 12 Algorithm for Patients with Lower Probability of Periprosthetic Knee Infection............ 13 Algorithm for Patients with Lower Probability of Periprosthetic Hip Infection with
Planned Reoperation ............................................................................................. 14 Algorithm for Patients with Lower Probability of Periprosthetic Hip Infection without
Planned Reoperation ............................................................................................. 14 ESR Meta-analysis Results - Likelihood Ratios............................................................... 56 CRP Results - Likelihood Ratios ...................................................................................... 57 ESR and CRP - Likelihood Ratios.................................................................................... 57 Radiography Results - Likelihood Ratios ......................................................................... 58 White Blood Cell Count Results - Likelihood Ratios....................................................... 58 Hip Aspiration Cultures Results - Meta-Analysis ............................................................ 92 Synovial Fluid WBC Count Results - Likelihood Ratios (Hip and Knee) ....................... 93 Neutrophil Percentage Results – Likelihood Ratios (Hip and Knee) ............................... 93 Technetium-labeled-Leukocyte Imaging Results – Likelihood Ratios .......................... 128 Indium-labeled-Leukocyte Imaging Results - Likelihood Ratios................................... 129 Combined Leukocyte/Bone Imaging Results – Likelihood Ratios................................. 129 Combined Leukocyte/Bone Marrow Imaging Results - Likelihood Ratios ................... 130 FDG-PET Imaging Results - Likelihood Ratios............................................................. 130 Technetium-99m Bone Imaging Results - Likelihood Ratios ........................................ 131 Other Nuclear Imaging Results - Likelihood Ratios....................................................... 132 CT Imaging Results - Likelihood Ratios ........................................................................ 150 Gram Stain Results - Likelihood Ratios ......................................................................... 156 Frozen Section Meta-Analysis – Threshold of 10 PMN in 5 Fields............................... 165 Frozen Section Meta-Analysis – Threshold of 5 PMN/HPF .......................................... 165 Frozen Section Results - Likelihood Ratios – Mixed Thresholds .................................. 166 Intraoperative Cultures Results - Threshold of 1 vs. 2 Positive Cultures....................... 178 Intraoperative Cultures Results - Tissue or Swab or Fluid ............................................. 178
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List of Tables Reference Standard Used in Included Diagnostic Studies.................................................. 6 Strength of recommendation descriptions .......................................................................... 8 AAOS Guideline Language ................................................................................................ 8 Interpreting Likelihood Ratios............................................................................................ 9 Results of Prognostic Studies - Hip .................................................................................. 18 Results of Prognostic Studies - Knee................................................................................ 19 Summary of Evidence – Diagnostic or Prevalence Studies.............................................. 20 Excluded Articles - Recommendation 1 ........................................................................... 21 Quality of Diagnostic Studies ........................................................................................... 34 Quality of Prognostic Studies ........................................................................................... 35 Risk Factors - Quality of Joint Registries ......................................................................... 38 Risk Factors - Quality of Randomized Trials ................................................................... 39 Pain as a Predictor of Periprosthetic Infection.................................................................. 40 Warmth, Erythema, Swelling as Predictors of Periprosthetic Infection ........................... 40 Early Implant Failure as a Predictor of Periprosthetic Infection ...................................... 41 Sinus Tract as a Predictor of Periprosthetic Infection ...................................................... 41 Prevalence of Periprosthetic Infection among Patients with Bacteremia ......................... 41 Prevalence of Periprosthetic Infection among Patients with Metachronous Periprosthetic
Infection ................................................................................................................ 42 Anticoagulation RCT........................................................................................................ 42 Use of Drains RCTs .......................................................................................................... 43 Radiography and Serology Summary of Evidence........................................................... 46 Excluded Articles - Recommendation 2 ........................................................................... 47 Radiography and Serology - Quality ................................................................................ 51 Erythrocyte Sedimentation Rate Results .......................................................................... 59 C-Reactive Protein Results ............................................................................................... 62 ESR and CRP Results ....................................................................................................... 65 Radiography Results ......................................................................................................... 67 White Blood Cell Count Results....................................................................................... 70 Knee Aspiration Summary of Evidence ........................................................................... 75 Excluded Articles - Recommendation 3 ........................................................................... 76 Knee Aspiration - Quality................................................................................................. 77 Aspiration Culture - Knee................................................................................................. 78 Synovial Fluid White Blood Cell Count........................................................................... 79 Synovial Fluid Neutrophil Percentage .............................................................................. 82 Aspiration Summary of Evidence..................................................................................... 86 Excluded Articles - Recommendation 4 ........................................................................... 87 Aspiration - Quality .......................................................................................................... 90 Aspiration Culture - Hip ................................................................................................... 94 Synovial Fluid White Blood Cell Count........................................................................... 96 Synovial Fluid Neutrophil Percentage .............................................................................. 99 Excluded Articles - Recommendation 5 ......................................................................... 102 Repeat Aspiration - Quality ............................................................................................ 103 Repeat Aspiration Results............................................................................................... 103
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Excluded Article - Recommendation 7........................................................................... 106 Excluded Articles - Recommendation 8 ......................................................................... 108 Preoperative Antibiotic Therapy - Quality ..................................................................... 109 Preoperative Antibiotics and False-Negative Cultures ................................................... 109 Nuclear Imaging Summary of Evidence......................................................................... 113 Excluded Articles - Recommendation 9 ......................................................................... 114 Nuclear Imaging - Quality .............................................................................................. 123 Technetium-99m-labeled-Leukocyte Imaging................................................................ 133 Indium-111-labeled-Leukocyte Imaging ........................................................................ 135 Combined Leukocyte/Bone Imaging .............................................................................. 136 Combined Leukocyte/Bone Marrow Imaging ................................................................ 138 Gallium-67 Imaging........................................................................................................ 141 FDG-PET Imaging.......................................................................................................... 142 Technetium-99m Bone Imaging ..................................................................................... 144 Other Nuclear Imaging tests ........................................................................................... 145 CT and MRI Summary of Evidence ............................................................................... 146 Excluded Articles - Recommendation 10 ....................................................................... 147 Study Quality - CT.......................................................................................................... 148 CT Imaging ..................................................................................................................... 151 Gram Stain Summary of Evidence ................................................................................. 153 Excluded Articles - Recommendation 11 ....................................................................... 154 Gram Stain - Quality....................................................................................................... 155 Intraoperative Gram Stain Results .................................................................................. 157 Frozen Section Summary of Evidence............................................................................ 160 Excluded Articles - Recommendation 12 ....................................................................... 161 Frozen Section - Quality ................................................................................................. 163 Frozen Section Results.................................................................................................... 167 Summary of Evidence..................................................................................................... 171 Excluded Articles - Recommendation 13 ....................................................................... 173 Intraoperative Cultures - Quality .................................................................................... 176 Overall and number of cultures results ........................................................................... 179 Tissue vs. Swab vs. Fluid................................................................................................ 186 Excluded Articles - Recommendation14 ........................................................................ 190 Preoperative Antibiotic Therapy - Quality ..................................................................... 191 Preoperative Antibiotics and False-Negative Cultures ................................................... 192 Excluded Articles - Recommendation 15 ....................................................................... 194 Preoperative Antibiotics - Diagnostic Study Quality...................................................... 197 Preoperative Antibiotics - Randomized Trial Quality .................................................... 198 Preoperative Antibiotics - Joint Registry Quality........................................................... 198 Preoperative Antibiotics and False-Negative Cultures ................................................... 199 Relative Risk of Infection - Placebo vs. Preoperative Antibiotics.................................. 199 Registry Data – Hazard Ratio of Revision due to Infection ........................................... 200
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I. INTRODUCTION OVERVIEW This clinical practice guideline is based on a systematic review of published studies on the diagnosis of periprosthetic joint infections of the hip and knee. In addition to providing practice recommendations, this guideline also highlights gaps in the literature and areas that require future research.
This guideline is intended to be used by all appropriately trained surgeons and all qualified physicians evaluating patients for periprosthetic joint infections of the hip and knee. It is also intended to serve as an information resource for decision makers and developers of practice guidelines and recommendations.
GOALS AND RATIONALE The purpose of this clinical practice guideline is to help improve treatment based on the current best evidence. Current evidence-based practice (EBP) standards demand that physicians use the best available evidence in their clinical decision making. This clinical practice guideline was developed following systematic review of the available literature regarding the diagnosis of periprosthetic infections of the hip and the knee. The systematic review detailed herein was conducted between October 2008 and September 2009 and demonstrates where there is good evidence, where evidence is lacking, and what topics future research must target in order to improve the diagnosis of periprosthetic joint infections of the hip and knee. AAOS staff and the physician work group systematically reviewed the available literature and subsequently wrote the following recommendations based on a rigorous, standardized process.
Musculoskeletal care is provided in many different settings by many different providers. We created this guideline as an educational tool to guide qualified physicians through a series of diagnostic decisions in an effort to improve the quality and efficiency of care. This guideline should not be construed as including all proper methods of care or excluding methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding any specific procedure or treatment must be made in light of all circumstances presented by the patient and the needs and resources particular to the locality or institution. Further, the scope of the guideline does not include information on laboratory techniques or tissue sampling techniques beyond the evidence presented to support Recommendations 13 and 14. It is assumed that the well qualified physician will use his/her best judgement, considering the individual patient circumstances as well as the available resources, when addressing these issues.
INTENDED USERS This guideline is intended to be used by orthopaedic surgeons and all qualified physicians managing the diagnosis of periprosthetic joint infections of the hip and knee. Typically, orthopaedic surgeons will have completed medical training, a qualified residency in orthopaedic surgery, and some may have completed additional sub-specialty training. It is also intended to serve as an information resource for professional healthcare practitioners and developers of practice guidelines and recommendations.
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PATIENT POPULATION This document addresses the diagnosis of periprosthetic joint infections in patients who have undergone arthroplasty of the hip or knee This guideline is not intended for patients with superficial infections.
ETIOLOGY Periprosthetic joint infection can be caused by entry of organisms into the wound during surgery, hematogenous spread, recurrence of sepsis in a previously infected joint, or contiguous spread of infection from a local source.22
INCIDENCE The incidence of periprosthetic joint infection after primary hip or knee arthroplasty is over 2% among the Medicare population.56, 76 The incidence of periprosthetic infection is higher after revision arthroplasty than after primary arthroplasty in both joints.64, 82
BURDEN OF DISEASE Periprosthetic joint infection requires significant resources to diagnose and treat. Infection is a common cause of revision arthroplasty, with 15% of revision total hip arthroplasties and 25% of revision total knee arthroplasties being due to infection.12, 13
RISK FACTORS Risk factors identified and supported by the evidence include prior infection of the joint (knee), superficial surgical site infection (hip and knee), obesity (hip), extended operative time (>2.5 hours, hip and knee) and immunosuppression (knee). The work group also discusses additional risk factors based on consensus in Recommendation 1.
EMOTIONAL AND PHYSICAL IMPACT Periprosthetic joint infection is a serious complication of total joint replacement resulting in significant morbidity, including pain, loss of function, and potential removal of the prosthesis.
POTENTIAL BENEFITS AND HARMS There is the possibility of harm resulting from diagnostic tests, including the possibility of the introduction of bacteria into the joint during an aspiration and patient pain and/or discomfort while undergoing the procedure. Therefore, discussion of available diagnostic procedures applicable to the individual patient rely on mutual communication between the patient and physician, weighing the potential risks and benefits for that patient.
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II. METHODS This section describes the methods used to prepare this guideline and systematic review, including search strategies used to identify literature, criteria for selecting eligible articles, determining the strength of the evidence, data extraction, methods of statistical analysis, and the review and approval of the guideline. The methods used to perform this systematic review were employed to minimize bias in the selection and analysis of the available evidence.17, 69 This is vital to the development of reliable, transparent, and accurate clinical recommendations for diagnosing periprosthetic joint infections of the hip and knee.
The AAOS Diagnosis of Periprosthetic Joint Infections of the Hip and Knee physician work group prepared this guideline and systematic review with the assistance of the AAOS Clinical Practice Guidelines Unit in the Department of Research and Scientific Affairs at the AAOS (Appendix I).
To develop this guideline, the work group held an introductory meeting to develop the scope of the guideline on October 17 and 18, 2008. Upon completion of the systematic review, the work group met again on September 12 and 13, 2009 to write and vote on the final recommendations and rationales for each recommendation. The resulting draft guidelines were then peer-reviewed, subsequently sent for public commentary, and then sequentially approved by the AAOS Evidence Based Practice Committee, AAOS Guidelines and Technology Oversight Committee, AAOS Council on Research, Quality Assessment, and Technology, and the AAOS Board of Directors (see Appendix II for a description of the AAOS bodies involved in the approval process)
FORMULATING PRELIMINARY RECOMMENDATIONS The work group began work on this guideline by constructing a set of preliminary recommendations. These recommendations specify [what] should be done in [whom], [when], [where], and [how often or how long]. They function as questions for the systematic review, not as final recommendations or conclusions. Preliminary recommendations are almost always modified on the basis of the results of the systematic review. Once established, these a priori preliminary recommendations cannot be modified until the final work group meeting, they must be addressed by the systematic review, and the relevant review results must be presented in the final guideline.
STUDY SELECTION CRITERIA We developed a priori article inclusion criteria for our review. These criteria are our “rules of evidence” and articles that do not meet them are, for the purposes of this guideline, not evidence.
To be included in our systematic reviews (and hence, in this guideline) an article had to be a report of a study that:
• Addressed the value of tests for diagnosis of periprosthetic joint infection in the hip and knee.
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• Was written in English and published in or after 1970. For MRI, CT and PET only studies published after 2000 were included. For other nuclear imaging modalities, only studies published after 1975 were considered.
• Was not an abstract, unpublished study report, letter, case report, historical
article, editorial, tutorial, traditional review or commentary.
• Was published in the peer-reviewed literature.
• Was not a cadaveric, animal, or an in vitro study.
• Included 25 or more patients per study arm.
• Reported sufficient data to construct a 2 x 2 table.
• Was of the highest level of available evidence (best available evidence), assuming that there were two or more studies of that higher level. Hip and knee studies were considered separately. For example, if there were two Level II studies of the hip and two Level II studies of the knee that addressed the recommendation Level III and IV studies were not included.
• Was not evaluating a test in a cohort where the infected prosthesis had already
been removed (no more than 10% of cohort or data from these patients reported separately).
INCLUSION OF STUDIES WITH MIXED PATIENT POPULATIONS The work group specified a priori to the literature search that data would be stratified by joint but that mixed studies could be accepted and reported as such.
BEST AVAILABLE EVIDENCE When examining primary studies, we analyzed the best available evidence regardless of study design. We first considered the randomized controlled trials identified by the search strategy. In the absence of two or more RCTs, we sequentially searched for prospective controlled trials, prospective comparative studies, retrospective comparative studies, and prospective case-series studies. Only studies of the highest level of available evidence were included, assuming that there were 2 or more studies of that higher level. For example, if there were two Level II studies that addressed the recommendation, Level III and IV studies were not included.
LITERATURE SEARCHES We attempted to make our searches for articles comprehensive. Using comprehensive literature searches ensures that the evidence we considered for this guideline is not biased for (or against) any particular point of view.
We searched for articles published from January 1970 to August 10, 2009. Strategies for searching electronic databases were constructed by a Medical Librarian to identify
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relevant clinical studies. We searched four electronic databases; PubMed, EMBASE, CINAHL, and The Cochrane Central Register of Controlled Trials.
All searches of electronic databases were supplemented with manual screening of the bibliographies of all retrieved publications. We also searched the bibliographies of recent systematic reviews and other review articles for potentially relevant citations. Finally, work group members provided a list of potentially relevant studies that were not identified by our searches. All articles identified were subject to the study selection criteria listed above.
The study attrition diagram in Appendix III provides details about the inclusion and exclusion of the studies considered for this guideline. The search strategies used to identify these studies are provided in Appendix IV.
DATA EXTRACTION Data elements extracted from studies were defined in consultation with the physician work group. One analyst completed data extraction for all studies. The elements extracted are shown in Appendix V. Evidence tables were constructed to summarize the best evidence pertaining to each preliminary recommendation. Disagreements about the accuracy of extracted data were resolved by discussion and consulting the physician work group.
The work group specified a priori to the literature search that data would be stratified by joint but that mixed studies could be accepted and reported as such. When studies did not separate the data by joint, we could not report them separately. If a study with mixed joints reported the data for each joint we reported them as such. If a study reported mixed joints but had fewer than 25 patients per joint, only the mixed data was reported.
JUDGING THE QUALITY OF EVIDENCE Determining the quality of the included evidence is vitally important when preparing any evidence-based work product. Doing so conveys the amount of confidence one can have in any study’s results. One has more confidence in high quality evidence than in low quality evidence.
Assigning a level of evidence on the basis of study design plus other quality characteristics ties the levels of evidence we report more closely to quality than levels of evidence based only on study design. Because we tie quality to levels of evidence, we are able to characterize the confidence one can have in their results. Accordingly, we characterize the confidence one can have in Level I evidence as high, the confidence one can have in Level II and III evidence as moderate, and the confidence one can have in Level IV and V evidence as low. Similarly, throughout the guideline we refer to Level I evidence as reliable, Level II and III evidence as moderately reliable, and Level IV and V evidence as not reliable.
DIAGNOSTIC STUDIES We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) instrument to identify potential bias and assess variability and the quality of reporting in studies
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reporting the effectiveness of diagnostic techniques.109 Studies without any indication of bias are categorized as Level I studies. Studies with a known bias are downgraded to Level IV or Level III (for a bias for which we have or have not found published evidence that this bias affects diagnostic results, respectively). Studies with more than one bias are downgraded to Level V. Those studies that do not sufficiently report their methods for a potential bias are downgraded to Level II since we are unable to determine if the bias did or did not bias the results of the study (see Appendix VI).
Although the definition of a reference standard varies in the periprosthetic joint infection literature, intraoperative cultures have been used most often as the reference standard in interpreting the results of a diagnostic test, as indicated in Table 1. Accordingly, when possible we also used intraoperative cultures as a reference standard when computing measures of test performance.
Table 1. Reference Standard Used in Included Diagnostic Studies
Reference Standard (Infection defined as positive results on following test(s)) Number of Studies
Intraoperative cultures 18 Intraoperative cultures and histology 7
Histology 4 At least 2 of intraoperative cultures, purulence, and histology 4
Intraoperative cultures or histology 3
Open wound or sinus communicating with the joint OR systemic infection with pain in the hip and purulent fluid within the joint
OR positive result on at least 3 tests (ESR, CRP, joint aspiration, intraoperative frozen section, and intraoperative culture)
3
Histology or purulence or sinus tract communicating with the prosthesis 2
Intraoperative cultures or purulence 2 Aspiration or intraoperative cultures 1
At least 2 of intraoperative cultures, purulence, and histology; or 2 positive cultures 1
Histology and gross operative findings 1 Intraoperative cultures or histology or purulence 1
Intraoperative cultures or histology or deep abscess 1 Cultures or purulence or histology or sinus tract communicating
with the prosthesis 1
Correlation between intraoperative cultures and histology; the appearance of the tissue intraoperatively; and the clinical course 1
Intraoperative cultures and gross sepsis 1 At least 3 of CRP, ESR, aspiration culture, intraoperative
purulence, intraoperative culture 1
7
Reference Standard (Infection defined as positive results on following test(s)) Number of Studies
Abscess or sinus tract communicating with the joint space OR aspiration culture OR ≥2 intraoperative cultures OR 1 culture and
purulence or histology OR purulence and histology 1
PROGNOSTIC STUDIES In studies investigating the effect of a characteristic on the outcome of disease, we assessed quality using a two-step process. Any study that investigated a prospectively enrolled cohort of patients and utilized regression analysis was initially categorized as a Level I study. A study that used regression analysis in a retrospectively enrolled cohort of patients was categorized as a Level II study. A case-control study that used regression analysis was categorized as a Level III study. We next assessed the outcome (dependent variable) for each prognostic factor (independent variable) using a quality questionnaire and, when quality standards were not met, we downgraded the level of evidence by one level (Appendix VI).
DEFINING THE STRENGTH OF THE RECOMMENDATIONS Judging the quality of evidence is only a stepping stone towards arriving at the strength of a guideline recommendation. Unlike Levels of Evidence (which apply only to a given result at a given follow-up time in a given study) strength of recommendation takes into account the quality, quantity, and applicability of the available evidence. Strength also takes into account the trade-off between the benefits and harms of a treatment or diagnostic procedure, and the magnitude of a treatment’s effect.
Strength of recommendation expresses the degree of confidence one can have in a recommendation. As such, the strength expresses how possible it is that a recommendation will be overturned by future evidence. It is very difficult for future evidence to overturn a recommendation that is based on many high quality randomized controlled trials that show a large effect. It is much more likely that future evidence will overturn recommendations derived from a few small case series. Consequently, recommendations based on the former kind of evidence are given a high strength of recommendation and recommendations based on the latter kind of evidence are given a low strength.
To develop the strength of a recommendation, AAOS staff first assigned a preliminary strength for each recommendation that took only the quality and quantity of the available evidence into account (see Table 2). Work group members then modified the preliminary strength using the ‘Form for Assigning Strength of Recommendation (Interventions)’ shown in Appendix VII.
8
Table 2. Strength of recommendation descriptions
Strength
Overall Quality of Evidence Description of Evidence
Strong Good Level I evidence from more than one study with consistent findings for recommending for or against the intervention or diagnostic.
Moderate Fair
Level II or III evidence from more than one study with consistent findings, or Level I evidence from a single study for recommending for or against the intervention or diagnostic.
Weak Poor
Level IV or V evidence from more than one study with consistent findings, or Level II or III evidence from a single study for recommending for against the intervention or diagnostic.
Inconclusive None or Conflicting
The evidence is insufficient or conflicting and does not allow a recommendation for or against the intervention or diagnostic.
Consensus No Evidence
There is no supporting evidence. In the absence of reliable evidence, the work group is making a recommendation based on their clinical opinion considering the known harms and benefits associated with the treatment.
Each recommendation was written using language that accounts for the final strength of the recommendation. This language, and the corresponding strength, is shown in Table 3.
Table 3. AAOS Guideline Language
Guideline Language Strength of Recommendation
We recommend Strong We suggest Moderate
option Weak We are unable to recommend for or against Inconclusive
In the absence of reliable evidence, it is the opinion of this work group Consensus
CONSENSUS DEVELOPMENT The recommendations and their strength were voted on using a structured voting technique known as the nominal group technique.71 We present details of this technique in Appendix VIII. Voting on guideline recommendations was conducted using a secret ballot and workgroup members were blinded to the responses of other members. If disagreement between workgroup members was significant, there was further discussion
9
to see whether the disagreement(s) could be resolved. Up to three rounds of voting were held to attempt to resolve disagreements. If disagreements were not resolved following three voting rounds, no recommendation was adopted. Lack of agreement is a reason that the strength for some recommendations are labeled as “Inconclusive.”
STATISTICAL METHODS Likelihood ratios, sensitivity, specificity and 95% confidence intervals were used to determine the accuracy of diagnostic modalities based on two by two diagnostic contingency tables extracted from the included studies. When possible, prognostic factors were analyzed according to sensitivity and specificity as well.80 Likelihood ratios (LR) indicate the magnitude of the change in probability of disease due to a given test result. For example, a positive likelihood ratio of 10 indicates that a positive test result is 10 times more common in patients with disease than in patients without disease. Likelihood ratios are interpreted according to previously published values, as seen in Table 4.42 Likelihood ratios, sensitivity, specificity and 95% confidence intervals were calculated in STATA 10.0 (StataCorp LP, College Station, Texas). For meta-analysis of diagnostic tests, we used the bivariate random effects model.38, 39, 89 Meta-analyses were conducted only if there were at least four studies for a given diagnostic test. When a meta-analysis indicated between-study heterogeneity (I2 >50%) and thresholds for a positive test result varied between studies, we included the threshold as a covariate in the model to determine whether the heterogeneity could be explained by the variation in thresholds.
Table 4. Interpreting Likelihood Ratios
Positive Likelihood Ratio
Negative Likelihood Ratio Interpretation
>10 <0.1 Large and conclusive change in probability
5-10 0.1-0.2 Moderate change in probability
2-5 0.2-0.5 Small (but sometimes important) change in probability
1-2 0.5-1 Small (and rarely important) change in probability
PEER REVIEW The draft of this guideline and evidence report was peer reviewed by an expert, outside advisory panel that was nominated a priori by the physician work group prior to the development of the guideline. The physician members of the AAOS Guidelines and Technology Oversight Committee and the Evidence Based Practice Committee also provided peer review of the draft document. Peer review was accomplished using a structured peer review form (see Appendix IX). The draft guideline was sent to a total of 11 reviewers and 10 of these members returned reviews (see Appendix X) within the designated time frame. The disposition of all non-editorial peer review comments was documented and accompanied this guideline through the public commentary and the AAOS guideline approval process.
10
PUBLIC COMMENTARY After modifying the draft in response to peer review, the guideline was subjected to a thirty day period of “Public Commentary.” Commentators consist of members of the AAOS Board of Directors (BOD), members of the Council on Research, Quality Assessment, and Technology (CORQAT), members of the Board of Councilors (BOC), and members of the Board of Specialty Societies (BOS). Based on these bodies, up to 185 commentators had the opportunity to provide input into this guideline development process. Of these, 10 members of the BOC and 7 members of the BOS requested that we send them the document during the period of public comment. In addition, the Executive Directors of the Hip Society and the Orthopaedic Trauma Association each requested that we send additional drafts to two of their members. A member of the IDSA also requested the opportunity to provide comment on the draft and was forwarded all materials. One of these 22 members returned public comments. The single peer reviewer who did not return his comments during the time frame for peer review returned his comments during the period of public comment. We responded to both of these revewers’ comments. (see Appendix X).
THE AAOS GUIDELINE APPROVAL PROCESS Following public commentary, the draft was again modified by the AAOS Clinical Practice Guidelines Unit and work group members. This final guideline draft was approved by the AAOS Guidelines Oversight Committee, the AAOS Evidence Based Practice Committee, the AAOS Council on Research, Quality Assessment, and Technology, and the AAOS Board of Directors. Descriptions of these bodies are provided in Appendix II.
REVISION PLANS This guideline represents a cross-sectional view of current diagnosis and may become outdated as new evidence becomes available. The AAOS may revise this guideline in accordance with new evidence, changing practice, rapidly emerging treatment options, or new technology. This guideline will be updated or withdrawn in five years in accordance with the standards of the National Guideline Clearinghouse.
GUIDELINE DISSEMINATION PLANS The primary purpose of the present document is to provide interested readers with full documentation about not only our recommendations, but also about how we arrived at those recommendations. This document is also posted on the AAOS website at http://www.aaos.org/research/guidelines/guide.asp.
Shorter versions of the guideline are available in other venues. Publication of most guidelines is announced by an Academy press release, articles authored by the work group and AAOS staff and published in the Journal of the American Academy of Orthopaedic Surgeons and the Journal of Bone & Joint Surgery, and articles published in AAOS Now. Most guidelines are also distributed at the AAOS Annual Meeting in various venues such as on Academy Row and at Committee Scientific Exhibits.
11
Selected guidelines are disseminated by webinar, an Online Module for the Orthopeadic Knowledge Online website, Radio Media Tours, Media Briefings, and by distributing them at relevant Continuing Medical Education (CME) courses and at the AAOS Resource Center.
Other dissemination efforts outside of the AAOS will include submitting the guideline to the National Guideline Clearinghouse and distributing the guideline at other medical specialty societies’ meetings.
12
III. ALGORITHMS This section presents algorithms illustrating the recommendations of the guideline. Readers are encouraged to use them when reading the document.
Figure 1. Algorithm for Patients with Higher Probability of Hip or Knee Periprosthetic Joint Infection
Patient at higher probability of periprosthetic joint infection of the hip or knee being assessed for infection
ESR/ CRP: either positive?
Yes
Infection Unlikely
No
Nuclear imaging: positive?
Yes Infection Likely
No
2
1
12
Yes
No
Is surgery planned?
Yes
No
Frozen section AND/OR Intra-operative synovial fluid white blood cell count/differential: positive?
Yes6
43
9
8
7
Aspirate joint
No
YesRepeat aspiration: positive?
No
Both Cell count/differential AND Culture positive?
Either cell count/differential OR culture positive?
No
10
Yes
Infection Likely
5
11
Box 7: Perform repeat aspiration when there is a discrepancy between the probability of infection and the initial aspiration culture result
Box 9: Perform frozen section when the diagnosis has not been established at the time of surgery; synovial fluid white blood cell count and differential may also be obtained intra-operatively
Box 10: Nuclear imaging modalities: Labeled leukocyte imaging combined with bone or bone marrow imaging, FDG-PET imaging, Gallium imaging, or labeled leukocyte imaging
13
Figure 2. Algorithm for Patients with Lower Probability of Periprosthetic Knee Infection
Patient at lower probability of periprosthetic knee infection being assessed for infection
ESR/ CRP: either positive?
Infection Unlikely
No
Yes Yes Infection Likely
No
Is surgery planned?
Yes
No
Yes
Observe and Re-evaluate at 3 months
1
2
6
543
9
8
7
Aspirate joint
No
YesRepeat aspiration: positive?
No
Both Cell count/differential AND Culture positive?
Either cell count/differential OR culture positive?
No
10
11
Yes
Frozen section AND/OR Intra-operative synovial fluid white blood cell count/differential: positive?
Box 7: Perform repeat aspiration when there is a discrepancy between the probability of infection and the initial aspiration culture result
Box 9: Perform frozen section when the diagnosis has not been established at the time of surgery; synovial fluid white blood cell count and differential may also be obtained intra-operatively
14
Figure 3. Algorithm for Patients with Lower Probability of Periprosthetic Hip Infection with Planned Reoperation
Patient with planned reoperationat lower probability of periprosthetic hip infection being assessed for infection
ESR/ CRP: either positive?
Infection Unlikely
No
YesAspiration (pre-or intraoperative) AND/OR Frozen section: positive?
Yes Infection Likely
No
2
1
34
5
Box 3: Perform aspiration (pre- or intraoperative) in all patients including synovial fluid white blood cell count and differential; perform frozen section when the diagnosis has not been established at the time of surgery.
Figure 4. Algorithm for Patients with Lower Probability of Periprosthetic Hip Infection without Planned Reoperation
Aspirate joint
No
Yes Repeat aspiration: positive?
Yes
EitherESR or CRP positive?
Yes
No
No
Observe and Re-evaluate at 3 months
6
3 4 Both Cell count/differential AND Culture positive?
Either cell count/differential OR culture positive?
No
Yes8 9
Patient without planned reoperationat lower probability of periprosthetic hip infection being assessed for infection
1
ESR/ CRP: bothpositive?
2
Infection Unlikely
5
No
Yes7
Infection Likely
5
Box 9: Perform repeat aspiration when there is a discrepancy between the probability of infection and the initial aspiration culture result.
15
IV. RECOMMENDATIONS AND SUPPORTING DATA RECOMMENDATION 1 In the absence of reliable evidence about risk stratification of patients with a potential periprosthetic joint infection, it is the opinion of the work group that testing strategies be planned according to whether there is a higher or lower probability that a patient has a hip or knee periprosthetic infection.
Strength of Recommendation: Consensus
Rationale
The diagnosis of periprosthetic infection can be difficult to make and many tests are available to the clinician. Identification of a periprosthetic joint infection is important, as subsequent treatment is fundamentally different between cases that have a septic as opposed to an aseptic mode of failure. Specifically, a missed diagnosis of infection can lead to a high rate of subsequent failure if specific treatment for the infection is not considered. Pre-test probability is weighted heavily in the performance of any diagnostic test. Thus the identification of a patient as having a higher or lower probability of periprosthetic joint infection, when initiating the diagnostic evaluation is important. Further, a determination of how likely or unlikely a diagnosis is, based on patient symptoms, risk factors, co-morbidities and the physical examination is typically an integral part of the evaluation that guides clinical decisions. Based on these factors, despite the paucity of high-level data that supports the specific identification of such factors as they relate to the probability of periprosthetic joint infection, it is important to outline factors that can assist the clinician in identifying patients who have a higher probability of periprosthetic infection and thus warrant a more extensive diagnostic evaluation. Similarly, in patients who are deemed to have a lower probability of periprosthetic infection, a less vigorous evaluation may be warranted. Clinicians oftentimes make such assessments of probability routinely in their practice that leads to more prudent selections among testing modalities that are based on specific individual patient characteristics. This routine assessment is of limited cost and low morbidity to the patient. While the list compiled by the work group is not meant to be exhaustive, several risk factors were identified as supported by the available evidence as associated with the presence of periprosthetic joint infection as outlined below. Additional factors, not supported by the available literature, but unanimously agreed upon by the work group as additional risk factors to consider were also identified. Finally, several potential risk factors were identified that the literature did not support as being associated with a greater probability of periprosthetic infection including smoking status, obesity for patients who have undergone total knee arthroplasty, the use of drains, and immunocompromising states for patients who have undergone a total hip arthroplasty. Analysis of the literature revealed that prolonged post-operative wound drainage and
16
hematoma formation appeared to increase the likelihood of periprosthetic joint infection on univariate analysis; however, this was not confirmed by multivariate analysis.
The work group proposes the following table for stratifying patients into higher or lower probability of infection:
Higher Probability of Infection
One or more symptoms, AND at least one or more: 1) risk factor;* OR 2) physical exam finding; OR 3) early implant loosening/osteolysis (as detected by x-ray)
Lower Probability of Infection
Pain or joint stiffness only and none of the following: 1) risk factors;* OR 2) physical exam findings; OR 3) early implant loosening/osteolysis (as detected by x-ray)
*risk factor supported by evidence or expert opinion
Factors for Risk Stratification
Symptoms Risk Factors Supported by Evidence
Risk Factors Supported by Consensus
Physical Exam Findings
Other
1. Pain in the replaced joint
2. Stiffness in the replaced joint
1. Prior infection of the joint (knee)
2. Superficial surgical site infection (hip and knee)
3. Obesity (hip) 4. Extended operative
time (>2.5 hours, hip and knee)
5. Immunosuppression* (knee)
1. Any recent (<1yr.) bacteremia or candidemia
2. Metachronous prosthetic joint infection
3. Skin disorders (psoriasis, chronic cellulitis, lymphedema, chronic venous stasis, skin ulcers)
4. IV drug use 5. Recent (<3 yrs.)
MRSA infection or colonization
6. Active infection at other site
1. Warmth, effusion, redness, swelling
2. Sinus tract associated with the joint
1. Early (<5 yrs.) implant loosening or osteolysis (as detected by x-ray)
Factors not supported as a risk by evidence
1. Smoking 2. Obesity (knee) 3. Use of drains 4. Hematoma or use of anticoagulation (INR>2 or low molecular weight heparins)
17
5. Immunosuppression* (hip) *The systematic review considered the following states as indicative of immunosuppression: HIV, diabetes, hepatitis, chemotherapy or other suppressive medication such as antimonoclonal antibodies (medications specified in search: prednisone, infliximab, adalimumab, methotrexate, etanercept), autoimmune diseases (lupus, rheumatoid arthritis, ankylosing spondylitis, Reiter’s syndrome, psoriatic arthropathy), inflammatory arthritis, renal disease (chronic renal failure, dialysis), liver failure, malnourishment, sickle cell disease, hemophilia, solid organ transplant
Supporting Evidence
We included four Level II, two Level III, one Level IV and one Level V prognostic studies of hip patients (or mixed hip and knee patients with a majority of hip patients).6,
24, 41, 50, 61, 86, 98, 112 We included the lower level studies if they addressed a specific risk factor that had not been addressed by multiple studies of higher quality. The results of each study may not be directly comparable with the other studies because the study authors included different covariates in each model. The results are summarized in Table 5.
We included five Level II, two Level III and one Level IV prognostic studies of knee patients (or mixed hip and knee patients with a majority of knee patients). 1, 10, 25, 41, 43, 79,
92, 112 We included the lower level studies if they addressed a specific risk factor that had not been addressed by multiple studies of higher quality. The results of each study may not be directly comparable with the other studies because the study authors included different covariates in each model. The results are summarized in Table 6.
We also included thirteen randomized trials investigating the use of drains and one randomized trial investigating the use of anticoagulation.7, 16, 18, 29, 36, 40, 44, 45, 51, 52, 74, 77, 91,
107 The anticoagulation trial and ten of the drain trials had no periprosthetic infections in either arm. None of the other three drain trials found a statistically significant difference in infection rates between groups (see Table 20).
We included seven diagnostic studies for this recommendation. Two studies of other diagnostic modalities reported data on patients with pain;63, 106 two reported on warmth, redness, or swelling;63, 102 one reported on sinus tracts;63 and one reported on early implant failure.57 Two prevalence studies addressed metachronous periprosthetic joint infection (PJI),62, 72 and one prevalence study addressed recent septicemia.70 With the exception of the study which reported on early implant failure, the data from these studies are of low quality and therefore not reliable. The results are summarized in Table 7.
There were no included studies that addressed stiffness, prior MRSA or VRE infection, skin disorders, IV drug use, or planned revision surgery. We did not include studies on the prevalence of infection after all revision surgeries because these studies included patients with revision surgeries planned due to infection. The inclusion of these patients limits the applicability of these studies.
18
SUMMARY OF EVIDENCE Table 5. Results of Prognostic Studies - Hip
Author N Level of Evidence W
ound
Dra
inag
e or
H
emat
oma
or A
ntic
oagu
latio
n
Exte
nded
Ope
rativ
e Ti
me
Prio
r Inf
ectio
n of
the
Join
t
Imm
unos
uppr
essi
on
Obe
sity
Smok
ing
Oth
er S
SI
Use
of D
rain
s
Oth
er V
aria
ble(
s)
( e.
g., A
ge, S
ex, e
tc.)
Huotari 5614 II x ● x ○ x x x x I
Lubbeke 2495 II x x x x ● x x x I
Smabrekke 28020 II x ● x x x x x x I
Wymenga 2547 II ○ ○ x ○ x x ● x I
Dowsey 1207 III x x x I ● x x x x
Pulido 9245 III ○ ○ x ○ ● x ○ x I
Berbari 924 IV ○ * ○ ○ ○ x ● ○ I
Khan 1767 V x x x x x ○ x x x * ● = statistically significant, ○ = not significant, x = not studied, I = included as covariate or matching variable, but data not reported * = extended operative time was studied but the results were reported by the authors as part of a composite measure.
19
Table 6. Results of Prognostic Studies - Knee
Author N Level of Evidence W
ound
Dra
inag
e or
H
emat
oma
or A
ntic
oagu
latio
n
Exte
nded
Ope
rativ
e Ti
me
Prio
r Inf
ectio
n of
the
Join
t
Imm
unos
uppr
essi
on
Obe
sity
Smok
ing
Oth
er S
SI
Use
of D
rain
s
Oth
er V
aria
ble(
s)
( e.
g., A
ge, S
ex, e
tc.)
Amin 82 II x x x x ○ x x x I
Bordini 9735 II x x x x ○ x x x I
Huotari 4217 II x ● x ○ x x x x I
Jamsen
primary: 38338 revision: 2061
II x ° x ● ● x x x ° x I
Wymenga 345 II ○ ○ x ○ x x ● x I
Dowsey 1214 III x x x ● ● ○ x Z I
Saleh 97 III x x x x x x ● x I
Peersman 349 IV x x x ● ● ● x x I * ● = statistically significant, ○ = not significant, x = not studied, I = included as covariate or matching variable, but data not reported, Z = statistically significant protection
° Jamsen study grouped postoperative complications together, including wound hematoma and wound infections; a postoperative complication was a statistically significant risk factor
20
Table 7. Summary of Evidence – Diagnostic or Prevalence Studies
Clinical Indication
Level of Evidence
Prevalence of Infection among Patients with Indication
Positive Likelihood Ratio (95% CI)
Negative Likelihood Ratio (95% CI)
Early Implant Loosening I 24% 2.1
(1.36, 3.25) 0.53 (0.29, 0.96)
Pain IV-V 15-51% 1 – 1.18 - Warmth, swelling IV 71-100% 2.3 – 2.88 0.82 – 0.92
Sinus Tract IV 100% - 0.86 (0.77, 0.96)
Recent Septicemia V 45% hematogenous n/a
Metachronous PJI V 15-19% n/a
*Prevalence based on two studies if range presented, one if a single number
21
EXCLUDED ARTICLES Table 8. Excluded Articles - Recommendation 1
Author Title Reason for Exclusion Abudu, et al.
2002 The outcome of perioperative wound infection after total hip and knee arthroplasty Not best available evidence
Abuzakuk, et al. 2007
Autotransfusion drains in total knee replacement. Are they alternatives to homologous transfusion?
Does not address recommendation
Ahlberg, et al. 1981 Secondary operations after knee joint replacement Not best available
evidence Ainscow, et al.
1984 The risk of haematogenous infection in total joint replacements Not best available evidence
Amin, et al. 2006
Does obesity influence the clinical outcome at five years following total knee replacement for osteoarthritis?
Not best available evidence
Amin, et al. 2008
A prospective randomised controlled trial of autologous retransfusion in total knee replacement
Does not address recommendation
Andrew, et al. 2008 Obesity in total hip replacement Not best available
evidence Andrews, et al.
1981 Deep infection after total hip replacement Not best available evidence
Asensio, et al. 2005
Preoperative low molecular weight heparin as venous thromboembolism prophylaxis in patients at risk for prosthetic infection after knee arthroplasty
Not best available evidence
Bahebeck, et al. 2009
Implant orthopaedic surgery in HIV asymptomatic carriers: Management and early outcome
<25 arthroplasty patients per group
Bedi, et al. 1997 An audit of early hospital readmission after primary knee joint replacement <25 patients/arm
Bengtson, et al. 1991 The infected knee arthroplasty. A 6-year follow-up of 357 cases Not best available
evidence
22
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Beyer, et al. 1991 Primary total knee arthroplasty in patients with psoriasis Not best available
evidence Bohm, et al.
1998 Is there a future for hinged prostheses in primary total knee arthroplasty? A 20-year
survivorship analysis of the Blauth prosthesis Not best available
evidence Bong, et al.
2004 Stiffness after total knee arthroplasty Narrative review, bibliography screened
Bongartz, et al. 2008
Incidence and risk factors of prosthetic joint infection after total hip or knee replacement in patients with rheumatoid arthritis
Not best available evidence
Bosch, et al. 1980 An analysis of 119 loosenings in total hip endoprostheses Insufficient Data
Bourne, et al. 1994
Pain in the thigh following total hip replacement with a porous-coated anatomic prosthesis for osteoarthrosis. A five-year follow-up study
Does not address recommendation
Brander, et al. 2003 Predicting Total Knee Replacement Pain: A Prospective, Observational Study Does not address
recommendation Byrne, et al.
2007 Outcome following deep wound contamination in cemented arthroplasty Not best available evidence
Cameron, 1993 Knee effusion after total knee replacement Narrative review,
bibliography screened Carlsson,
1981 351 total hip replacements according to Charnley. A review of complications and function Not best available evidence
Chan, et al. 1996 Obesity and quality of life after primary hip arthroplasty Does not address
recommendation Charnley,
1972 Postoperative infection after total hip replacement with special reference to air
contamination in the operating room Not best available
evidence
23
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Cherney, et al. 1983 Total hip replacement in the previously septic hip No comparison group
Chesney, et al. 2008 Infection after knee arthroplasty a prospective study of 1509 cases Not best available
evidence Choong, et al.
2007 Risk factors associated with acute hip prosthetic joint infections and outcome of treatment
with a rifampinbased regimen Not best available
evidence Clements, et al.
2007 Risk stratification for surgical site infections in Australia: evaluation of the US National
Nosocomial Infection Surveillance risk index Not relevant - not
specific to pji Dennis,
2004 Evaluation of painful total knee arthroplasty Narrative review, bibliography screened
Deshmukh, et al. 2002 Does body weight influence outcome after total knee arthroplasty? A 1-year analysis Not relevant - not
specific to pji Dowsey, et al.
2008 Early outcomes and complications following joint arthroplasty in obese patients: a review
of the published reports Systematic review,
bibliography screened Dowsey, et al.
2008 Obesity is a major risk factor for prosthetic infection after primary hip arthroplasty Not best available evidence
Drancourt, et al. 1997 Psoriasis is a risk factor for hip-prosthesis infection <25 patients
Drinkwater, et al. 1995 Optimal timing of wound drain removal following total joint arthroplasty Does not address
recommendation Duffy, et al.
2005 Evaluation of patients with pain following total hip replacement Narrative review, bibliography screened
Duffy, et al. 2006 Evaluation of patients with pain following total hip replacement Narrative review,
bibliography screened
24
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Ehrenkranz, 1981
Surgical wound infection occurrence in clean operations; risk stratification for interhospital comparisons
Not relevant - not specific to pji
Espehaug, et al. 1997
Patient-related risk factors for early revision of total hip replacements. A population register-based case-control study of 674 revised hips
Not best available evidence
Fan, et al. 2008 Infection in primary total knee replacement Insufficient Data
Fernandez, et al. 1997 Risk infection factors in the total hip replacement
Not relevant - no relevant risk factors
investigated Fitzgerald, et al.
1977 Deep wound sepsis following total hip arthroplasty Not best available evidence
Foldes, et al. 1992 Ultrasonography after hip arthroplasty <25 patients/arm
Foran, et al. 2004 The outcome of total knee arthroplasty in obese patients Not best available
evidence Foran, et al.
2004 Total knee arthroplasty in obese patients: a comparison with a matched control group Not best available evidence
Gaine, et al. 2000 Wound infection in hip and knee arthroplasty Not relevant - not
specific to pji Galat, et al.
2008 Early return to surgery for evacuation of a postoperative hematoma after primary total
knee arthroplasty Not best available
evidence Galat, et al.
2009 Surgical treatment of early wound complications following primary total knee arthroplasty Not relevant - not specific to pji
Garibaldi, et al. 1991 Risk factors for postoperative infection Not relevant - not
specific to pji
25
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Gonzalez, et al. 2004 The failed total knee arthroplasty: evaluation and etiology Narrative review,
bibliography screened Gordon, et al.
1990 Risk factors for wound infections after total knee arthroplasty Not best available evidence
Grant, et al. 2008
Two-year outcomes in primary THA in obese male veterans administration medical center patients
Not relevant - not specific to pji
Greene, et al. 1991
Preoperative nutritional status of total joint patients. Relationship to postoperative wound complications
Not best available evidence
Hamilton, et al. 2008 Deep infection in total hip arthroplasty Not best available
evidence Horberg, et al.
2006 Surgical outcomes in human immunodeficiency virus-infected patients in the era of highly
active antiretroviral therapy Not relevant - not
specific to pji Horne, et al.
2008 The influence of steroid injections on the incidence of infection following total knee
arthroplasty Not relevant - not
specific to pji Ibrahim, et al.
2005 No influence of body mass index on early outcome following total hip arthroplasty Not best available evidence
Ilstrup, et al. 1973 Factors influencing the results in 2,012 total hip arthroplasties Insufficient Data
Jaberi, et al. 2008
Procrastination of wound drainage and malnutrition affect the outcome of joint arthroplasty
Does not address recommendation
Jacobsen, et al. 1980
Prophylactic coverage of dental patients with artificial joints: a retrospective analysis of thirty-three infections in hip prostheses
Does not address recommendation
Jacobson, et al. 1986 Dental treatment and late prosthetic joint infections Does not address
recommendation
26
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Jain, et al. 2005 Comorbidities increase complication rates in patients having arthroplasty Not relevant - not
specific to pji James, et al.
1982 Total hip revision arthroplasty: does sepsis influence the results? Narrative review, bibliography screened
Jensen, et al. 1982 Nutrition in orthopaedic surgery Insufficient Data
Jerry, et al. 1988 Old sepsis prior to total knee arthroplasty No comparison group
Jibodh, et al. 2004 In-hospital outcome and resource use in hip arthroplasty: Influence of body mass Not best available
evidence Jiganti, et al.
1993 A comparison of the perioperative morbidity in total joint arthroplasty in the obese and
nonobese patient Not best available
evidence Johnson, et al.
1986 The outcome of infected arthroplasty of the knee Not best available evidence
Jones, et al. 1979 GUEPAR knee arthroplasty results and late complications Not best available
evidence Jupiter, et al.
1981 Total hip arthroplasty in the treatment of adult hips with current or quiescent sepsis No comparison group
Kaspar, et al. 2005 Infection in hip arthroplasty after previous injection of steroid Not best available
evidence Kessler, et al.
2003 Influence of operation duration on perioperative morbidity in revision total hip arthroplasty Not relevant - not specific to pji
Khuri, et al. 1995
The National Veterans Administration Surgical Risk Study: risk adjustment for the comparative assessment of the quality of surgical care
Not relevant - not specific to pji
27
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Kim, 1991 Total arthroplasty of the hip after childhood sepsis No comparison group
Kim, et al. 2003 Total hip arthroplasty in adult patients who had childhood infection of the hip No comparison group
Kim, et al. 2006 Clinical impact of obesity on stability following revision total hip arthroplasty Insufficient Data
Kim, et al. 2004
Stiffness after total knee arthroplasty. Prevalence of the complication and outcomes of revision
Does not address recommendation
Knobben, et al. 2006 Intraoperative contamination influences wound discharge and periprosthetic infection Not best available
evidence Knutson, et al.
1986 Survival of knee arthroplasties. A nation-wide multicentre investigation of 8000 cases Not best available evidence
Lai, et al. 2007
Presence of medical comorbidities in patients with infected primary hip or knee arthroplasties
Not best available evidence
Lawton, et al. 1999
The use of heparin in patients in whom a pulmonary embolism is suspected after total hip arthroplasty
Not best available evidence
Lazzarini, et al. 2001 Postoperative infections following total knee replacement: an epidemiological study Not best available
evidence Leong, et al.
2006 Duration of operation as a risk factor for surgical site infection: comparison of English and
US data Not relevant - not
specific to pji Lonner, et al.
1999 Prodromes of failure in total knee arthroplasty Does not address recommendation
Lubbeke, et al. 2008 Outcomes of obese and nonobese patients undergoing revision total hip arthroplasty Not best available
evidence
28
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Mac, et al. 1993
Comparison of autoreinfusion and standard drainage systems in total joint arthroplasty patients
Does not address recommendation
Malinzak, et al. 2009
Morbidly Obese, Diabetic, Younger, and Unilateral Joint Arthroplasty Patients Have Elevated Total Joint Arthroplasty Infection Rates
Not best available evidence
Mandalia, et al. 2008 Evaluation of patients with a painful total knee replacement Narrative review,
bibliography screened Marchant, et al.
2009 The impact of glycemic control and diabetes mellitus on perioperative outcomes after total
joint arthroplasty Not relevant - not
specific to pji McDonald, et al.
1989 Two-stage reconstruction of a total hip arthroplasty because of infection No comparison group
McLaughlin, et al. 2006 The outcome of total hip replacement in obese and non-obese patients at 10- to 18-years Not best available
evidence Meding, et al.
2003 Total Knee Replacement in Patients with Diabetes Mellitus Not best available evidence
Menon, et al. 1983 Charnley low-friction arthroplasty in patients with psoriasis Not best available
evidence Minnema, et al.
2004 Risk factors for surgical-site infection following primary total knee arthroplasty Not relevant - not specific to pji
Mont, et al. 1996
Cementless total knee arthroplasty in obese patients: A comparison with a matched control group
Not relevant - not specific to pji
Moran, et al. 2005 Does body mass index affect the early outcome of primary total hip arthroplasty? Insufficient Data
Muilwijk, et al. 2006
Random effect modelling of patient-related risk factors in orthopaedic procedures: results from the Dutch nosocomial infection surveillance network 'PREZIES'
Not best available evidence
29
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Mulhall, et al. 2006 Current etiologies and modes of failure in total knee arthroplasty revision Not best available
evidence Mulier, et al.
1973 Postoperative infection in total hip replacement Not best available evidence
Murphy, et al. 1993 The effectiveness of suction drainage in total hip arthroplasty <25 patients/arm
Murray, 1973 Results in patients with total hip replacement arthroplasty Insufficient Data
Namba, et al. 2005 Obesity and perioperative morbidity in total hip and total knee arthroplasty patients Not best available
evidence Nelson, et al.
2005 Stiffness after total knee arthroplasty. Surgical technique Does not address recommendation
Niki, et al. 2006
Phenotypic characteristics of joint fluid cells from patients with continuous joint effusion after total knee arthroplasty
Not best available evidence
Niki, et al. 2007 Five types of inflammatory arthritis following total knee arthroplasty Not best available
evidence Ong, et al.
2009 Prosthetic Joint Infection Risk After Total Hip Arthroplasty in the Medicare Population Not best available evidence
Papagelopoulos, et al. 1996
Long term outcome and survivorship analysis of primary total knee arthroplasty in patients with diabetes mellitus
Not best available evidence
Parker, et al. 2004 Closed suction drainage for hip and knee arthroplasty: a meta-analysis Systematic review,
bibliography screened Parker, et al.
2007 Closed suction surgical wound drainage after orthopaedic surgery Systematic review, bibliography screened
30
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Parratte, et al. 2008 The Stiff Total Knee Arthroplasty: A Contemporary Approach Narrative review,
bibliography screened Partanen, et al.
2006 Impact of deep infection after hip fracture surgery on function and mortality Not relevant - not specific to pji
Partio, et al. 1994 Survival of the Townley knee. 360 cases with 8 (0.1-15) years' follow-up Not best available
evidence Parvizi, et al.
2007 Does 'excessive' anticoagulation predispose to periprosthetic infection? Not best available evidence
Parvizi, et al. 2006 Management of stiffness following total knee arthroplasty Does not address
recommendation Pasticci, et al.
2007 Prosthetic infections following total knee arthroplasty: A six-year prospective study (1997-
2002) Does not address recommendation
Patel, et al. 2007
Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty
Not relevant - not specific to pji
Peersman, et al. 2006
Prolonged operative time correlates with increased infection rate after total knee arthroplasty
Not best available evidence
Peersman, et al. 2008
ASA physical status classification is not a good predictor of infection for total knee replacement and is influenced by the presence of comorbidities Duplicate data
Perka, et al. 2000
The influence of obesity on perioperative morbidity and mortality in revision total hip arthroplasty
Not best available evidence
Petty, et al. 1975 Infection after total knee arthroplasty Not best available
evidence Pons, et al.
1999 Infected total hip arthroplasty--the value of intraoperative histology Composite measure
31
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Poss, et al. 1984
Factors influencing the incidence and outcome of infection following total joint arthroplasty
Not best available evidence
Pritchett, et al. 1991 Knee replacement in morbidly obese women Not best available
evidence Ragni, et al.
1995 Postoperative infection following orthopaedic surgery in human immunodeficiency virus-
infected hemophiliacs with CD4 counts (less-than or equal to) 200/mm(3) Not best available
evidence Ridgeway, et al.
2005 Infection of the surgical site after arthroplasty of the hip Not relevant - not specific to pji
Robbins, et al. 2002
Evaluation of pain in patients with apparently solidly fixed total hip arthroplasty components
Narrative review, bibliography screened
Rodriguez-Merchan, 2007 Total knee replacement in haemophilic arthropathy Not best available
evidence Sachs, et al.
2003 Does anticoagulation do more harm than good?: A comparison of patients treated without
prophylaxis and patients treated with low-dose warfarin after total knee arthroplasty Not best available
evidence Sadr, et al.
2006 The impact of tobacco use and body mass index on the length of stay in hospital and the
risk of post-operative complications among patients undergoing total hip replacement Not relevant - not
specific to pji Schmalzried, et al.
1992 Etiology of deep sepsis in total hip arthroplasty. The significance of hematogenous and
recurrent infections Not best available
evidence Scuderi,
2005 The stiff total knee arthroplasty: Causality and solution Narrative review, bibliography screened
Serna, et al. 1994 Total knee arthroplasty in diabetic patients. Comparison to a matched control group Not best available
evidence Shih, et al.
2004 Total knee arthroplasty in patients with liver cirrhosis Not best available evidence
32
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Shrader, et al. 2003 Primary TKA in Patients with Lymphedema Not best available
evidence Silva, et al.
2005 Long-term results of primary total knee replacement in patients with hemophilia Not best available evidence
Solomon, et al. 2006
Development of a preliminary index that predicts adverse events after total knee replacement
Does not address recommendation
Spicer, et al. 2001 Body mass index as a predictor of outcome in total knee replacement Not best available
evidence Stern, et al.
1989 Total knee arthroplasty in patients with psoriasis <25 patients
Stern, et al. 1990 Total knee arthroplasty in obese patients Does not address
recommendation Surin, et al.
1983 Infection after total hip replacement. With special reference to a discharge from the wound Not best available evidence
Tannenbaum, et al. 1997 Infection around joint replacements in patients who have a renal or liver transplantation <25 patients
van Loon, et al. 2000 The kinematic total knee arthroplasty. A 10- to 15-year follow-up and survival analysis Not best available
evidence Vannini, et al.
1984 Diabetes as pro-infective risk factor in total hip replacement Not best available evidence
Varley, et al. 1995
Wound drains in proximal femoral fracture surgery: a randomized prospective trial of 177 patients
Not relevant - not specific to pji
Waldman, et al. 1997 Total knee arthroplasty infections associated with dental procedures Does not address
recommendation
33
Table 8. Excluded Articles (Continued) Author Title Reason for Exclusion
Wang, 1984 Clinical observations on Blauth's total endoprosthesis of the knee joint Insufficient Data
Weiss, et al. 1993 Persistent wound drainage after primary total knee arthroplasty <25 patients
Went, et al. 1995 Recurrence of infection after revision of infected hip arthroplasties No comparison group
White, et al. 1990 Early morbidity after total hip replacement: rheumatoid arthritis versus osteoarthritis Not relevant - not
specific to pji Wilson, et al.
1990 Infection as a complication of total knee-replacement arthroplasty. Risk factors and
treatment in sixty-seven cases Not best available
evidence Winiarsky, et al.
1998 Total knee arthroplasty in morbidly obese patients Not best available evidence
Yasunaga, et al. 2009
Analysis of factors affecting operating time, postoperative complications, and length of stay for total knee arthroplasty: Nationwide web-based survey
Not relevant - not specific to pji
Yasunaga, et al. 2009
High-volume surgeons in regard to reductions in operating time, blood loss, and postoperative complications for total hip arthroplasty
Not relevant - not specific to pji
Yong, et al. 2001 Risk factors for infection in total hip replacement surgery at Hospital Kuala Lumpur Not relevant - not
specific to pji Zamora-Navas, et al.
1999 Closed suction drainage after knee arthroplasty. A prospective study of the effectiveness of
the operation and of bacterial contamination <25 patients per group
34
STUDY QUALITY Table 9. Quality of Diagnostic Studies
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Lachiewicz 142 Implant in situ <5 years I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Teller 161 Local signs (erythema,
warmth, edema) IV ○ ● ● ● ● ● ● ● ● ● ? ● ● ●
Magnuson 98 Warmth IV ○ ● ● ● ● ● ● ● ? ● ? ● ● ●
Magnuson 98 Swelling or erythema IV ○ ● ● ● ● ● ● ● ? ● ? ● ● ●
Magnuson 98 Sinus tract IV ○ ● ● ● ● ● ● ● ? ● ? ● ● ● Magnuson 98 Pain IV ○ ● ● ● ● ● ● ● ? ● ? ● ● ● Virolainen 68 Pain V ? ○ ● ● ● ● ● ● ● ? ● ● ● ●
35
Table 10. Quality of Prognostic Studies
● = Yes ○ = No
? = Not Reported n/a = Not Applicable
Author Risk Factor N Joint Level of Evidence
pros
pect
ive
varia
bles
iden
tifie
d in
Met
hods
all v
aria
bles
dis
cuss
ed in
resu
lts
suff
icie
nt p
atie
nts p
er v
aria
ble
(10)
suff
icie
nt e
vent
s per
var
iabl
e (1
0)
unam
bigu
ous c
odin
g
colli
near
ity te
sted
or n
ot re
leva
nt
fittin
g pr
oced
ure
stat
ed
good
ness
of f
it st
ats r
epor
ted
mod
el v
alid
atio
n
Wymenga Hematoma 2547 Hip II ● ○ ? ● ○ ● ○ ● ○ ○
Wymenga Hematoma 345 Knee II ● ○ ? ● ○ ● ○ ● ○ ○
Pulido Hematoma/ wound drainage 9245 Mixed III ○ ● ● ● ○ ● ○ ● ○ ○
Smabrekke Operating time 28020 Hip II ● ● ○ ● ● ● ● ● ○ ○
Huotari Operating time 5614 Hip II ● ● ● ● ○ ● ○ ● ○ ○
Huotari Operating time 4217 Knee II ● ● ● ● ○ ● ○ ● ○ ○
Wymenga Operating time 2547 Hip II ● ○ ? ● ○ ● ○ ● ○ ○
Wymenga Operating time 345 Knee II ● ○ ? ● ○ ● ○ ● ○ ○
Jamsen Prior infection 819 Knee II Multiple Regression of Joint Registry Data (see below for registry quality)
Berbari Prior joint infection 924 Mixed IV (case-control) ○ ○ ● ● ● ● ● ● ○ ●
Huotari Rheumatoid arthritis 5614 Hip II ● ● ● ● ○ ● ○ ● ○ ○
36
Table 10. Quality of Prognostic Studies (Continued)
● = Yes ○ = No
? = Not Reported n/a = Not Applicable
Author Risk Factor N Joint Level of Evidence
pros
pect
ive
varia
bles
iden
tifie
d in
Met
hods
all v
aria
bles
dis
cuss
ed in
resu
lts
suff
icie
nt p
atie
nts p
er v
aria
ble
(10)
suff
icie
nt e
vent
s per
var
iabl
e (1
0)
unam
bigu
ous c
odin
g
colli
near
ity te
sted
or n
ot re
leva
nt
fittin
g pr
oced
ure
stat
ed
good
ness
of f
it st
ats r
epor
ted
mod
el v
alid
atio
n
Huotari Rheumatoid arthritis 4217 Knee II ● ● ● ● ○ ● ○ ● ○ ○
Wymenga Diabetes 2547 Hip II ● ○ ? ● ○ ● ○ ● ○ ○
Wymenga Use of steroids 2547 Hip II ● ○ ? ● ○ ● ○ ● ○ ○
Wymenga Diabetes 345 Knee II ● ○ ? ● ○ ● ○ ● ○ ○
Wymenga Use of steroids 345 Knee II ● ○ ? ● ○ ● ○ ● ○ ○
Jamsen Rheumatoid arthritis primary: 38338revision: 2061 Knee II Multiple Regression of Joint Registry Data
(see below for registry quality)
Lubbeke Obesity (BMI ≥30) 2495 Hip II ● ● ● ● ○ ● ● ● ○ ○
Dowsey Obesity 1207 Hip III ○ ● ● ● ● ● ● ● ○ ○
Amin Obesity 82 Knee II ● ● ● n/a ○ ● ● ● ○ ○
Bordini Obesity 9735 Knee II Multiple Regression of Joint Registry Data (see below for registry quality)
37
Table 10. Quality of Prognostic Studies (Continued)
● = Yes ○ = No
? = Not Reported n/a = Not Applicable
Author Risk Factor N Joint Level of Evidence
pros
pect
ive
varia
bles
iden
tifie
d in
Met
hods
all v
aria
bles
dis
cuss
ed in
resu
lts
suff
icie
nt p
atie
nts p
er v
aria
ble
(10)
suff
icie
nt e
vent
s per
var
iabl
e (1
0)
unam
bigu
ous c
odin
g
colli
near
ity te
sted
or n
ot re
leva
nt
fittin
g pr
oced
ure
stat
ed
good
ness
of f
it st
ats r
epor
ted
mod
el v
alid
atio
n
Pulido Obesity (BMI >40) 9245 Mixed III ○ ● ● ● ○ ● ○ ● ○ ○
Dowsey Smoking 1214 Knee III ○ ● ● ● ○ ● ○ ○ ○ ○
Peersman Smoking 349 Knee IV (case-contol) ○ ○ ○ ? ? ● ● ● ● ○
Khan Smoking 1767 Hip V (univariate) ● n/a n/a n/a n/a n/a n/a n/a n/a n/a
Wymenga Wound infection 2547 Hip II ● ○ ? ● ○ ● ○ ● ○ ○
Wymenga Wound infection 345 Knee II ● ○ ? ● ○ ● ○ ● ○ ○
Pulido Wound infection 9245 Mixed III ○ ● ● ● ○ ● ○ ● ○ ○
Saleh Surgical site infection 97 Mixed III ○ ● ● n/a ○ ● ● ● ○ ○
38
Table 11. Risk Factors - Quality of Joint Registries
● = Yes ○ = No ? = Not Reported
Author Risk Factor N Joint Level of Evidence
Man
dato
ry D
ata
Su
bmis
sion
Popu
latio
n-B
ased
Reg
istry
Val
idat
ed D
ata
>90%
of p
atie
nts c
aptu
red
Stat
istic
al Q
ualit
y C
ontro
l M
easu
res P
erfo
rmed
Ensu
res c
orre
ct d
iagn
osis
Jamsen Prior infection
(reason for revision was infection)
819 Knee II ● ● ○ ● ? ●
Jamsen Rheumatoid arthritis primary: 38338revision: 2061 Knee II ● ● ○ ● ? ●
Bordini Obesity 9735 Knee II ● ● ? ● ? ●
39
Table 12. Risk Factors - Quality of Randomized Trials
● = Yes ○ = No ? = Not Reported
Author Treatment Control N Level of Evidence St
ocha
stic
Ran
dom
izat
ion
Allo
catio
n C
once
alm
ent
Subj
ects
Blin
d
Ass
esso
r Blin
d
>80%
Fol
low
-Up
Sim
ilar i
n O
utco
me
at
Bas
elin
e
Confalonieri Drain No Drain 78 II ? ● ○ ○ ● ● Crevoisier Drain No Drain 98 II ? ● ○ ○ ● ●
Esler Drain No Drain 100 II ? ● ○ ○ ● ● Gonzalez Della
Valle Drain No Drain 104 II ● ○ ○ ○ ● ● Holt Drain No Drain 137 II ○ ○ ○ ○ ● ●
Jenny Drain No Drain 60 II ? ● ○ ○ ● ● Johansson Drain No Drain 105 II ? ● ○ ○ ● ●
Kim Drain No Drain 138 II ● ● ○ ○ ● ● Kim Drain No Drain 96 II ● ● ○ ○ ● ●
Niskanen Drain No Drain 97 II ? ○ ○ ○ ● ● Ovadia Drain No Drain 88 II ? ● ○ ○ ● ● Ritter Drain No Drain 415 II ? ○ ○ ○ ● ●
Walmsley Drain No Drain 577 II ? ● ○ ○ ● ●
Bergqvist Thromboprophylaxis No Thromboprophylaxis 161 II ? ○ ○ ○ ● ●
40
STUDY RESULTS Table 13. Pain as a Predictor of Periprosthetic Infection
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
IV Magnuson 98 Pain Intraoperative
Cultures or Histology
Mixed 1 - 1 (0.93, 1)
0 (0, .07) 50 48 0 0
V Virolainen 68 Pain Intraoperative Cultures Mixed 1.18
(1.06, 1.31) 0 1 (0.66, 1)
.15 (.07, .27) 9 50 0 9
Table 14. Warmth, Erythema, Swelling as Predictors of Periprosthetic Infection
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
IV Magnuson 98 Warmth Intraoperative
Cultures or Histology
Mixed 2.88 (0.61, 13.6)
0.92 (0.82, 1.03)
0.12 (0.05, 0.24)
0.96 (0.86, 0.99)
6 2 44 46
IV Magnuson 98 Swelling
or Erythema
Intraoperative Cultures or Histology
Mixed 2.3 (0.88, 6.05)
0.85 (0.71, 1.02)
0.24 (0.13, 0.38)
0.90 (0.77, 0.97)
12 5 38 43
IV Teller 161
Local Signs
(erythema, warmth, edema)
Intraoperative Cultures or
Frank Purulence
Mixed - 0.82 (0.67, 0.99)
0.18 (0.05, 0.40)
1 (0.97, 1) 4 0 18 139
41
Table 15. Early Implant Failure as a Predictor of Periprosthetic Infection
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Lachiewicz 142 Implant in situ
<5 years
Intraoperative Cultures or
Gross Purulence
Hip 2.1 (1.36, 3.25)
0.53 (0.29, 0.96)
0.63 (0.38, 0.84)
0.70 (0.61, 0.78) 12 37 7 86
Table 16. Sinus Tract as a Predictor of Periprosthetic Infection
Level of Evidence Author Risk Factor Joint N Results
IV Magnuson sinus tract Mixed 98 OR undefined - all 7 with sinus tract had infection (p=.01)
Table 17. Prevalence of Periprosthetic Infection among Patients with Bacteremia
Level of Evidence Author Risk Factor N Infections %
V Murdoch S. aureus bacteremia 53 24 hematogenous, 9 primary
45% hematogenous, 62% overall
42
Table 18. Prevalence of Periprosthetic Infection among Patients with Metachronous Periprosthetic Infection
Level of Evidence Author Risk Factor N Infections %
V Luessenhop Metachronous PJI 145 27 19% V Murray Metachronous PJI 68 10 15%
Table 19. Anticoagulation RCT
Level of Evidence Author Risk Factor Joint N Results
II Bergqvist Anticoagulation Hip 161 - (RCT with no infections)
43
Table 20. Use of Drains RCTs Level of Evidence Author Risk Factor Joint N Results
Odds Ratio (95% CI) II Esler Drains Knee 100 0 (0, 39) II Kim Drains Knee 138 0 (0, 5.3) II Walmsley Drains Hip 577 1.05 (.08, 14.5)
II Confalonieri Drains Knee 78 - (no infections)
II Crevoisier Drains Mixed 98 - (no infections)
II Gonzalez Della Valle Drains Hip 104 -
(no infections)
II Holt Drains Knee 137 - (no infections)
II Jenny Drains Knee 60 - (no infections)
II Johansson Drains Hip 105 - (no infections)
II Kim Drains Hip 96 - (no infections)
II Niskanen Drains Mixed 97 - (no infections)
II Ovadia Drains Mixed 88 - (no infections)
II Ritter Drains Mixed 415 - (no infections)
44
RECOMMENDATION 2 We recommend erythrocyte sedimentation rate and C-reactive protein testing for patients assessed for periprosthetic joint infection.
Strength of Recommendation: Strong
Rationale
Six Level I studies evaluating the ESR,11, 21, 37, 48, 93, 96 six Level I studies evaluating the CRP,11, 21, 31, 37, 93, 96 and two Level I studies evaluating the combined use of ESR and CRP 37, 96 were used for analysis.
The use of screening inflammatory markers (ESR and CRP) is the starting point in the work-up investigations for the diagnosis or exclusion of periprosthetic joint infection. Our systematic review of the literature found strong evidence for using both ESR and CRP testing. We recommend use of this combination of tests to “rule out” infection.
The combined use of ESR and CRP is a very good “rule out” test. When both the ESR and CRP are negative, periprosthetic infection is unlikely (negative likelihood ratio 0 – 0.06). When both tests are positive, periprosthetic infection must be considered (positive likelihood ratio 4.3 – 12.1), and this result warrants further investigations. However, the clinician also needs to be aware of other inflammatory conditions such as rheumatoid arthritis, neoplasms, coronary artery disease, polymyalgia rheumatica, inflammatory bowel disease, etc. that can lead to elevation of inflammatory markers. The use of either test alone is less reliable for either ‘ruling out’ or ‘ruling in’ infection than when both tests are combined. A negative ESR is better at ‘ruling out’ infection than a positive result is for ‘ruling in’ infection (better negative likelihood ratio than positive likelihood ratio). Similarly, the CRP is a better test for ‘ruling out’ infection, but somewhat better than the ESR at ‘ruling in’ infection.
The evidence strongly supports obtaining an ESR and CRP in all patients being assessed for periprosthetic infection.
Supporting Evidence
The systematic review for this recommendation included studies investigating the diagnostic utility of not only ESR and CRP, but also radiographs and peripheral white blood cell counts. With the exception of two studies that investigated the joint use of ESR and CRP, 37, 96 there are no data looking at the use of a combination of these tests. The available data are from studies that investigated each test in isolation.
For erythrocyte sedimentation rates, we included three studies of hip patients, two of knee patients, and one of mixed hip and knee patients. 11, 21, 37, 48, 93, 96 All studies produced reliable data. Meta-analysis of all ESR studies indicated that threshold effects may be responsible for much of the differences between studies. Using a threshold of 30 mm/hr, a positive result produced a small (but sometimes important) change in the
45
probability of infection, while a negative result produced a moderate change (see Figure 5).
For C-reactive protein, we included two studies of hip patients, three of knee patients, and one of mixed hip and knee patients. 11, 21, 31, 37, 93, 96 All studies produced reliable data. Meta-analysis of all CRP studies indicated significant between-study heterogeneity (I2
=83%), and adjusting for differences in thresholds did not explain the variation between studies. With the exception of one study with wide confidence intervals,93 the positive and negative likelihood ratios were statistically significant (see Table 25).
We included two studies with reliable data that looked at using a combination of ESR and CRP to diagnose infection.37, 96 A negative result on both tests was very good at ruling out infection. A positive result on one of the tests produced a small (likelihood ratio <5) change in probability, so it was not very good at ruling in infection. A positive result on both tests was a better “rule in” test (see Table 26).
For radiographs, we included one study of hip patients with reliable data,19 one study of hip patients with moderately reliable data,9 and one study of knee patients with moderately reliable data.5 There was no consistent evidence of statistically significant diagnostic benefit (see Table 27) however, findings such as periostitis or early osteolysis may indicate infection. In addition, radiographs can provide alternative explanations for joint pain or dysfunction and are routinely obtained in the evaluation of the painful or failed hip or knee arthroplasty.
For peripheral white blood cell counts, we included three studies of hip patients and one of mixed hip and knee patients with reliable data.11, 83, 93, 99 We included three additional studies of mixed hip and knee patients with moderately reliable data.8, 23, 105 The thresholds differed in each study. Meta-analysis of all peripheral white blood cell count studies indicated significant between-study heterogeneity (I2 =98%), and adjusting for differences in thresholds did not explain the variation between studies. With the exception of one study with wide confidence intervals,93 the positive and negative likelihood ratios were statistically significant (see Table 28).
46
SUMMARY OF EVIDENCE Table 21. Radiography and Serology Summary of Evidence
Test Number
of Studies
Positive Likelihood Ratio
(95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)
ESR – meta-analysis (I2=26%)
6 2.9 (1.7, 4.8)
0.15 (0.09, 0.27)
0.90 (0.82, 0.94)
0.69 (0.51, .82)
CRP (range) 6 2.4 – 27.1 0.05 – 0.8 0.30 – 0.95 0.71 – 0.96
ESR and CRP - positive if both positive (range)
2 4.34 – 12.1 0.14 - 0.21 0.80 – 0.89 0.79 – 0.93
ESR and CRP - positive if one
positive (range) 2 1.74 – 4.22 0 – 0.06 0.96 - 1 0.43 – 0.77
Radiograph – lucency (range) 2 1.2 – 2.99 0.55 – 0.95 0.25 – 0.55 0.79 – 0.82
Radiograph – periostitis
(range) 2 1.04 – 20.8 0.82 - 0.92 0.17 – 0.70 0.33 - 1
Radiograph – other measures
(range) 3 0.52 – 2.4 0.3 - 1.23 0.17 – 0.80 0.67 – 0.84
WBC (range) 7 1.77 – 8.45 0.08 – 0.89 0.10 – 0.94 0.60 -1 *Range presented when fewer than four studies or when meta-analysis indicated heterogeneity
47
EXCLUDED ARTICLES Table 22. Excluded Articles - Recommendation 2
Author Title Reason for Exclusion Austin, et al.
2008 A simple, cost-effective screening protocol to rule out periprosthetic infection Not best available evidence
Bare, et al. 2006 Preoperative evaluations in revision total knee arthroplasty Not best available
evidence Bergstrom, et al.
1974 Radiographic abnormalities caused by postoperative infection following total hip
arthroplasty <25 patients/arm
Canner, et al. 1984 The infected hip after total hip arthroplasty Not relevant - not
diagnostic study Carlsson, et al.
1978 Erythrocyte sedimentation rate in infected and non-infected total-hip arthroplasties <25 patients/arm
Chevillotte, et al. 2008 Inflammatory Laboratory Markers in Periprosthetic Hip Fractures Not best available
evidence Choudhry, et al.
1992 Plasma viscosity and C-reactive protein after total hip and knee arthroplasty Not relevant - not diagnostic study
Chryssikos, et al. 2008 FDG-PET imaging can diagnose periprosthetic infection of the hip Not best available
evidence Covey, et al.
1987 Clinical significance of the erythrocyte sedimentation rate in orthopaedic surgery Narrative review, bibliography screened
Duff, et al. 1996 Aspiration of the knee joint before revision arthroplasty Not best available
evidence Dupont, et al.
2008 The value of C-reactive protein for postoperative monitoring of lower limb arthroplasty Not relevant - not specific to pji
Eisler, et al. 2001 Ultrasound for diagnosis of infection in revision total hip arthroplasty Insufficient Data
48
Table 22. Excluded Articles (Continued) Author Title Reason for Exclusion
Feldman, et al. 1995 The role of intraoperative frozen sections in revision total joint arthroplasty Not best available
evidence Forster, et al.
1982 Sedimentation rate in infected and uninfected total hip arthroplasty Not best available evidence
Ghanem, et al. 2008 Determining 'true' leukocytosis in bloody joint aspiration Not best available
evidence
Ghanem, et al. 2009
The use of receiver operating characteristics analysis in determining erythrocyte sedimentation rate and C-reactive protein levels in diagnosing periprosthetic infection prior
to revision total hip arthroplasty
Not best available evidence
Ginai, et al. 1996 Digital subtraction arthrography in preoperative evaluation of painful total hip arthroplasty Not relevant - not
specific to pji Itasaka, et al.
2001 Diagnosis of infection after total hip arthroplasty Not best available evidence
Lachiewicz, et al. 1996
Aspiration of the hip joint before revision total hip arthroplasty. Clinical and laboratory factors influencing attainment of a positive culture
Not best available evidence
Levitsky, et al. 1991
Evaluation of the painful prosthetic joint. Relative value of bone scan, sedimentation rate, and joint aspiration
Not best available evidence
Lyons, et al. 1985 Evaluation of radiographic findings in painful hip arthroplasties Not best available
evidence Magnuson, et al.
1988 In-111-labeled leukocyte scintigraphy in suspected orthopedic prosthesis infection:
comparison with other imaging modalities Not best available
evidence Maury, et al.
1984 Control of the acute-phase serum amyloid A and C-reactive protein response: comparison
of total replacement of the hip and knee Not relevant - not diagnostic study
Miniaci, et al. 1990
Analysis of radionuclide arthrograms, radiographic arthrograms, and sequential plain radiographs in the assessment of painful hip arthroplasty
Not relevant - not specific to pji
49
Table 22. Excluded Articles (Continued) Author Title Reason for Exclusion
Moreschini, et al. 2001
Postoperative physiopathological analysis of inflammatory parameters in patients undergoing hip or knee arthroplasty
Not relevant - not diagnostic study
Mulier, et al. 1973 Postoperative infection in total hip replacement Not best available
evidence
Muller, et al. 2008
Diagnosis of periprosthetic infection following total hip arthroplasty - evaluation of the diagnostic values of pre- and intraoperative parameters and the associated strategy to
preoperatively select patients with a high probability of joint infection
Not best available evidence
Nilsdotter- Augustinsson, et al.
2007
Inflammatory response in 85 patients with loosened hip prostheses: a prospective study comparing inflammatory markers in patients with aseptic and septic prosthetic loosening
Not best available evidence
Niskanen, et al. 1996 Serum C-reactive protein levels after total hip and knee arthroplasty Not relevant - not
diagnostic study Okafor, et al.
1998 Postoperative changes of erythrocyte sedimentation rate, plasma viscosity and C-reactive
protein levels after hip surgery Not relevant - not diagnostic study
Panousis, et al. 2005
Poor predictive value of broad-range PCR for the detection of arthroplasty infection in 92 cases
Not best available evidence
Park, et al. 2008 Normative Temporal Values of CRP and ESR in Unilateral and Staged Bilateral TKA Not relevant - not
diagnostic study Parvizi, et al.
2008 Diagnosis of infected total knee: findings of a multicenter database Insufficient Data
Rosas, et al. 1998
Contribution of laboratory tests, scintigraphy, and histology to the diagnosis of lower limb joint replacement infection Insufficient Data
Sanzen, et al. 1988 The erythrocyte sedimentation rate following exchange of infected total hips <25 patients/arm
Sanzen, et al. 1989 The diagnostic value of C-reactive protein in infected total hip arthroplasties Not best available
evidence
50
Table 22. Excluded Articles (Continued) Author Title Reason for Exclusion
Sanzen, et al. 1997
Periprosthetic low-grade hip infections. Erythrocyte sedimentation rate and C-reactive protein in 23 cases <25 patients
Schneider, et al. 1982 Radiologic evaluation of painful joint prostheses Narrative review,
bibliography screened Schulak, et al.
1982 The erythrocyte sedimentation rate in orthopaedic patients Narrative review, bibliography screened
Schwenger, et al. 1998 CRP levels in autoimmune disease can be specified by measurement of procalcitonin Not relevant - not
specific to pji Sciuk, et al.
1992 White blood cell scintigraphy with monoclonal antibodies in the study of the infected
endoprosthesis Not best available
evidence Shih, et al.
1987 Erythrocyte sedimentation rate and C-reactive protein values in patients with total hip
arthroplasty Not best available
evidence Simon, et al.
2004 Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a
systematic review and meta-analysis Not relevant - not
specific to pji Stumpe, et al.
2004 FDG PET for differentiation of infection and aseptic loosening in total hip replacements:
comparison with conventional radiography and three-phase bone scintigraphy Not best available
evidence Sudanese, et al.
1994 Diagnostic protocol in prosthetic loosening Not best available evidence
Tehranzadeh, et al. 1981 Radiological evaluation of painful total hip replacement Not best available
evidence Teller, et al.
2000 Sequential indium-labeled leukocyte and bone scans to diagnose prosthetic joint infection Not best available evidence
Thoren, et al. 1991 Erythrocyte sedimentation rate in infection of total hip replacements Not best available
evidence Uzzan, et al.
2006 Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or
trauma: a systematic review and meta-analysis Not relevant
51
Table 22. Excluded Articles (Continued) Author Title Reason for Exclusion
Virolainen, et al. 2002 The reliability of diagnosis of infection during revision arthroplasties Not best available
evidence Walker, et al.
1991 Arthrography of painful hips following arthroplasty: digital versus plain film subtraction Not relevant - not specific to pji
White, et al. 1998 C-reactive protein level after total hip and total knee replacement Not relevant - not
diagnostic study
STUDY QUALITY Table 23. Radiography and Serology - Quality
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Savarino 26 ESR (>15mm/hr) I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Savarino 26 ESR (>15mm/hr) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Savarino 26 ESR (>15mm/hr) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Schinsky 201 ESR (>30 mm/hr) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
52
Table 23. Radiography and Serology – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Savarino 26 ESR (>50 mm/hr) I ● ● ● ● ● ● ● ● ● ● ● ● ● ● Savarino 26 ESR (>50 mm/hr) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Savarino 26 ESR (>50 mm/hr) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Kamme 63 ESR (>30mm/hr) I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Greidanus 151 ESR (>22.5 mm/hr) I ● ● ● ● ● ● ● ● ? ● ● ● ● ● Greidanus 151 ESR (>30 mm/hr) I ● ● ● ● ● ● ● ● ? ● ● ● ● ●
Bottner 78 ESR (>32 mm/hr) I ● ? ● ● ● ● ● ● ● ● ? ● ● ● Della Valle 94 ESR (>30 mm/hr) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Savarino 26 CRP (>0.5mg/dL) I ● ● ● ● ● ● ● ● ● ● ● ● ● ● Savarino 26 CRP (>0.5mg/dL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Savarino 26 CRP (>0.5mg/dL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Schinsky 201 CRP (>1 mg/dL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Savarino 26 CRP (>2 mg/dL) I ● ● ● ● ● ● ● ● ● ● ● ● ● ● Savarino 26 CRP (>2 mg/dL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Savarino 26 CRP (>2 mg/dL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Greidanus 151 CRP (>1.0 mg/dL) I ● ● ● ● ● ● ● ● ? ● ● ● ● ●
53
Table 23. Radiography and Serology – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Greidanus 151 CRP (>1.35 mg/dL) I ● ● ● ● ● ● ● ● ? ● ● ● ● ● Fink 145 CRP (>1.35 mg/dL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Bottner 78 CRP (>1.5 mg/dL) I ● ? ● ● ● ● ● ● ● ● ? ● ● ● Bottner 78 CRP (>3.2 mg/dL) I ● ? ● ● ● ● ● ● ● ● ? ● ● ●
Della Valle 94 CRP (>1 mg/dL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Greidanus 151 ESR and CRP (22.5/1.35) I ● ● ● ● ● ● ● ● ? ● ● ● ● ● Greidanus 151 ESR and CRP (30/1.0) I ● ● ● ● ● ● ● ● ? ● ● ● ● ● Greidanus 151 ESR or CRP (22.5/1.35) I ● ● ● ● ● ● ● ● ? ● ● ● ● ● Greidanus 151 ESR or CRP (30/1.0) I ● ● ● ● ● ● ● ● ? ● ● ● ● ● Schinsky 201 ESR or CRP (30/1.0) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Cyteval 65 radiograph - asymmetric position of femoral head I ● ● ● ● ● ● ● ● ● ● ● ? ● ●
Cyteval 65
radiograph - bone abnormalities (focal or
nonfocal lucency, periostitis)
I ● ● ● ● ● ● ● ● ● ● ● ? ● ●
Cyteval 65 radiograph - focal lucency I ● ● ● ● ● ● ● ● ● ● ● ? ● ●
54
Table 23. Radiography and Serology – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Cyteval 65 radiograph - nonfocal lucency I ● ● ● ● ● ● ● ● ● ● ● ? ● ●
Cyteval 65 radiograph - periostitis I ● ● ● ● ● ● ● ● ● ● ● ? ● ● Bernay 31 radiograph II ● ● ? ● ● ● ● ○ ● ● ? ● ● ●
Barrack 69 radiograph: complete
radiolucent line adjacent to tibial component
III ● ● ● ● ● ● ● ● ● ● ○ ● ● ●
Barrack 69 radiograph: gross loosening III ● ● ● ● ● ● ● ● ● ● ○ ● ● ●
Barrack 69
radiograph: Knee Society Grade 3 classification for
tibial component radiolucency in addition to
Grade 1 under femoral component
III ● ● ● ● ● ● ● ● ● ● ○ ● ● ●
Barrack 69 radiograph: periostitis III ● ● ● ● ● ● ● ● ● ● ○ ● ● ● Spangehl 202 WBC (>11.0*10^9/L) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Savarino 26 WBC (>9500/mm^3) I ● ● ● ● ● ● ● ● ● ● ● ● ● ● Savarino 26 WBC (>9500/mm^3) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
55
Table 23. Radiography and Serology – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Savarino 26 WBC (>9500/mm^3) I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Pill 92 WBC (>11000/μL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Spangehl 202 WBC differential (>75% neutrophils) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Bottner 78 WBC (>6200/μL) I ● ? ● ● ● ● ● ● ● ● ? ● ● ● Di Cesare 58 WBC (>11.0*10^9) II ● ● ● ● ● ● ● ● ○ ● ? ● ● ●
Bernard 228 Polynuclear neutrophil count (≥6000 cells/ml) II ? ● ● ● ● ● ● ● ○ ● ● ● ● ○
Trampuz 296 WBC (>10x10^9/L) II ? ● ● ● ● ● ● ● ● ● ? ● ● ○
56
STUDY RESULTS Figure 5. ESR Meta-analysis Results - Likelihood Ratios
StudyId
COMBINED
Bottner - 32mm/hr
Della Valle - 30mm/hr
Kamme - 30mm/hr
Schinsky - 30mm/hr
Greidanus - 22.5mm/hr
Savarino - 15mm/hr
1 2 5 10DLR POSITIVE
StudyId
COMBINED
Bottner - 32mm/hr
Della Valle - 30mm/hr
Kamme - 30mm/hr
Schinsky - 30mm/hr
Greidanus - 22.5mm/hr
Savarino - 15mm/hr
1.1 .2 .5DLR NEGATIVE
INTERPRETING THE FOREST PLOTS Throughout the guideline we use descriptive diagrams or forest plots to present data from studies comparing a diagnostic test to a reference standard. The positive and negative likelihood ratios are the effect measures used to depict study results. The horizontal line running through each point represents the 95% confidence interval for that point. In the graphs above, the solid vertical line represents “no effect” where the likelihood ratio is equal to one. The dashed line represents the value of a likelihood ratio that indicates a large and conclusive change in the probability of disease.
For example, in the figures above, the summary estimate (indicated by the diamond) indicates a positive likelihood ratio close to 3 and a negative likelihood ratio of between 0.2 and 0.1. This result is statistically significant because the 95% Confidence Interval does not cross the “no effect” line. Also please note that summary measures (diamond) are not reported in the plot if high heterogeneity (>50%) is present.
57
Figure 6. CRP Results - Likelihood Ratios
StudyId
Bottner - 3.2 mg/dL
Savarino - 2 mg/dL
Bottner - 1.5 mg/dL
Greidanus - 1.35 mg/dL
Fink - 1.35 mg/dL
Greidanus - 1 mg/dL
Schinsky - 1 mg/dL
Della Valle - 1 mg/dL
Savarino - 0.5mg/dL
1 2 5 10DLR POSITIVE
StudyId
Bottner - 3.2 mg/dL
Savarino - 2 mg/dL
Bottner - 1.5 mg/dL
Greidanus - 1.35 mg/dL
Fink - 1.35 mg/dL
Greidanus - 1 mg/dL
Schinsky - 1 mg/dL
Della Valle - 1 mg/dL
Savarino - 0.5mg/dL
1.1.2 .5DLR NEGATIVE
Figure 7. ESR and CRP - Likelihood Ratios
StudyId
Schinsky – 1 or both positive (30/1.0)
Greidanus – 1 or both positive (30/1.0)
Greidanus – 1 or both positive (22.5/1.35)
Schinsky - both positive (30/1.0)
Greidanus – both positive (30/1.0)
Greidanus – both positive (22.5/1.35)
1 2 5 10DLR POSITIVE
StudyId
Schinsky – 1 or both positive (30/1.0)
Greidanus – 1 or both positive (30/1.0)
Greidanus – 1 or both positive (22.5/1.35)
Schinsky - both positive (30/1.0)
Greidanus – both positive (30/1.0)
Greidanus – both positive (22.5/1.35)
.1.2 .5 1DLR NEGATIVE
58
Figure 8. Radiography Results - Likelihood Ratios
StudyId
Cyteval - femoral head asymmetry
Cyteval - bone abnormalities
Cyteval - focal lucency
Cyteval - nonfocal lucency
Cyteval - periostitis
Bernay - plain radiograph
Barrack - radiolucent line
Barrack - gross loosening
Barrack - radiolucency grade
Barrack - periostitis
1 2 5 10
DLR POSITIVE
StudyId
Cyteval - femoral head asymmetry
Cyteval - bone abnormalities
Cyteval - focal lucency
Cyteval - nonfocal lucency
Cyteval - periostitis
Bernay - plain radiograph
Barrack - radiolucent line
Barrack - gross loosening
Barrack - radiolucency grade
Barrack - periostitis
.1 .2 .5 1
DLR NEGATIVE
Figure 9. White Blood Cell Count Results - Likelihood Ratios
StudyId
Spangehl - WBC count
Savarino
Pill
Spangehl - % neutrophils
Bottner
Di Cesare
Trampuz
Bernard
1 2 5 10DLR POSITIVE
StudyId
Spangehl - WBC count
Savarino
Pill
Spangehl - % neutrophils
Bottner
Di Cesare
Trampuz
Bernard
1.1 .2 0.5DLR NEGATIVE
59
Table 24. Erythrocyte Sedimentation Rate Results
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Savarino 26 ESR (15mm/hr)
Intraoperative Cultures Hip 0.94
(0.48, 1.82)1.09
(0.43, 2.8) 0.56
(0.3, 0.8)
0.4 (0.12, 0.74)
9 7 6 4
I Savarino 26 ESR (15mm/hr) Histology Hip 1.02
(0.53, 1.97)0.97
(0.39, 2.4)
0.58 (0.28, 0.85)
0.43 (0.18, 0.71)
7 5 8 6
I Savarino 26 ESR (15mm/hr)
Intraoperative cultures and
histology Hip 1.07
(0.55, 2.08)0.91
(0.36, 2.34)
0.6 (0.26, 0.88)
0.44 (0.2, 0.7) 6 4 9 7
I Schinsky 201 ESR (30
mm/hr)
at least 2 of: 1)a positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathological result consistent with infection
(average of >10 PMN in the 5
most cellular high power fields)
Hip 1.58 (1.37, 1.82)
0.09 (0.02, 0.37)
0.96 (0.87, 1)
0.39 (0.31, 0.47)
53 2 89 57
I Savarino 26 ESR (50
mm/hr)
Intraoperative Cultures Hip
3.75 (0.53, 26.73)
0.69 (0.45, 1.07)
0.38 (0.15, 0.65)
0.9 (0.55, 1) 6 10 1 9
60
Table 24. Erythrocyte Sedimentation Rate Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Savarino 26 ESR (50
mm/hr) Histology Hip
7 (0.97, 50.27)
0.54 (0.3, 0.97)
0.5 (0.21, 0.79)
0.93 (0.66, 1) 6 6 1 13
I Savarino 26 ESR (50
mm/hr)
Intraoperative cultures and
histology Hip
9.6 (1.35, 68.43)
0.43 (0.2, 0.92)
0.6 (0.26, 0.88)
0.94 (0.7, 1) 6 4 1 15
I Kamme 63 ESR (30mm/hr)
Intraoperative Cultures Hip 3.2
(1.69, 6.05)0.15
(0.06, 0.38)
0.89 (0.75, 0.97)
0.72 (0.51, 0.88)
34 4 7* 18
I Greidanus 151 ESR (22.5
mm/hr)
Cultures –Intraoperative or Aspiration
Knee 5.5 (3.58, 8.43)
0.08 (0.03, 0.24)
0.93 (0.82, 0.99)
0.83 (0.74, 0.9) 42 3 18 88
I Greidanus 151 ESR (30
mm/hr)
Cultures –Intraoperative or Aspiration
Knee 6.7
(3.96, 11.36)
0.2 (0.11, 0.38)
0.82 (0.68, 0.92)
0.88 (0.8, 0.93) 37 8 13 93
61
Table 24. Erythrocyte Sedimentation Rate Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Della Valle 94
ESR (30
mm/hr)
at least 2 of 3 positive
intraoperative cultures on
solid media or if 2 of following:
1)at least 1 positive culture
2)final histopathology consistent with
infection 3)gross
purulence seen at time of revision
Knee 2.66 (1.8, 3.92)
0.15 (0.06, 0.38)
0.9 (0.77, 0.97)
0.66 (0.52, 0.78)
37 4 18 35
I Bottner 78 ESR (32
mm/hr)
Intraoperative cultures and
histology
Mixed (50 hip, 28
knee)
7.69 (3.51, 16.86)
0.21 (0.09, 0.52)
0.81 (0.58, 0.95)
0.89 (0.78, 0.96)
17 4 6 51
*Five false positives were from patients with rheumatoid arthritis, one malignancy, and one with elevated ESR prior to primary operation
62
Table 25. C-Reactive Protein Results
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Savarino 26 CRP (0.5mg/dL)
Intraoperative Cultures Hip 1.25
(0.4, 3.9)
0.89 (0.51, 1.56)
0.38 (0.15, 0.65)
0.7 (0.35, 0.93)
6 10 3 7
I Savarino 26 CRP (0.5mg/dL) Histology Hip
0.93 (0.32, 2.71)
1.04 (0.59, 1.81)
0.33 (0.1, 0.65)
0.64 (0.35, 0.87)
4 8 5 9
I Savarino 26 CRP (0.5mg/dL)
Intraoperative cultures and
histology Hip 0.8
(0.26, 2.5)
1.12 (0.64, 1.95)
0.3 (0.07, 0.65)
0.63 (0.35, 0.85)
3 7 6 10
I Schinsky 201 CRP (1 mg/dL)
at least 2 of: 1)a positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathological result consistent with infection
(average of >10 PMN in the 5
most cellular high power fields)
Hip 3.29
(2.53, 4.28)
0.08 (0.03, 0.23)
0.95 (0.85, 0.99)
0.71 (0.63, 0.78)
52 3 42 104
I Savarino 26 CRP (2 mg/dL)
Intraoperative Cultures Hip
0.94 (0.19, 4.67)
1.02 (0.69, 1.5)
0.19 (0.04, 0.46)
0.8 (0.44, 0.97)
3 13 2 8
63
Table 25. C-Reactive Protein Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Savarino 26 CRP
(2 mg/dL)
Histology Hip 4.67 (0.6, 36.29)
0.72 (0.47, 1.1)
0.33 (0.1, 0.65)
0.93 (0.66, 1) 4 8 1 13
I Savarino 26 CRP
(2 mg/dL)
Intraoperative cultures and
histology Hip
2.4 (0.48, 11.95)
0.8 (0.51, 1.25)
0.3 (0.07, 0.65)
0.88 (0.62, 0.98)
3 7 2 14
I Greidanus 151 CRP (1.0
mg/dL)
Cultures –Intraoperative or
Aspiration Knee 5.5
(3.58, 8.43) 0.08
(0.03, 0.24)
0.93 (0.82, 0.99)
0.83 (0.74, 0.9) 42 3 18 88
I Greidanus 151 CRP (1.35
mg/dL)
Cultures –Intraoperative or
Aspiration Knee 6.9
(4.2, 11.33) 0.1
(0.04, 0.26)
0.91 (0.79, 0.98)
0.87 (0.79, 0.93)
41 4 14 92
I Fink 145 CRP (1.35
mg/dL)
Intraoperative cultures and
histology Knee 3.81
(2.46, 5.9) 0.34
(0.2, 0.57)
0.73 (0.56, 0.85)
0.81 (0.72, 0.88)
29 11 20 85
64
Table 25. C-Reactive Protein Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Della Valle 94
CRP (1
mg/dL)
at least 2 of 3 positive
intraoperative cultures on solid media or if 2 of following: 1)at least 1 positive culture 2)final histopathology consistent with
infection 3)gross purulence seen at time of revision
Knee 3.88 (2.41, 6.25)
0.06 (0.02, 0.25)
0.95 (0.83, 0.99)
0.75 (0.62, 0.86)
39 2 13 40
I Bottner 78 CRP (1.5
mg/dL)
Intraoperative cultures and
histology
Mixed (50
hip, 28 knee)
10.86 (4.67, 25.22)
0.05 (0.01, 0.35)
0.95 (0.76, 1)
0.91 (0.81, 0.97)
20 1 5 52
I Bottner 78 CRP (3.2
mg/dL)
Intraoperative cultures and
histology
Mixed (50
hip, 28 knee)
27.14 (6.93, 106)
0.05 (0.01, 0.33)
0.95 (0.76, 1)
0.96 (0.88, 1) 20 1 2 55
65
Table 26. ESR and CRP Results
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Greidanus 151
ESR and CRP –
positive if both
positive (22.5/1.35)
Cultures –Intraoperative or Aspiration
Knee 13.5 (6.53, 27.7)
0.12 (0.05, 0.27)
0.89 (0.76, 0.96)
0.93 (0.87, 0.97)
40 5 7 99
I Greidanus 151
ESR and CRP –
positive if both
positive (30/1.0)
Cultures –Intraoperative or Aspiration
Knee 12.1 (5.83, 25.2)
0.21 (0.12, 0.38)
0.8 (0.65, 0.90)
0.93 (0.87, 0.97)
36 9 7 99
I Schinsky 201
ESR and CRP –
positive if both
positive (30/1.0)
At least 2 of: 1)positive
intraoperative culture (on solid media) 2)gross
purulence 3)final
histopathology
Hip 4.34 (3.11, 6.04)
0.14 (0.06, 0.26)
0.89 (0.78, 0.96)
0.79 (0.72, 0.86)
49 6 30 116
I Greidanus 151
ESR and CRP –
positive if one
positive (22.5/1.35)
Cultures –Intraoperative or Aspiration
Knee 4.22 (2.95, 6.03)
0.06 (0.01, 0.22)
0.96 (0.85, 0.99)
0.77 (0.68, 0.85)
43 2 24 82
66
Table 26. ESR and CRP Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Greidanus 151
ESR and CRP –
positive if one
positive (30/1.0)
Cultures –Intraoperative or
Aspiration Knee 4.22
(2.95, 6.03) 0.06
(0.01, 0.22)
0.96 (0.84, 0.99)
0.77 (0.68, 0.85)
43 2 24 82
I Schinsky 201
ESR and CRP –
positive if one
positive (30/1.0)
At least 2 of: 1)positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
Hip 1.74 (1.51, 2.0) 0 1
(0.94, 1)
0.43 (0.34, 0.51)
55 0 84 62
67
Table 27. Radiography Results
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Cyteval 65
Radiograph - asymmetric position of
femoral head
Intraoperative Cultures (≥2) Hip 0.52
(0.14, 1.95) 1.23
(0.9, 1.68)
0.17 (0.02, 0.48)
0.68 (0.54, 0.8) 2 10 17 36
I Cyteval 65
Radiograph - bone
abnormalities (focal or nonfocal lucency,
periostitis)
Intraoperative Cultures (≥2) Hip 1.05
(0.72, 1.51) 0.88
(0.3, 2.57)
0.75 (0.43, 0.95)
0.28 (0.17, 0.42)
9 3 38 15
I Cyteval 65 Radiograph - focal lucency
Intraoperative Cultures (≥2) Hip 1.2
(0.4, 3.66) 0.95
(0.66, 1.35)
0.25 (0.05, 0.57)
0.79 (0.66, 0.89)
3 9 11 42
I Cyteval 65 Radiograph -
nonfocal lucency
Intraoperative Cultures (≥2) Hip 0.98
(0.53, 1.83) 1.02
(0.54, 1.91)
0.5 (0.21, 0.79)
0.49 (0.35, 0.63)
6 6 27 26
I Cyteval 65 Radiograph - periostitis
Intraoperative Cultures (≥2) Hip 20.77
(1.06, 407) 0.82
(0.62, 1.06)
0.17 (0.02, 0.48)
1 (0.93, 1) 2 10 0 53
II Bernay 31 Radiograph
Pathological and Gross Operative Findings
Hip 2.4 (1.22, 4.74)
0.3 (0.08, 1.07)
0.8 (0.44, 0.97)
0.67 (0.43, 0.85)
8 2 7 14
68
Table 27. Radiography Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
III Barrack 69
Radiograph: complete
radiolucent line adjacent to
tibial component
Intraoperative cultures on solid media, aspiration
culture confirmed by intraoperative
culture in liquid media, or
intraoperative histology
Knee 1.96 (0.59, 6.56)
0.89 (0.7, 1.13)
0.2 (0.06, 0.44)
0.9 (0.78, 0.97)
4 16 5 44
III Barrack 69 Radiograph:
gross loosening
Intraoperative cultures on solid media, aspiration
culture confirmed by intraoperative
culture in liquid media, or
intraoperative histology
Knee 0.92 (0.27, 3.11)
1.02 (0.81, 1.27)
0.15 (0.03, 0.38)
0.84 (0.7, 0.93) 3 17 8 41
69
Table 27. Radiography Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
III Barrack 69
Radiograph: Knee Society
Grade 3 classification
for radiolucency for the tibial
component in addition to
Grade 1 under femoral
component
Intraoperative cultures on solid media, aspiration
culture confirmed by intraoperative
culture in liquid media, or
intraoperative histology
Knee 2.99 (1.47, 6.1)
0.55 (0.33, 0.91)
0.55 (0.32, 0.77)
0.82 (0.68, 0.91)
11 9 9 40
III Barrack 69 Radiograph: periostitis
Intraoperative cultures on solid media, aspiration
culture confirmed by intraoperative
culture in liquid media, or
intraoperative histology
Knee 1.04 (0.73, 1.47)
0.92 (0.42, 2.01)
0.7 (0.46, 0.88)
0.33 (0.2, 0.48) 14 6 33 16
70
Table 28. White Blood Cell Count Results
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Spangehl 202 WBC (11.0x10^9/L
at least 1 of: 1)open wound of sinus in
communication with the joint 2)systemic
infection with pain in the joint and purulent fluid
within the joint 3)positive result on at
least 3 investigations(ESR>30, CRP>10, preoperative
aspiration with at least 1 positive culture, frozen
section with >5PMN/HPF,
intraoperative culture (>1/3 of cultures
positive)
Hip 5.57
(1.99, 15.56)
0.83 (0.7, 0.98)
0.2 (0.08, 0.37)
0.96 (0.92, 0.99)
7 28 6 161
I Savarino 26 WBC (9500/mm^3) Intraoperative cultures Hip
1.94 (0.09, 43.5)
0.96 (0.79, 1.16)
0.06 (0, 0.3)
1 (0.69, 1) 1 15 0 10
I Savarino 26 WBC (9500/mm^3) Histology Hip
3.46 (0.15, 77.86)
0.92 (0.74, 1.14)
0.08 (0, 0.38)
1 (0.77, 1) 1 11 0 14
I Savarino 26 WBC (9500/mm^3)
Intraoperative cultures and histology Hip
4.64 (0.21, 103.9)
0.89 (0.69, 1.14)
0.1 (0, 0.45)
1 (0.79, 1) 1 9 0 16
71
Table 28. White Blood Cell Count Results (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Pill 92 WBC (11000/μL)
at least 1 of 3 criteria: 1)an open wound or
sinus communicating with the joint 2)
systemic infection with pain in the hip and
purulent fluid within the joint 3)positive result on
at least 3 tests (ESR, CRP, joint aspiration, intraoperative frozen
section, and intraoperative culture)
Hip 8.45
(1.77, 40.46)
0.78 (0.62, 1)
0.24 (0.08, 0.47)
0.97 (0.9, 1) 5 16 2 69
72
Table 28. White Blood Cell Count Results (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
I Spangehl 202
WBC differential
(75% neutrophils)
at least 1 of: 1)open wound of sinus in
communication with the joint 2)systemic
infection with pain in the joint and purulent fluid within the joint 3)positive result on at
least 3 investigations(ESR>30, CRP>10, preoperative
aspiration with at least 1 positive culture, frozen
section with >5PMN/HPF,
intraoperative culture (>1/3 of cultures
positive)
Hip 2.01
(0.96, 4.22)
0.87 (0.72, 1.05)
0.23 (0.1, 0.4)
0.89 (0.83, 0.93)
8 27 19 148
I Bottner 78 WBC (6200/μL)
Intraoperative cultures and histology
Mixed (50 hip, 28
knee)
1.77 (1.17, 2.68)
0.48 (0.24, 0.97)
0.71 (0.48, 0.89)
0.6 (0.46, 0.72)
15 6 23 34
II Di Cesare 58 WBC
(11.0x10^9) Intraoperative cultures
and histology Mixed4.29
(2.38, 7.73)
0.08 (0.01, 0.51)
0.94 (0.71, 1)
0.78 (0.62, 0.89)
16 1 9 32
73
Table 28. White Blood Cell Count Results (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FN FP TN
II Trampuz 296 WBC count (10x10^9/L)
at least 1 of: 1)visible purulence of synovial
fluid or area surrounding the
prosthesis 2)acute inflammation on
histopathologic exam of permanent
periprosthetic tissue sections (as determined
by the clinical pathologist) 3)a sinus tract communicating with the prosthesis
Mixed (207 knee, 124 hip)
3.11 (1.51, 6.4)
0.87 (0.78, 0.97)
0.18 (0.1, 0.29)
0.94 (0.9, 0.97) 13 59 13 211
II Bernard 228
Polynuclear neutrophil
count (6000
cells/ml)
Intraoperative cultures
Mixed (167 hip, 63
knee)
2.84 (1.17, 6.92)
0.57 (0.44, 0.73)
0.54 (0.47, 0.61)
0.81 (0.58, 0.95)
112 95 4 17
74
RECOMMENDATION 3 We recommend joint aspiration of patients being assessed for periprosthetic knee infections that have abnormal erythrocyte sedimentation rate AND/OR C-reactive protein results. We recommend that the aspirated fluid be sent for microbiologic culture, synovial fluid white blood cell count and differential.
Strength of Recommendation: Strong
Rationale
Our systematic review of the literature suggests that ESR/CRP testing is valuable for screening (ruling out) of periprosthetic infection with extremely high sensitivity (>90%). These tests are not, however, specific for diagnosis of periprosthetic infection and may be elevated with any type of infection or inflammation. Hence, for patients with abnormal ESR/CRP who are being investigated for periprosthetic infection of the knee, the most appropriate next test is aspiration of the knee joint. We recommend that the fluid obtained from the joint be sent for analysis of synovial fluid white blood cell count, percentage of neutrophils, and also culture for aerobic and anerobic organisms. Studies suggest either synovial fluid white blood cell count over 1700 cells/μl (range, 1100-3000) or neutrophil percentage greater than 65% (range 64%-80%) is highly suggestive of chronic periprosthetic infection.21, 31, 103 However, the threshold for cell count and neutrophil percentage indicative of acute periprosthetic joint infection (within six weeks of index arthroplasty) is yet to be determined and the values and ranges reported above may not be applicable when diagnosing acute periprosthetic infections.
Supporting Evidence
Two studies with reliable data addressed the diagnostic efficacy of aspiration cultures among patients being assessed for periprosthetic knee infections.21, 31, 103 Both studies indicated that this test is a good “rule in” test but only moderately good at ruling out infection (positive likelihood ratio: 14.2-15.2, negative LR: 0.21-0.29; see Table 32).
Three studies with reliable data addressed synovial fluid white blood cell count and differential among patients being assessed for periprosthetic knee infections.21, 33 The studies indicated that both of these tests are good “rule in” and “rule out” tests (synovial fluid white blood cell count: LR+: 7.6-35.6, LR-: 0.01-0.11; differential: LR+: 6.5-48, LR-: 0.03-0.05; see Table 33, Table 34).
75
SUMMARY OF EVIDENCE Table 29. Knee Aspiration Summary of Evidence
Test Number of Studies
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)
Aspiration Cultures (range)
2 14.2 – 15.2 0.21 – 0.29 0.73 – 0.80 0.94 – 0.95
Synovial fluid WBC Count
(range) 3 7.6 – 35.6 0.01 – 0.11 0.91 – 1.0 0.88 – 0.98
Synovial fluid Neutrophil Percentage
(range)
3 6.5 – 48.0 0.03 – 0.05 0.95 – 0.98 0.85 – 0.98
76
EXCLUDED ARTICLES Table 30. Excluded Articles - Recommendation 3
Author Title Reason for Exclusion Bach, et al.
2002 Total knee arthroplasty infection: significance of delayed aspiration Does not address recommendation
Barrack, et al. 1997 The Coventry Award. The value of preoperative aspiration before total knee revision Not best available
evidence Duff, et al.
1996 Aspiration of the knee joint before revision arthroplasty Not best available evidence
Kersey, et al. 2000
White blood cell counts and differential in synovial fluid of aseptically failed total knee arthroplasty
Does not address recommendation
Mason, et al. 2003 The value of white blood cell counts before revision total knee arthroplasty Not best available
evidence Parvizi, et al.
2006 Periprosthetic infection: What are the diagnostic challenges? Not best available evidence
Parvizi, et al. 2008 Diagnosis of infected total knee: findings of a multicenter database Not best available
evidence Trampuz, et al.
2006 Sonication of explanted prosthetic components in bags for diagnosis of prosthetic joint
infection is associated with risk of contamination Not best available
evidence Trampuz, et al.
2007 Sonication of removed hip and knee prostheses for diagnosis of infection Not best available evidence
Van den Bekerom, et al. 2006
The value of pre-operative aspiration in the diagnosis of an infected prosthetic knee: a retrospective study and review of literature
Not best available evidence
Virolainen, et al. 2002 The reliability of diagnosis of infection during revision arthroplasties Not best available
evidence
77
STUDY QUALITY Table 31. Knee Aspiration - Quality
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Della Valle 94 Aspiration culture I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Fink 145 Aspiration culture I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Della Valle 94 Synovial fluid WBC count (>3000/μL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Ghanem 429 Synovial fluid WBC count (>1100/μL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Trampuz 133 Synovial fluid WBC count (>1700/μL) I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
Della Valle 94 Synovial fluid WBC differential (>65%
PMN) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Ghanem 429 Synovial fluid % neutrophil (>64%) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Trampuz 133 Synovial fluid % neutrophil (>65%) I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
78
STUDY RESULTS Table 32. Aspiration Culture - Knee
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Della Valle 94
Aspiration culture on
solid media
At least 2 of 3 positive intraoperative cultures on solid media or 2 of following: 1)at least 1 positive culture 2)final
histopathology consistent with
infection 3)gross purulence at revision
Knee14.22 (4.69, 43.12)
0.21 (0.11, 0.39)
0.8 (0.65, 0.91)
0.94 (0.84, 0.99)
3 3 8 50
I Fink 145 Aspiration culture
Intraoperative Cultures and Histology Knee
15.23 (6.34, 36.58)
0.29 (0.17, 0.48)
0.73 (0.56, 0.85)
0.95 (0.89, 0.98)
29 5 11 100
79
Table 33. Synovial Fluid White Blood Cell Count
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Della Valle 94 WBC
(3.0x10^3/μL)
At least 2 of 3 positive
intraoperative cultures on solid
media or 2 of following: 1)at least
1 positive culture 2)final
histopathology consistent with
infection 3)gross purulence at revision
Knee35.57 (7.34, 172.4)
0.01 (0, 0.19)
1 (0.91, 1)
0.98 (0.9, 1) 41 0 1 52
80
Table 33. Synovial Fluid White Blood Cell Count (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Ghanem 429 WBC
(1.1x10^3 /μL)
at least 1 of 3 criteria: 1)presence of an
abscess or sinus tract communicating with the
joint space 2)positive culture of aspirate on solid medium 3)≥2
positive intraoperative cultures of the same
organism, or one positive culture on solid
medium and the presence of gross
intracapsular purulence or abnormal histological findings; when cultures were negative, infection was present if had both grossly purulent fluid
and an abnormal frozen section (Mirra et al.
criteria)
Knee7.59
(5.47, 10.55)
0.11 (0.07, 0.17)
0.91 (0.85, 0.95)
0.88 (0.84, 0.92)
146 32 15 236
81
Table 33. Synovial Fluid White Blood Cell Count (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Trampuz 133 WBC
(1.7x10^3 /μL)
at least 1 of the following criteria: growth of the same microorganism in at least 2 cultures of synovial fluid or
periprosthetic tissue; visible synovial fluid
purulence at the time of arthrocentesis or during
surgery; acute inflammation on histopathologic examination of
permanent periprosthetic tissue
sections; or presence of a sinus tract
communicating with the prosthesis
Knee7.76
(4.54, 13.28)
0.07 (0.02, 0.26)
0.94 (0.8, 0.99)
0.88 (0.8, 0.94) 32 12 2 87
Note: Authors of other articles49, 66 investigating synovial fluid cell counts who expressed counts in milliliters (ml) were contacted; they confirmed that the units reported for the cell count in the published report were incorrect. The actual units to indicate periprosthetic infection were microliters (µl) and fall within the limits cited above.90 Although the units to express cell count differs between published reports, the American College of Rheumatology (ACR) recommends that cell count be expressed as cells/μl.90
82
Table 34. Synovial Fluid Neutrophil Percentage
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Della Valle 94 >65%
PMN
At least 2 of 3 positive intraoperative cultures on
solid media or 2 of following: 1)at least 1 positive culture 2)final
histopathology consistent with infection 3)gross purulence at revision
Knee6.46
(3.41, 12.26)
0.03 (0, 0.2)
0.98 (0.87, 1)
0.85 (0.72, 0.93) 40 8 1 45
83
Table 34. Synovial Fluid Neutrophil Percentage (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Ghanem 429 > 64% Neutrophils
at least 1 of 3 criteria: 1)presence of an
abscess or sinus tract communicating with
the joint space 2)positive culture of
aspirate on solid medium 3)≥2 positive intraoperative cultures of the same organism, or one positive culture on solid medium and the presence of gross
intracapsular purulence or abnormal histological findings; when cultures were negative, infection was present if had
both grossly purulent fluid and an abnormal frozen section (Mirra
et al. criteria)
Knee18.19
(10.91, 30.33)
0.05 (0.03, 0.1)
0.95 (0.9, 0.98)
0.95 (0.91, 0.97)
153 14 8 254
84
Table 34. Synovial Fluid Neutrophil Percentage (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Trampuz 133 > 65% Neutrophils
at least 1 of the following criteria: growth of the same microorganism in at least 2 cultures of synovial fluid or
periprosthetic tissue; visible synovial fluid purulence at the time of arthrocentesis or
during surgery; acute inflammation on histopathologic examination of
permanent periprosthetic tissue sections; or presence
of a sinus tract communicating with
the prosthesis
Knee48.04
(12.17, 189.65)
0.03 (0, 0.21)
0.97 (0.85, 1)
0.98 (0.93, 1) 33 2 1 97
85
RECOMMENDATION 4 We recommend a selective approach to aspiration of the hip based on the patient’s probability of periprosthetic joint infection and the results of the erythrocyte sedimentation rate (ESR) AND C-reactive protein (CRP). We recommend that the aspirated fluid be sent for microbiologic culture, synovial fluid white blood cell count and differential.
Selection of Patients for Hip Aspiration Probability of
Infection ESR and CRP
Results Planned Reoperation
Status Recommended Test
Higher + + or + − Planned or not planned Aspiration
Lower + + or + − Planned Aspiration or Frozen Section
Lower + + Not planned Aspiration
Lower + − Not planned Please see Recommendation 6
Higher or Lower − − Planned or not planned No further testing Key for ESR and CRP results + + = ESR and CRP test results are abnormal + − = either ESR or CRP test result is abnormal − − = ESR and CRP test results are normal Strength of Recommendation: Strong
Rationale
AAOS conducted a systematic review that identified six Level I hip,4, 27, 57, 65, 68, 111 and one hip and knee study35 on the diagnostic performance of hip aspiration and culture. (Please see Recommendation 3 for data supporting knee patients.) These studies did not stratify patients as to whether they were at higher or lower probability for infection, and all patients underwent re-operation. The indications for patients having an aspiration varied between studies, with aspiration often a routine part of preoperative investigations. Our meta-analysis indicated that hip aspiration for culture has a moderate to large ability to “rule in” infection but a small to moderate ability to “rule out” infection (positive likelihood ratio 9.8, negative LR 0.33). Based on the meta-analysis, hip aspiration is a useful test to diagnose periprosthetic hip infection. Therefore, we recommend hip aspiration in all “higher probability or lower probability” patients undergoing reoperation of the hip with abnormal ESR and/or CRP results. 4, 27, 35, 57, 65, 68, 111
Given the potential problems with instituting treatment and missing the diagnosis of infection, “higher probability” patients with an abnormal ESR AND/OR CRP without planned reoperation should also receive hip aspiration.
There is no reliable evidence, however, on the diagnostic performance of hip aspirations in patients who are not to undergo reoperation. Possible harms include the possibility of false positive results, the possibility of the introduction of bacteria into the joint during the procedure and patient pain and/or discomfort while undergoing the procedure.4 There
86
are also concerns about the cost of the procedure.4 Therefore, universal hip aspiration does not seem indicated. Aspiration is indicated for lower probability hip patients without planned reoperation only if both ESR AND CRP levels are abnormal. Lower probability hip arthroplasty patients without planned reoperation who have an abnormal ESR OR CRP are addressed in Recommendation 6.
We do not recommend that “higher or lower probability” patients with normal ESR and CRP have hip aspiration prior to planned reoperation.
Supporting Evidence
Six studies of hip patients4, 27, 57, 65, 68, 111 and one study of mixed hip and knee (80% hip)35 patients, all with reliable data, addressed the diagnostic efficacy of hip aspiration cultures. Our meta-analysis of these studies indicated that this test is a good “rule in” test, but not as good at ruling out infection (LR+: 9.8, LR-: 0.33; see Figure 10). The indications for patients having an aspiration varied between studies, with aspiration often a routine part of preoperative investigations. Two studies reported that patients were off antibiotics for at least two weeks prior to aspiration.4, 35 Three studies reported injecting saline for re-aspiration,35, 68, 111 while three studies reported not doing so.4, 27, 57
Two studies of hip patients with reliable data addressed synovial fluid white blood cell count and differential.96, 99 The data from these studies indicated that synovial fluid white blood cell count is a good “rule in” and possibly a good “rule out” test (LR+: 12-55, LR-: 0.18-0.65; see Figure 11). The higher threshold used in one study99 may account for its higher negative likelihood ratio (0.65). Neutrophil percentage (both studies used an 80% threshold) was a moderately good “rule in” and “rule out” test (LR+: 4.8-5.9, LR-: 0.13-0.22; see Figure 12).
None of the results presented includes data based on the use of diagnostic arthrography.
SUMMARY OF EVIDENCE Table 35. Aspiration Summary of Evidence
Test Number of Studies
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)
Aspiration Cultures (I2=0%)
7 9.8 (5.4, 17.9)
0.33 (0.18, 0.60)
0.69 (0.50, 0.84)
0.93 (0.89, 0.95)
Synovial fluid WBC Count
(range) 2 12.2 – 55.4 0.18 – 0.65 0.36 – 0.84 0.93 – 0.99
Synovial fluid Neutrophil Percentage
(range)
2 4.8 – 5.9 0.13 – 0.22 0.82 – 0.89 0.83 – 0.85
*Range presented when fewer than four studies
87
EXCLUDED ARTICLES Table 36. Excluded Articles - Recommendation 4
Author Title Reason for Exclusion Ali, et al.
2006 Accuracy of joint aspiration for the preoperative diagnosis of infection in total hip
arthroplasty Not best available
evidence Bernard, et al.
2004 Value of preoperative investigations in diagnosing prosthetic joint infection: retrospective
cohort study and literature review Not best available
evidence Buchholz, et al.
1981 Management of deep infection of total hip replacement Not best available evidence
Cheung, et al. 1997
The role of aspiration and contrast-enhanced arthrography in evaluating the uncemented hip arthroplasty
Not best available evidence
Chryssikos, et al. 2008 FDG-PET imaging can diagnose periprosthetic infection of the hip Not best available
evidence Dussault, et al.
1977 Radiologic diagnosis of loosening and infection in hip prostheses Insufficient Data
Fehring, et al. 1996 Aspiration as a guide to sepsis in revision total hip arthroplasty Not best available
evidence Gelman,
1976 Arthrography in total hip prosthesis complications Case report/commentary
Gould, et al. 1990 Role of routine percutaneous hip aspirations prior to prosthesis revision Not best available
evidence Guercio, et al.
1990 Arthrography of the prosthesetized painful hip: the importance of imaging and functional
testing Does not address recommendation
Itasaka, et al. 2001 Diagnosis of infection after total hip arthroplasty Not best available
evidence Johnson, et al.
1988 Detection of occult infection following total joint arthroplasty using sequential technetium-
99m HDP bone scintigraphy and indium-111 WBC imaging Not best available
evidence
88
Table 36. Excluded Articles (Continued) Author Title Reason for Exclusion
Kraemer, et al. 1993
Bone scan, gallium scan, and hip aspiration in the diagnosis of infected total hip arthroplasty
Not best available evidence
Levitsky, et al. 1991
Evaluation of the painful prosthetic joint. Relative value of bone scan, sedimentation rate, and joint aspiration
Not best available evidence
Lieberman, et al. 1993 Evaluation of painful hip arthroplasties. Are technetium bone scans necessary? Not best available
evidence Lyons, et al.
1985 Evaluation of radiographic findings in painful hip arthroplasties Not best available evidence
Magnuson, et al. 1988
In-111-labeled leukocyte scintigraphy in suspected orthopedic prosthesis infection: comparison with other imaging modalities
Not best available evidence
Maus, et al. 1987 Arthrographic study of painful total hip arthroplasty: refined criteria Insufficient Data
McLaughlin, et al. 1977 Evaluation of the painful hip by aspiration and arthrography Insufficient Data
Muller, et al. 2008
Diagnosis of periprosthetic infection following total hip arthroplasty - evaluation of the diagnostic values of pre- and intraoperative parameters and the associated strategy to
preoperatively select patients with a high probability of joint infection
Not best available evidence
Murray, et al. 1975
Arthrography for the assessment of pain after total hip replacement. A comparison of arthrographic findings in patients with and without pain <25 patients
O'Neill, et al. 1984
Failed total hip replacement: assessment by plain radiographs, arthrograms, and aspiration of the hip joint
Not best available evidence
Phillips, et al. 1983 Efficacy of preoperative hip aspiration performed in the radiology department Not best available
evidence Pons, et al.
1999 Infected total hip arthroplasty--the value of intraoperative histology Not best available evidence
89
Table 36. Excluded Articles (Continued) Author Title Reason for Exclusion
Roberts, et al. 1992
Diagnosing infection in hip replacements. The use of fine-needle aspiration and radiometric culture
Not best available evidence
Salenius, et al. 1979
Arthrography of the hip in the diagnosis of postoperative painful conditions after total hip replacement
Does not address recommendation
Salvati, et al. 1971
Arthrography for complications of total hip replacement. A review of thirty-one arthrograms Insufficient Data
Somme, et al. 2003
Contribution of routine joint aspiration to the diagnosis of infection before hip revision surgery
Not best available evidence
Taylor, et al. 1995 Fine needle aspiration in infected hip replacements Not best available
evidence Teller, et al.
2000 Sequential indium-labeled leukocyte and bone scans to diagnose prosthetic joint infection Not best available evidence
Tigges, et al. 1993
Hip aspiration: a cost-effective and accurate method of evaluating the potentially infected hip prosthesis
Not best available evidence
90
STUDY QUALITY Table 37. Aspiration - Quality
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Barrack 291 Aspiration culture I ● ● ● ● ● ● ● ● ? ● ? ● ● ● Barrack 260 aspiration (initial) I ● ● ● ● ● ● ● ● ? ● ? ● ● ● Barrack 31 aspiration (repeat) I ● ● ● ● ● ● ● ● ? ● ? ● ● ● Eisler 57 Aspiration culture I ? ● ● ● ● ● ● ● ● ● ● ● ● ●
Glithero 54 Aspiration culture I ● ● ● ● ● ● ● ● ● ● ● ● ● ● Lachiewicz 156 Aspiration culture I ● ● ● ● ● ● ● ● ● ● ? ● ● ● Malhotra 41 Aspiration culture I ? ● ● ● ● ● ● ● ● ● ? ● ● ● Mulcahy 71 Aspiration culture I ? ● ● ● ● ● ● ● ● ● ? ● ● ● Williams 273 Aspiration culture I ? ● ● ● ● ● ● ● ● ● ● ● ● ●
91
Table 37. Aspiration – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Schinsky 201 Synovial fluid WBC count (>4200/μl) I ● ● ● ● ● ● ● ? ● ● ? ● ● ●
Spangehl 183 Synovial fluid WBC count (>50000/μL) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Schinsky 201 Synovial fluid WBC differential (>80%
PMN) I ● ● ● ● ● ● ● ? ● ● ? ● ● ●
Spangehl 181 Synovial fluid % neutrophils (>80%) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
92
STUDY RESULTS Figure 10. Hip Aspiration Cultures Results - Meta-Analysis
StudyId
COMBINED
Lachiewicz
Williams
Mulcahy
Eisler
Malhotra
Barrack
Glithero
1 2 5 10DLR POSITIVE
StudyId
COMBINED
Lachiewicz
Williams
Mulcahy
Eisler
Malhotra
Barrack
Glithero
1.1 .2 .5DLR NEGATIVE
93
Figure 11. Synovial Fluid WBC Count Results - Likelihood Ratios (Hip and Knee)
StudyId
Spangehl (hip)- 50000/uL
Schinsky (hip) - 4200/uL
Della Valle (knee)- 3000/uL
Trampuz (knee) - 1700/uL
Ghanem (knee)- 1100/uL
1 2 510DLR POSITIVE
StudyId
Spangehl (hip) - 50000/uL
Schinsky (hip) - 4200/uL
Della Valle (knee) - 3000/uL
Trampuz (knee) - 1700/uL
Ghanem (knee) - 1100/uL
1.1.2 .5DLR NEGATIVE
Figure 12. Neutrophil Percentage Results – Likelihood Ratios (Hip and Knee)
StudyId
Spangehl (hip)
Schinsky (hip)
Ghanem (knee)
Trampuz (knee)
Della Valle (knee)
1 2 5 10DLR POSITIVE
StudyId
Spangehl (hip)
Schinsky (hip)
Ghanem (knee)
Trampuz (knee)
Della Valle (knee)
.1 .2 .5 1DLR NEGATIVE
94
Table 38. Aspiration Culture - Hip
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood Ratio (95%
CI)
Negative Likelihood Ratio (95%
CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Barrack 291 Aspiration culture
Correlation between intraoperative cultures
and histology; the appearance of the
tissue intraoperatively; and
the clinical course
Hip 5.11 (2.81, 9.3)
0.45 (0.21, 0.97)
0.6 (0.26, 0.88)
0.88 (0.84, 0.92) 6 33 4 248
I Barrack 260 Aspiration (initial)
Correlation between intraoperative cultures
and histology; the appearance of the
tissue intraoperatively; and
the clinical course
Hip 4 (1.42, 11.23)
0.57 (0.21, 1.52)
0.5 (0.07, 0.93)
0.88 (0.83, 0.91) 2 33 2 224
I Barrack 31 Aspiration (repeat)
Correlation between intraoperative cultures
and histology; the appearance of the
tissue intraoperatively; and
the clinical course
Hip 16.67 (2.25,
123.39)
0.35 (0.11, 1.08)
0.67 (0.22, 0.96)
0.96 (0.8, 1) 4 1 2 24
95
Table 38. Aspiration Culture (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood Ratio (95%
CI)
Negative Likelihood Ratio (95%
CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Eisler 57 Aspiration culture
Intraoperative Cultures Hip 2.16
(0.12, 39.05) 0.94
(0.7, 1.27) 0
(0, 0.6) 0.96
(0.87, 1) 0 2 4 51
I Glithero 54 Aspiration culture
Intraoperative Cultures
Mixed (43
hip, 11 knee)
31.32 (4.51, 217)
0.11 (0.03, 0.4)
0.89 (0.67, 0.99)
0.97 (0.85, 1) 17 1 2 34
I Lachiewicz 156 Aspiration culture
Intraoperative Cultures or
Gross Purulence
Hip 27.47
(10.34, 73.01)
0.15 (0.06, 0.38)
0.85 (0.66, 0.96)
0.97 (0.92, 0.99) 23 4 4 125
I Malhotra 41 Aspiration culture Histology Hip 4.74
(1.29, 17.42) 0.61
(0.34, 1.11) 0.44
(0.14, 0.79) 0.91
(0.75, 0.98) 4 3 5 29
I Mulcahy 71 Aspiration culture
Intraoperative Cultures and
Histology Hip 7.56
(3.08, 18.58) 0.34
(0.17, 0.71) 0.69
(0.41, 0.89) 0.91
(0.8, 0.97) 11 5 5 50
I Williams 273 Aspiration culture
Intraoperative Cultures Hip 12.47
(7.28, 21.37) 0.21
(0.13, 0.34) 0.8
(0.69, 0.89) 0.94
(0.89, 0.97) 57 13 14 189
96
Table 39. Synovial Fluid White Blood Cell Count
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Schinsky 201 WBC (4.2x10^3/μl)
At least 2 of: 1)a positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
Hip 12.21 (6.64, 22.46)
0.18 (0.1, 0.32)
0.84 (0.71, 0.92)
0.93 (0.88, 0.97)
46 10 9 136
I Schinsky 79
WBC (3.0x10^3/μl),
among patients with elevated ESR
and CRP
At least 2 of: 1)a positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
Hip 8.98 (3.06, 26.4)
0.11 (0.05, 0.26)
0.90 (0.78, 0.97)
0.90 (0.73, 0.98)
44 3 5 27
I Schinsky 79
WBC (9.0x10^3/μl),
among patients with elevated ESR
and CRP
At least 2 of: 1)a positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
Hip 8.16 (2.77, 24.1)
0.20 (0.11, 0.37)
0.82 (0.68, 0.91)
0.90 (0.73, 0.98)
40 3 9 27
97
Table 39. Synovial Fluid White Blood Cell Count (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Schinsky 60
WBC (3.0x10^3/μl),
among patients with elevated ESR or CRP, not
both
At least 2 of: 1)a positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
Hip 6.43 (2.95, 14)
0.19 (0.03, 1.15)
0.83 (0.36, 1)
0.87 (0.75, 0.95)
5 7 1 47
I Schinsky 60
WBC (9.0x10^3/μl),
among patients with elevated ESR or CRP, not
both
At least 2 of: 1)a positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
Hip 86.4 (5.3, 1402)
0.22 (0.05, 0.89)
0.83 (0.36, 1)
1 (0.93, 1) 5 0 1 54
98
Table 39. Synovial Fluid White Blood Cell Count (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Spangehl 183 WBC (5.0x10^4/μL)
at least 1 of: 1)open wound of sinus in
communication with the joint 2)systemic infection with pain
in the joint and purulent fluid within the joint 3)positive result on at least 3
investigations(ESR, CRP, preoperative aspiration, frozen
section, intraoperative
cultures
Hip 55.36 (7.37, 415.6)
0.65 (0.49, 0.85)
0.36 (0.19, 0.56)
0.99 (0.96, 1) 10 1 18 154
99
Table 40. Synovial Fluid Neutrophil Percentage
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Schinsky 201 >80% PMN
At least 2 of: 1)positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
Hip 4.78 (3.27, 6.97)
0.22 (0.12, 0.39)
0.82 (0.69, 0.91)
0.83 (0.76, 0.89) 45 25 10 121
I Schinsky 79
>80% PMN, among patients
with elevated ESR and
CRP
At least 2 of: 1)positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
Hip 8.78 (2.98, 25.8)
0.14 (0.06, 0.29)
0.88 (0.75, 0.95)
0.90 (0.73, 0.98) 43 3 6 27
100
Table 40. Synovial Fluid Neutrophil Percentage (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Spangehl 181 >80% Neutrophils
at least 1 of: 1)open wound of sinus in
communication with the joint 2)systemic
infection with pain in the joint and purulent fluid within the joint 3)positive result on at least 3 investigations
(ESR, CRP, preoperative
aspiration, frozen section, intraoperative
cultures
Hip 5.94 (3.99, 8.84)
0.13 (0.04, 0.37)
0.89 (0.72, 0.98)
0.85 (0.78, 0.9) 25 23 3 130
101
RECOMMENDATION 5 We suggest a repeat hip aspiration when there is a discrepancy between the probability of periprosthetic joint infection and the initial aspiration culture result.
Strength of Recommendation: Moderate
Rationale
A repeat hip aspiration is suggested when there is a discrepancy between the clinical probability of infection and the result of the initial aspiration culture.
One Level I study addressed this recommendation. This study examined performing a repeat hip aspiration in 28 patients because their initial aspiration result conflicted with the clinical suspicion for periprosthetic infection.4 This report suggests that repeat aspiration of the hip be considered when 1) the clinical probability of infection is low but the initial aspiration culture result is positive, or 2) if the clinical probability of infection is high and the initial aspiration culture result is negative (see Supporting Evidence below, for details).
The results of additional tests will raise or lower the probability of periprosthetic infection. The study on which this recommendation is based predated the more routine use and acceptance of synovial fluid white blood cell count and differential. Thus, depending on the results of the synovial fluid white blood cell count and differential, as well as the ESR and CRP, the diagnosis or exclusion of periprosthetic infection may be apparent and repeat aspiration may not be necessary.
Supporting Evidence
One study4 with reliable data performed repeat aspiration in 28 patients because the initial aspiration results contradicted clinical suspicions: 25 patients had a positive initial culture but no clinical or radiographic indication of infection while 3 patients had either a negative culture or a culture positive for S. epidermidis only but infection was clinically suspected. 24 of the 25 with a positive initial culture had a negative repeat aspiration; the other had a false positive repeat aspiration. The three patients with suspected infection each had two repeat aspirations. The second aspiration was negative in two and positive in one, while the third aspiration was positive in all three. Repeat aspiration was attempted but no fluid was obtained in five additional hips. The results are presented in Table 43.
102
EXCLUDED ARTICLES Table 41. Excluded Articles - Recommendation 5
Author Title Reason for Exclusion Fehring, et al.
1996 Aspiration as a guide to sepsis in revision total hip arthroplasty <25 patients
Glithero, et al. 1993 White cell scans and infected joint replacements. Failure to detect chronic infection <25 patients
Lachiewicz, et al. 1996
Aspiration of the hip joint before revision total hip arthroplasty. Clinical and laboratory factors influencing attainment of a positive culture <25 patients
Somme, et al. 2003
Contribution of routine joint aspiration to the diagnosis of infection before hip revision surgery <25 patients
Spangehl, et al. 1999
Prospective analysis of preoperative and intraoperative investigations for the diagnosis of infection at the sites of two hundred and two revision total hip arthroplasties <25 patients
Taylor, et al. 1995 Fine needle aspiration in infected hip replacements <25 patients
103
STUDY QUALITY Table 42. Repeat Aspiration - Quality
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Barrack 260 aspiration (initial) I ● ● ● ● ● ● ● ● ? ● ? ● ● ● Barrack 31 aspiration (repeat) I ● ● ● ● ● ● ● ● ? ● ? ● ● ●
STUDY RESULTS Table 43. Repeat Aspiration Results
Level of Evidence Author N Test Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood Ratio (95%
CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Barrack 260 Initial Aspiration Hip 4
(1.42, 11.23) 0.57
(0.21, 1.52) 0.5
(0.07, 0.93)
0.88 (0.83, 0.91)
2 33 2 224
I Barrack 31 Repeat Aspiration Hip 16.67
(2.25, 123.4) 0.35
(0.11, 1.08) 0.67
(0.22, 0.96) 0.96
(0.8, 1) 4 1 2 24
104
RECOMMENDATION 6 In the absence of reliable evidence, it is the opinion of the work group that lower probability hip arthroplasty patients without planned reoperation who have abnormal erythrocyte sedimentation rates OR abnormal C-reactive protein levels be re-evaluated for infection within three months. We are unable to recommend specific diagnostic tests at the time of this follow-up.
Strength of Recommendation: Consensus
Rationale
In the opinion of the work group, the possible harms associated with performing hip aspiration need to be weighed when conflicting erythrocyte sedimentation rates OR abnormal C-reactive protein levels are found in the patient. Lower probability hip arthroplasty patients without planned reoperation who have an abnormal ESR OR CRP are to be re-evaluated within three months. If the patient is asymptomatic, further testing may not be necessary.
Hip aspiration is a useful test to diagnose periprosthetic hip infection in patients who have a higher probability of infection and abnormal ESR or CRP as referenced in Recommendation 4. However, possible harms of joint aspiration include the possibility of false positive results, the possibility of the introduction of bacteria into the joint during the procedure and patient pain and/or discomfort while undergoing the procedure.4 There are also concerns about the cost of the procedure.4 Lower probability hip arthroplasty patients without planned reoperation who have an abnormal ESR OR CRP are to be re-evaluated within three months.
There is insufficient evidence to address whether further observation alone, diagnostic testing, or both can be recommended based on lack of available evidence to address the recommendation.
Hip arthroplasty patients at a lower probability of infection who have an isolated elevation in ESR OR CRP levels but without other objective or subjective evidence of periprosthetic infection include patients who have a known unrelated cause for this elevation. Such patients may not require future observation. However, this patient group also includes the low-grade subclinical infection or early onset periprosthetic infection that has not fully declared itself.
Because of the often insidious nature of periprosthetic infection, the orthopedic surgeon will need to use clinical judgment in each individual case. Options to consider include simple future observation with repeat ESR and CRP testing and reentering the patient into the diagnostic algorithm versus attempting to immediately establish the presence or absence of periprosthetic infection with additional testing. Discussion of available diagnostic procedures applicable to the individual patient relies on mutual communication between the patient and physician, weighing the potential risks and benefits for that patient. The ultimate judgment regarding any specific procedure or treatment must be made in light of all circumstances presented by the patient.
105
Supporting Evidence
We found no data specific to this patient population.
106
RECOMMENDATION 7 In the absence of reliable evidence, it is the opinion of the work group that a repeat knee aspiration be performed when there is a discrepancy between the probability of periprosthetic joint infection and the initial aspiration culture result.
Strength of Recommendation: Consensus
Rationale
It was the consensus of the work group that data be extrapolated from recommendation 5 for periprosthetic knee infections even though there was no reliable evidence pertaining to the utility of a repeat knee aspiration. (The available study5 enrolled too few patients to be reliable.) It is the opinion of the work group that repeat aspiration be performed when 1) the clinical probability of infection is low but the initial aspiration culture result is positive, or 2) if the clinical probability of infection is high and the initial aspiration culture result is negative. The final decision on whether to perform a repeat knee aspiration may also be influenced by other factors. The results of additional tests will raise or lower the probability of periprosthetic infection. Thus, depending on the results of ESR and CRP, as well as the synovial fluid white blood cell count and differential, the diagnosis or exclusion of periprosthetic infection may be more apparent and repeat aspiration may not be necessary.
Supporting Evidence
No studies met the inclusion criteria for this recommendation.
EXCLUDED ARTICLES Table 44. Excluded Article - Recommendation 7
Author Title Reason for Exclusion
Barrack, et al. 1997
The Coventry Award. The value of preoperative aspiration before total knee revision <25 patients
107
RECOMMENDATION 8 We suggest patients be off of antibiotics for a minimum of 2 weeks prior to obtaining intra-articular culture.
Strength of Recommendation: Moderate
Rationale
Culture “yield” (isolation of infecting organism) is lower in patients who are receiving or have recently (within two weeks) received antibiotics.105 This may be because elution of antibiotics into the joint fluid interferes with isolating the infecting organism by culture. Although, the exact “antibiotic-free” time needed to allow ”wash-out” of antibiotics from systemic circulation and the joint is not known, the work group has accepted two weeks as the minimum time required. One study showed that the false negative rate of cultures was significantly higher in patients who received antibiotics within two weeks of aspiration of a joint.105
Supporting Evidence
One included study with reliable data addressed whether antibiotic therapy decreases the sensitivity of intraoperative cultures in diagnosing periprosthetic infection.105 The group of patients who had received antimicrobial therapy within 14 days of surgery had a statistically significantly higher rate of false-negative culture results than those who had not. In this study, a positive result was defined as growth from at least two specimens.
108
EXCLUDED ARTICLES Table 45. Excluded Articles - Recommendation 8
Author Title Reason for Exclusion Barrack, et al.
1997 The Coventry Award. The value of preoperative aspiration before total knee revision <25 patients/arm
Datz, et al. 1986 Effect of antibiotic therapy on the sensitivity of indium-111-labeled leukocyte scans Not relevant - not
specific to pji Spangehl, et al.
1999 Prospective analysis of preoperative and intraoperative investigations for the diagnosis of
infection at the sites of two hundred and two revision total hip arthroplasties <25 patients/arm
Spangehl, et al. 1999
The role of intraoperative gram stain in the diagnosis of infection during revision total hip arthroplasty <25 patients/arm
Trampuz, et al. 2006
Sonication of explanted prosthetic components in bags for diagnosis of prosthetic joint infection is associated with risk of contamination <25 patients
109
STUDY QUALITY Table 46. Preoperative Antibiotic Therapy - Quality
● = Yes ○ = No
? =Unclear
Author N Index Test Level of Evidence Sp
ectru
m b
ias a
void
ed
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as a
void
ed
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Trampuz 78 Intraoperative Cultures (≥2) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
STUDY RESULTS Table 47. Preoperative Antibiotics and False-Negative Cultures Level of Evidence Author N Joint Reference Standard False Negatives Risk Ratio p-
value
I Trampuz 79 Mixed
At least 1 of: 1)visible purulence of synovial fluid or area surrounding the prosthesis
2)acute inflammation on histopathologic exam of permanent periprosthetic tissue
sections 3)a sinus tract communicating with the prosthesis
Antibiotics within 14 days: 55% No antibiotics within 14 days: 23%
2.38 (1.26, 4.51)
0.004
110
RECOMMENDATION 9 Nuclear imaging (Labeled leukocyte imaging combined with bone or bone marrow imaging, FDG-PET imaging, Gallium imaging, or labeled leukocyte imaging) is an option in patients in whom diagnosis of periprosthetic joint infection has not been established and are not scheduled for reoperation.
Strength of Recommendation: Weak
Rationale
The information presented throughout this guideline shows that there is no single preoperative investigation that can reliably diagnose an infection. Diagnosis usually depends on the combined use of numerous tests. Recognizing subclinical infections before revision surgery is, therefore, a major concern.
Patients in whom diagnosis of infection has not been established includes patients with a higher probability of infection who have abnormal ESR and/or CRP levels, but whose aspiration results are inconclusive (i.e., fluid cannot be obtained from the joint or culture and cell count results disagree).
The studies included for this recommendation, while of Level I and Level II quality, were not specific to patients not scheduled for reoperation, so the work group downgraded the strength of the recommendation from moderate to weak.
In addition, imaging studies may require special expertise and consultation with the imaging provider.
Technetium-99- or Indium-111-labeled-Leukocyte Imaging
Four included studies indicated that a Tc-99-labeled white blood cell scan was possibly a useful “rule in” test (range of positive LR:1.4-22),35, 93, 97, 101 while five included In-111 studies indicated that it was possibly useful as both a “rule in” and “rule out” test (range of positive LR: 2-14; range of negative LR: 0.03-0.63).35, 46, 63, 85, 87
Combined labeled-Leukocyte/Bone Imaging
Three included studies of combined Tc-99 bone scans and In-111 white blood cell scans also indicated the possible utility of these tests for confirming and excluding infection (range of positive LR:3-18, range of negative LR: 0.12- 0.47).46, 95, 102 One study of combined Tc-99 bone scans and Tc-99 white blood cell scans produced similar results (positive LR: 6, negative LR: 0.44).84
Combined labeled-Leukocyte/Bone Marrow Imaging
The four included studies of combined leukocyte/bone marrow imaging indicated that the test may be a good “rule in” and “rule out” test, but the results varied between studies (range of positive LR: 9.8-45, range of negative LR: 0.02- 0.34).47, 60, 67, 97
111
Gallium-67 Imaging
Two included studies indicated that it may be a good “rule in” test but the ability of this test to rule out infection was unclear (range of positive LR: 24-111, range of negative LR: 0.07-0.62).55, 88
FDG-PET Imaging
Three included studies of FDG-PET imaging indicated that the test is possibly good at both ruling in and ruling out infection but, again, the results varied between studies (range of positive LR: 11-19; range of negative LR: 0.16-0.66).15, 20, 60
Technetium-99m Bone Imaging
The three included studies of triple-phase Tc-99m bone scintigraphy varied in their estimates of the test’s diagnostic efficacy, limiting the ability to determine whether the test is effective at either confirming or excluding infection (range of positive LR: 2-8, range of negative LR: 0.1-0.8).9, 58, 73 One included study of two-phase Tc-99m bone scintigraphy provided no evidence of diagnostic efficacy (positive LR: 1.0, negative LR: 1.7).97 Based on these studies, triple-phase Tc-99m bone imaging may be possibly useful; however, there is no consistent evidence of diagnostic benefit. Therefore more study is needed.
Computed Tomography (CT) and Magnetic Resonance Imaging, MRI
Please refer to Recommendation 10 for information concerning these modalities.
Supporting Evidence
The indications for performing nuclear imaging varied between studies, and thus the results presented here are not specific to patients not scheduled for reoperation. This reduces the applicability of these studies’ findings and, hence, the strength of recommendation.
Technetium-labeled leukocyte imaging: We included four studies: one study of mixed hip and knee patients with reliable data (could separate out according to site but less than 25 knee patients), two studies of hip patients with moderately reliable data, and one study of mixed patients with moderately reliable data.35, 93, 97, 101 Estimates of the positive likelihood ratio ranged from 1.4-22, while estimates of the negative LR ranged from 0.06-0.52. Meta-analysis of these studies indicated between-study heterogeneity (I2 = 97%), limiting the ability to draw conclusions. The results are presented in Table 51.
Indium-labeled leukocyte imaging: We included five studies: one of hip patients, one of knee patients, and three of mixed patients.35, 46, 63, 85, 87 All but one study contained moderately reliable data. Meta-analysis of these studies indicated between-study heterogeneity (I2 = 85%), as the positive likelihood ratio point estimates ranged from 2-14 and the negative LR ranged from 0.03-0.63. The results are presented in Table 52.
112
Combined labeled-leukocyte/bone imaging: We included three Tc-99m HDP/In-111 leukocyte studies of mixed patients (could separate hip from knee patients in one) with reliable data in one study and moderately reliable data in the other two.46, 95, 102 We also included one Tc-99m MDP/Tc-99 leukocyte study of hip patients with moderately reliable data.82 Each study found statistically significant results for positive and negative likelihood ratios (range of positive LR:3-18, range of negative LR: 0.12- 0.47). Meta-analysis of these four studies indicates small or moderate diagnostic effects (positive LR: 5.8, negative LR: 0.32). The results are presented in Table 53.
Combined labeled-leukocyte/bone marrow imaging: We included three studies of mixed patients with reliable data in one study and moderately reliable data in the other two.47, 60,
97 We also included one study of hip patients with moderately reliable data.67 Each study found statistically significant results for positive and negative likelihood ratios (range of positive LR: 9.8-45, range of negative LR: 0.02- 0.34). Meta-analysis of these studies indicated between-study heterogeneity (I2 = 55%), limiting the ability to draw conclusions. The results are presented in Table 54.
Gallium imaging: We included two studies with moderately reliable data.55, 88 Both positive and negative likelihood ratios were statistically significant and suggest that gallium imaging may be a good “rule in” test (range of positive LR: 24-111), but its usefulness at ruling out infection is unclear (negative LR range: 0.07 – 0.62). The results are presented in Table 55.
FDG-PET: We included one study of hip patients with reliable data and two studies of mixed hip and knee patients with moderately reliable data.15, 20, 60 All three studies found a statistically significant result for positive likelihood ratios, and two of the three found a statistically significant result for negative likelihood ratios. The results are presented in Table 56.
Tc-99m bone imaging: We included two studies of hip patients (one with reliable data, one with moderately reliable data) and two studies of mixed hip and knee patients (both with reliable data).9, 58, 73, 97 Three of the studies investigated triple-phase bone imaging, 9,
58, 73 while one investigated two-phase bone imaging.97 For triple-phase bone imaging, estimates of the positive likelihood ratio ranged from 2.3-8.5 and estimates of the negative likelihood ratio ranged from 0.1-0.8, indicating possible, but inconsistent, small-to-moderate diagnostic benefit. The two-phase bone imaging results (positive LR of 1.0 and a negative LR of 1.7) indicated a lack of diagnostic benefit. The results are presented in Table 57.
Other imaging: We included one additional study with reliable data of antigranulocyte antibody scintigraphy among knee patients53 and one study with moderately reliable data of nanocolloid scintigraphy among hip patients.9 The diagnostic effects were significant but with wide confidence intervals for both studies. The results are presented in Table 58.
113
SUMMARY OF EVIDENCE Table 48. Nuclear Imaging Summary of Evidence
Test Number
of Studies
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)
Tc-labeled WBC imaging (range) 4 1.39 – 22.0 0.06 – 0.52 0.5 - 1 0.31 - 1
In-labeled WBC imaging (range) 5 1.9 – 14.0 0.03 – 0.63 0.38 - 1 0.5 - 1
Combined bone/ labeled WBC
imaging 4 5.8 (3.1, 10.8)
0.32 (0.20, 0.50)
0.72 (0.59, 0.82)
0.88 (0.79, 0.93)
Combined bone marrow/labeled WBC imaging
(range) 4 9.8 – 45.5 0.02 – 0.34 0.67 - 1 0.91 – 1
Gallium imaging (range) 2 24.4 -111 0.07 – 0.62 0.38 – 0.95 1
FDG-PET imaging (range) 3 11.4 – 19.2 0.16 – 0.66 0.36 – 0.85 0.93 – 1
Triple-phase bone imaging
(range) 3 2.33 – 8.53 0.13 - 0.78 0.33 – 0.88 0.76 – 0.90
Dual-phase bone imaging 1 0.99
(0.94, 1.05) 1.72
(0.04, 84.59) 1
(0.88, 1) 0
(0, 0.07)
*Range presented when fewer than four studies or when meta-analysis indicated heterogeneity
114
EXCLUDED ARTICLES Table 49. Excluded Articles - Recommendation 9
Author Title Reason for Exclusion Achong, et al.
1994 The computer-generated bone marrow subtraction image: a valuable adjunct to combined
In-111 WBC/Tc-99m in sulfur colloid scintigraphy for musculoskeletal infection Not relevant - not
specific to pji Aliabadi, et al.
1989 Cemented total hip prosthesis: radiographic and scintigraphic evaluation Not best available evidence
Bauer, et al. 1973 85Sr radionuclide scintimetry in infected total hip arthroplasty <25 patients/arm
Becker, et al. 1996 Rapid imaging of infections with a monoclonal antibody fragment (LeukoScan) <25 patients
Bernard, et al. 2004
Value of preoperative investigations in diagnosing prosthetic joint infection: retrospective cohort study and literature review
Not best available evidence
Boubaker, et al. 1995
Immunoscintigraphy with antigranulocyte monoclonal antibodies for the diagnosis of septic loosening of hip prostheses
Not best available evidence
Britton, et al. 1997 Clinical evaluation of technetium-99m infecton for the localisation of bacterial infection Not relevant - not
specific to pji Chacko, et al.
2003 Applications of fluorodeoxyglucose positron emission tomography in the diagnosis of
infection Not best available
evidence Chacko, et al.
2002 The importance of the location of fluorodeoxyglucose uptake in periprosthetic infection in
painful hip prostheses Not best available
evidence Chafetz, et al.
1985 Multinuclide digital subtraction imaging in symptomatic prosthetic joints Not best available evidence
Chik, et al. 1996
Tc-99m stannous colloid-labeled leukocyte scintigraphy in the evaluation of the painful arthroplasty
Not best available evidence
115
Table 49. Excluded Articles (Continued) Author Title Reason for Exclusion
Crokaert, et al. 1982 Gallium-67 citrate as an aid to the diagnosis of infection in hip surgery <25 patients/arm
Dams, et al. 2000
99mTc-PEG liposomes for the scintigraphic detection of infection and inflammation: clinical evaluation <25 patients
Datz, et al. 1994 The efficacy of indium-111-polyclonal IgG for the detection of infection and inflammation Not relevant - not
specific to pji Datz, et al.
1986 Effect of antibiotic therapy on the sensitivity of indium-111-labeled leukocyte scans Not relevant - not specific to pji
de Lima Ramos, et al. 1996
Simultaneous administration of 99Tcm-HMPAO-labelled autologous leukocytes and 111In-labelled non-specific polyclonal human immunoglobulin G in bone and joint
infections <25 patients
de Winter, et al. 2001
Fluorine-18 fluorodeoxyglucose-position emission tomography: a highly accurate imaging modality for the diagnosis of chronic musculoskeletal infections <25 patients
Demirkol, et al. 1997 99Tc(m)-polyclonal IgG scintigraphy in the detection of infected hip and knee prostheses Not best available
evidence Devillers, et al.
1995 Technetium-99m hexamethylpropylene amine oxime leucocyte scintigraphy for the
diagnosis of bone and joint infections: a retrospective study in 116 patients Not best available
evidence El Esper, et al.
2004 The usefulness of 99mTc sulfur colloid bone marrow scintigraphy combined with 111In
leucocyte scintigraphy in prosthetic joint infection Not best available
evidence Feith, et al.
1976 Strontium 87mSr bone scanning for the evaluation of total hip replacement Not relevant - not specific to pji
Flivik, et al. 1993
Technetium-99m-nanocolloid scintigraphy in orthopedic infections: a comparison with indium-111-labeled leukocytes <25 patients
Gomez-Luzuriaga, et al. 1988 Scintigraphy with Tc, Ga and In in painful total hip prostheses <25 patients/arm
116
Table 49. Excluded Articles (Continued) Author Title Reason for Exclusion
Hall, et al. 1998 Evaluation of the efficacy of 99mTc-Infecton, a novel agent for detecting sites of infection Not relevant - not
specific to pji Henderson, et al.
1996 The value of skeletal scintigraphy in predicting the need for revision surgery in total knee
replacement Not best available
evidence Itasaka, et al.
2001 Diagnosis of infection after total hip arthroplasty Not best available evidence
Ivancevic, et al. 2002
Imaging of low-grade bone infection with a technetium-99m labelled monoclonal anti-NCA-90 Fab' fragment in patients with previous joint surgery <25 patients
Iyengar, et al. 2005 Role of 99mTc Sulesomab in the diagnosis of prosthetic joint infections Not best available
evidence Jaruskova, et al.
2006 Role of FDG-PET and PET/CT in the diagnosis of prolonged febrile states Not relevant - not specific to pji
Jensen, et al. 1990 Tc-99m-MDP scintigraphy not informative in painful total hip arthroplasty Not relevant - not
specific to pji Larikka, et al.
2001 Improved method for detecting knee replacement infections based on extended combined
99mTc-white blood cell/bone imaging Not best available
evidence Larikka, et al.
2001 Extended combined 99mTc-white blood cell and bone imaging improves the diagnostic
accuracy in the detection of hip replacement infections Not best available
evidence
Larikka, et al. 2002
Comparison of 99mTc ciprofloxacin, 99mTc white blood cell and three-phase bone imaging in the diagnosis of hip prosthesis infections: improved diagnostic accuracy with
extended imaging time
Not best available evidence
Li, et al. 1994
Bone scintigraphy of hip prostheses: Can analysis of patterns of abnormality improve accuracy?
Not relevant - not specific to pji
Lieberman, et al. 1993 Evaluation of painful hip arthroplasties. Are technetium bone scans necessary? Not best available
evidence
117
Table 49. Excluded Articles (Continued) Author Title Reason for Exclusion
Love, et al. 2001 Role of nuclear medicine in diagnosis of the infected joint replacement Narrative review,
bibliography screened Manthey, et al.
2002 The use of [18 F]fluorodeoxyglucose positron emission tomography to differentiate
between synovitis, loosening and infection of hip and knee prostheses <25 patients
McInerney, et al. 1978 Technetium 99Tcm pyrophosphate scanning in the assessment of the painful hip prosthesis Insufficient Data
Merkel, et al. 1985
Comparison of indium-labeled-leukocyte imaging with sequential technetium-gallium scanning in the diagnosis of low-grade musculoskeletal sepsis. A prospective study <25 patients
Merkel, et al. 1986
Sequential technetium-99m HMDP-gallium-67 citrate imaging for the evaluation of infection in the painful prosthesis
>10% prostheses already removed
Miles, et al. 1992
Scintigraphic abnormalities in patients with painful hip replacements treated conservatively Insufficient Data
Moragas, et al. 1991 99Tcm-HMPAO leucocyte scintigraphy in the diagnosis of bone infection Not best available
evidence Mountford, et al.
1986 99Tcm-MDP, 67Ga-citrate and 111In-leucocytes for detecting prosthetic hip infection Not best available evidence
Mumme, et al. 2005
Diagnostic values of positron emission tomography versus triple-phase bone scan in hip arthroplasty loosening Insufficient Data
Nijhof, et al. 1997 Hip and knee arthroplasty infection. In-111-IgG scintigraphy in 102 cases Not best available
evidence Nijhof, et al.
1997 Evaluation of infections of the locomotor system with indium-111-labeled human IgG
scintigraphy Not best available
evidence Ouzounian, et al.
1987 Evaluation of musculoskeletal sepsis with indium-111 white blood cell imaging <25 patients
118
Table 49. Excluded Articles (Continued) Author Title Reason for Exclusion
Oyen, et al. 1991
Detection of subacute infectious foci with indium-111-labeled autologous leukocytes and indium-111-labeled human nonspecific immunoglobulin G: a prospective comparative
study
Not relevant - not specific to pji
Oyen, et al. 1990
Scintigraphic detection of bone and joint infections with indium-111-labeled nonspecific polyclonal human immunoglobulin G
Not relevant - not specific to pji
Oyen, et al. 1992
Diagnosis of bone, joint, and joint prosthesis infections with In-111-labeled nonspecific human immunoglobulin G scintigraphy
Not best available evidence
Pakos, et al. 2007
Prosthesis infection: diagnosis after total joint arthroplasty with antigranulocyte scintigraphy with 99mTc-labeled monoclonal antibodies--a meta-analysis
Systematic review, bibliography screened
Pakos, et al. 2007
Use of (99m)Tc-sulesomab for the diagnosis of prosthesis infection after total joint arthroplasty <25 patients
Palermo, et al. 1998
Comparison of technetium-99m-MDP, technetium-99m-WBC and technetium-99m-HIG in musculoskeletal inflammation
Not relevant - not specific to pji
Palestro, et al. 1990
Total-hip arthroplasty: periprosthetic indium-111-labeled leukocyte activity and complementary technetium-99m-sulfur colloid imaging in suspected infection
Not best available evidence
Palestro, et al. 1992
Diagnosis of musculoskeletal infection using combined In-111 labeled leukocyte and Tc-99m SC marrow imaging
Not relevant - not specific to pji
Palestro, et al. 1991
Infected knee prosthesis: diagnosis with In-111 leukocyte, Tc-99m sulfur colloid, and Tc-99m MDP imaging
Not best available evidence
Parvizi, et al. 2006 Periprosthetic infection: What are the diagnostic challenges? Not best available
evidence Pearlman, et al.
1980 The painful hip prosthesis: value of nuclear imaging in the diagnosis of late complications Insufficient Data
Pelosi, et al. 2004
99mTc-HMPAO-leukocyte scintigraphy in patients with symptomatic total hip or knee arthroplasty: improved diagnostic accuracy by means of semiquantitative evaluation
Not best available evidence
119
Table 49. Excluded Articles (Continued) Author Title Reason for Exclusion
Pill, et al. 2006
Comparison of fluorodeoxyglucose positron emission tomography and (111)indium-white blood cell imaging in the diagnosis of periprosthetic infection of the hip
Not best available evidence
Prchal, et al. 1987 Detection of musculoskeletal infection with the indium-III leukocyte scan Not relevant - not
specific to pji Pring, et al.
1986 Indium-granulocyte scanning in the painful prosthetic joint Duplicate data
Reinartz, et al. 2009
FDG-PET in patients with painful hip and knee arthroplasty: technical breakthrough or just more or the same
Systematic review, bibliography screened
Reinartz, et al. 2005
Radionuclide imaging of the painful hip arthroplasty: positron-emission tomography versus triple-phase bone scanning
Not best available evidence
Reuland, et al. 1991
Detection of infection in postoperative orthopedic patients with technetium-99m-labeled monoclonal antibodies against granulocytes
Not relevant - not specific to pji
Rosas, et al. 1998
Contribution of laboratory tests, scintigraphy, and histology to the diagnosis of lower limb joint replacement infection <25 patients per group
Rubello, et al. 1995 Three-phase bone scintigraphy pattern of loosening in uncemented hip prostheses Not relevant - not
specific to pji Rubello, et al.
2004 Role of anti-granulocyte Fab' fragment antibody scintigraphy (LeukoScan) in evaluating
bone infection: acquisition protocol, interpretation criteria and clinical results Not relevant - not
specific to pji Rubello, et al.
2008 Diagnosis of infected total knee arthroplasty with anti-granulocyte scintigraphy: the
importance of a dual-time acquisition protocol Not best available
evidence Rubin, et al.
1989 111In-labeled nonspecific immunoglobulin scanning in the detection of focal infection Not relevant - not specific to pji
Rushton, et al. 1982 The value of technetium and gallium scanning in assessing pain after total hip replacement Not best available
evidence
120
Table 49. Excluded Articles (Continued) Author Title Reason for Exclusion Ryan, 2002 Leukoscan for orthopaedic imaging in clinical practice Not best available
evidence Sayle, et al.
1985 Indium-111 chloride imaging in the detection of infected prostheses <25 patients
Sciuk, et al. 1992
White blood cell scintigraphy with monoclonal antibodies in the study of the infected endoprosthesis
Not best available evidence
Serafini, et al. 1991
Clinical evaluation of a scintigraphic method for diagnosing inflammations/infections using indium-111-labeled nonspecific IgG
Not relevant - not specific to pji
Sfakianakis, et al. 1982
Comparisons of scintigraphy with In-111 leukocytes and Ga-67 in the diagnosis of occult sepsis
Not relevant - not specific to pji
Simonsen, et al. 2007
White blood cell scintigraphy for differentiation of infection and aseptic loosening: a retrospective study of 76 painful hip prostheses
Not best available evidence
Smith, et al. 2001
Radionuclide bone scintigraphy in the detection of significant complications after total knee joint replacement
Not best available evidence
Spinelli, 1976
The role of scintigraphy in the diagnosis of late complications of total prosthesis of the hip. (Infection, loosening, ossification) Insufficient Data
Streule, et al. 1988
99Tcm-labelled HSA-nanocolloid versus 111In oxine-labelled granulocytes in detecting skeletal septic process <25 eligible patients
Stumpe, et al. 2004
FDG PET for differentiation of infection and aseptic loosening in total hip replacements: comparison with conventional radiography and three-phase bone scintigraphy
Not best available evidence
Stumpe, et al. 2006 The value of FDG-PET in patients with painful total knee arthroplasty Not best available
evidence Taylor, et al.
1989 A simple method of identifying loosening or infection of hip prostheses in nuclear
medicine Not best available
evidence Tehranzadeh, et al.
1981 Radiological evaluation of painful total hip replacement Not best available evidence
121
Table 49. Excluded Articles (Continued) Author Title Reason for Exclusion
Van Acker, et al. 2001
FDG-PET, 99mtc-HMPAO white blood cell SPET and bone scintigraphy in the evaluation of painful total knee arthroplasties <25 patients
Vanquickenborne, et al. 2003 The value of (18)FDG-PET for the detection of infected hip prosthesis <25 patients per arm
Vicente, et al. 2004
Diagnosis of orthopedic infection in clinical practice using Tc-99m sulesomab (antigranulocyte monoclonal antibody fragment Fab'2)
Not best available evidence
Vinjamuri, et al. 1996
Comparison of 99mTc infecton imaging with radiolabelled white-cell imaging in the evaluation of bacterial infection
Not relevant - not specific to pji
Virolainen, et al. 2002 The reliability of diagnosis of infection during revision arthroplasties Not best available
evidence von Rothenburg, et al.
2004 Imaging of infected total arthroplasty with Tc-99m-labeled antigranulocyte antibody
Fab'fragments Not best available
evidence Weiss, et al.
1979 99mTc-methylene diphosphonate bone imaging in the evaluation of total hip prostheses <25 patients/arm
Wellman, et al. 1988 Evaluation of metallic osseous implants with nuclear medicine Insufficient Data
Williams, et al. 1977
99Tcm-diphosphonate scanning as an aid to diagnosis of infection in total hip joint replacements <25 patients/arm
Williams, et al. 1981 Gallium-67 scanning in the painful total hip replacement Not best available
evidence Wolf, et al.
2003 Localization and diagnosis of septic endoprosthesis infection by using 99mTc-HMPAO
labelled leucocytes Not best available
evidence Wukich, et al.
1987 Diagnosis of infection by preoperative scintigraphy with indium-labeled white blood cells <25 patients with prosthesis
122
Table 49. Excluded Articles (Continued) Author Title Reason for Exclusion
Yapar, et al. 2001
The efficacy of technetium-99m ciprofloxacin (Infecton) imaging in suspected orthopaedic infection: a comparison with sequential bone/gallium imaging <25 patients
Zhuang, et al. 2002 Persistent non-specific FDG uptake on PET imaging following hip arthroplasty <25 patients
Zhuang, et al. 2001 The promising role of 18F-FDG PET in detecting infected lower limb prosthesis implants Not best available
evidence Zoccali, et al.
2009 The role of FDG-PET in distinguishing between septic and aseptic loosening in hip
prosthesis: a review of literature Systematic review,
bibliography screened
123
STUDY QUALITY Table 50. Nuclear Imaging - Quality
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Nagoya 46 3-phase bone scintigraphy I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Klett 28 antigranulocyte antibody BW 250/183 scintigraphy I ? ● ● ● ● ● ● ● ● ● ● ● ● ●
Glithero 25 In-111 leukocyte scan I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Joseph 36 In-111 leukocyte/Tc-99m sulfur colloid scans I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Joseph 58 In -111 leukocyte/Tc-99m sulfur colloid scans I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Joseph 36 In -111 leukocyte/Tc-99m sulfur
colloid scans and with blood pooling and flow phase data
I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Joseph 58 In -111 leukocyte/Tc-99m sulfur
colloid scans and with blood pooling and flow phase data
I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Glithero 31 Tc-99m HMPAO leukocyte scintigraphy I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Glithero 45 Tc-99m HMPAO or In-111-oxine leukocyte scan I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
124
Table 50. Nuclear Imaging – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Glithero 56 Tc-99m HMPAO or In-111-oxine leukocyte scan I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Teller 166 Tc-99m HPD/In-111 leukocyte scan I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
Reing 79 Ga-67 scan II ? ○ ● ● ● ● ● ● ○ ● ● ● ● ●
Pring 40 In-111 granulocyte scan II ? ○ ● ● ● ● ● ● ● ● ? ● ● ●
Mulamba 30 In-111 leukocyte/sulfur colloid scan II ? ○ ● ● ● ● ● ● ○ ● ● ● ● ●
Rand 38 In-111 leukocyte scan II ● ○ ● ● ● ● ● ● ● ● ? ● ● ●
Magnuson 98 In-111 leukocyte scan II ? ○ ● ● ● ● ● ● ? ● ? ● ● ●
Johnson 29 In-111 leukocyte scan II ● ● ● ● ● ● ● ● ○ ● ● ● ● ●
Kraemer 33 sequential scan and aspiration II ? ? ● ● ● ● ● ? ○ ● ● ● ● ●
Kraemer 43 sequential Tc-99m bone scan/Ga-67 scan II ? ? ● ● ● ● ● ? ○ ● ● ● ● ●
Johnson 29 Tc-99m HDP/In-111 leukocyte scan II ● ● ● ● ● ● ● ● ○ ● ● ● ● ●
125
Table 50. Nuclear Imaging – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Scher 91 Tc-99m HDP/indium-111-labeled
leukocyte scan (positive if incongruent scans)
II ? ○ ● ● ● ● ● ● ● ● ? ● ● ●
Scher 40 Tc-99m HDP/indium-111-labeled
leukocyte scan (positive if incongruent scans)
II ? ○ ● ● ● ● ● ● ● ● ? ● ● ●
Savarino 26 Tc-99m –HMPAO scan II ● ● ● ● ● ● ● ○ ● ● ● ● ● ○
Savarino 26 Tc-99m –HMPAO scan II ● ● ● ● ● ● ● ○ ● ? ? ● ● ○
Savarino 26 Tc-99m –HMPAO scan II ● ● ● ● ● ● ● ○ ● ? ? ● ● ○ Benitez Segura 77 Tc-99m HMPAO leukocyte
scintigraphy II ● ● ● ● ● ● ● ● ○ ● ● ● ● ●
Benitez Segura 77
Tc-99m HMPAO leukocyte/Tc-99m stannous microcolloid bone marrow
scan II ● ● ● ● ● ● ● ● ○ ● ● ● ● ●
Benitez Segura 77
Tc-99m HMPAO leukocyte/Tc-99m stannous microcolloid bone marrow
scan/Tc-99m MDP bone scan II ● ● ● ● ● ● ● ● ○ ● ● ● ● ●
Benitez Segura 77 Tc-99m MDP bone scan II ● ● ● ● ● ● ● ● ○ ● ● ● ● ●
126
Table 50. Nuclear Imaging – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Bernay 31 Tc-99m MDP scintigraphy II ● ● ? ● ● ● ● ○ ● ● ? ● ● ●
Levitsky 58 Tc-99m MDP TPBI II ● ? ● ● ● ● ● ● ● ● ● ? ● ○
Levitsky 54 Tc-99m MDP TPBI and plain radiographs II ● ? ● ● ● ● ● ? ● ● ● ? ● ○
Pons 78
Tc-99m MDP, Tc-99 HmPAO white blood cells scintigraphy (positive if areas of increased isotope uptake for Tc were congruent with high levels of white blood cell labelled with Tc)
II ● ○ ● ● ● ● ● ● ○ ● ? ? ● ●
Bernay 31 Tc-99m nanocolloid scintigraphy II ● ● ? ● ● ● ● ○ ● ● ? ● ● ●
Sudanese 35 Tc-99m-labelled granulocyte bone scan II ? ? ● ● ● ● ● ● ○ ● ● ● ● ●
Love 59 WBC/marrow imaging II ? ● ● ● ● ● ● ● ○ ● ? ● ● ●
Chryssikos 127 FDG-PET - increased FDG uptake at prosthesis-bone interface I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Delank 27 FDG-PET - FDG uptake in the periprosthetic soft tissue II ● ● ? ● ● ● ● ● ○ ● ? ● ● ●
127
Table 50. Nuclear Imaging – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Love 59
FDG-PET - activity at bone-prosthesis interface (of femoral
component for hip, femoral or tibial for knee)
II ? ● ● ● ● ● ● ● ○ ● ? ● ● ●
Love 59 FDG-PET - any periprosthetic activity II ? ● ● ● ● ● ● ● ○ ● ? ● ● ●
Love 59 FDG-PET - semiquantitative
analysis of bone-prostesis interface activity (target-background ratio)
II ? ● ● ● ● ● ● ● ○ ● ? ● ● ●
Love 59
FDG-PET/WBC marrow - any perisprosthetic activity on FDG image without corresponding
activity on marrow image
II ? ● ● ● ● ● ● ● ○ ● ? ● ● ●
128
STUDY RESULTS Figure 13. Technetium-labeled-Leukocyte Imaging Results – Likelihood Ratios
StudyId
Glithero - Hip - Tc or In
Savarino
Sudanese
Glithero - Hip and Knee - Tc only
Glithero - Hip and Knee - Tc or In
Benitez Segura
101 2 5
DLR POSITIVE
StudyId
Glithero - Hip - Tc or In
Savarino
Sudanese
Glithero - Hip and Knee - Tc only
Glithero - Hip and Knee - Tc or In
Benitez Segura
1.1 .2 .5
DLR NEGATIVE
129
Figure 14. Indium-labeled-Leukocyte Imaging Results - Likelihood Ratios
StudyId
Glithero
Rand
Magnuson
Johnson
Pring
10521DLR POSITIVE
StudyId
Glithero
Rand
Magnuson
Johnson
Pring
1.1 .2 .5DLR NEGATIVE
Figure 15. Combined Leukocyte/Bone Imaging Results – Likelihood Ratios
StudyId
COMBINED
Teller
Johnson
Scher
Pons
1 2 5 10DLR POSITIVE
StudyId
COMBINED
Teller
Johnson
Scher
Pons
0 .1 .2 .5 1DLR NEGATIVE
130
Figure 16. Combined Leukocyte/Bone Marrow Imaging Results - Likelihood Ratios
StudyId
Love
Benitez Segura
Mulamba
Joseph - Hip & Knee with phase data
Joseph - Hip & Knee
Joseph - Hip with phase data
Joseph - Hip
101 2 5
DLR POSITIVE
StudyId
Love
Benitez Segura
Mulamba
Joseph - Hip & Knee with phase data
Joseph - Hip & Knee
Joseph - Hip with phase data
Joseph - Hip
1.1 .2 .5
DLR NEGATIVE
Figure 17. FDG-PET Imaging Results - Likelihood Ratios
StudyId
Love - FDG-PET/WBC marrow
Love - semiquantitative analysis of BPI activity
Love - any periprosthetic activity
Love - activity at BPI
Delank - uptake in the periprosthetic soft tissue
Chryssikos - increased uptake at BPI
1 2 5 10
DLR POSITIVE
StudyId
Love - FDG-PET/WBC marrow
Love - semiquantitative analysis of BPI activity
Love - any periprosthetic activity
Love - activity at BPI
Delank - uptake in the periprosthetic soft tissue
Chryssikos - increased uptake at BPI
1.1 .2 .5
DLR NEGATIVE
131
Figure 18. Technetium-99m Bone Imaging Results - Likelihood Ratios
StudyId
Nagoya
Bernay
Benitez Segura
Levitsky
1 2 5 10DLR POSITIVE
StudyId
Nagoya
Bernay
Benitez Segura
Levitsky
.1.2 .5 1DLR NEGATIVE
*Benitez Segura used 2-phase rather than 3-phase bone imaging
132
Figure 19. Other Nuclear Imaging Results - Likelihood Ratios
StudyId
Bernay - nanocolloid scintigraphy
Klett - antibody BW 250/183 scintigraphy
Kraemer - Sequential scan or aspiration
Kraemer - Sequential bone/Ga-67 scan
Reing - Ga-67 scan
1 2 510
DLR POSITIVE
StudyId
Bernay - nanocolloid scintigraphy
Klett - antibody BW 250/183 scintigraphy
Kraemer - Sequential scan or aspiration
Kraemer - Sequential bone/Ga-67 scan
Reing - Ga-67 scan
.1 .2 .5 1
DLR NEGATIVE
133
Table 51. Technetium-99m-labeled-Leukocyte Imaging
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Glithero 45
Tc-99m HMPAO or
In-111-oxine
leukocyte scan
Intraoperative cultures Hip
16.5 (0.91,
298.82)
0.76 (0.56, 1.03)
0.23 (0.05, 0.54)
1 (0.89, 1) 3 0 10 32
II Savarino 26
Tc-99m-HMPAO
granulocyte scintigraphy
Intraoperative cultures Hip
7.12 (0.44,
116.34)
0.71 (0.5, 1.01)
0.31 (0.11, 0.59)
1 (0.69, 1) 5 0 11 10
II Savarino 26
Tc-99m-HMPAO
granulocyte scintigraphy
Histology Hip 12.69 (0.77,
208.34)
0.6 (0.37, 0.96)
0.42 (0.15, 0.72)
1 (0.77, 1) 5 0 7 14
II Savarino 26
Tc-99m-HMPAO
granulocyte scintigraphy
Intraoperative cultures and
histology Hip
17 (1.04,
277.87)
0.52 (0.28, 0.94)
0.5 (0.19, 0.81)
1 (0.79, 1) 5 0 5 16
II Sudanese 35 Tc-99m
granulocyte bone scan
Intraoperative cultures Hip
7.56 (2.8,
20.39)
0.06 (0, 0.94)
1 (0.63, 1)
0.89 (0.71, 0.98)
8 3 0 24
134
Table 51. Technetium-99m-labeled-Leukocyte Imaging (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Glithero 31
Tc-99m HMPAO leukocyte
scintigraphy
Intraoperative cultures
Mixed (20 hip, 11
knee)
22 (1.33,
362.92)
0.51 (0.28, 0.93)
0.5 (0.19, 0.81)
1 (0.84, 1) 5 0 5 21
I Glithero 56
Tc-99m HMPAO or
In-111-oxine
leukocyte scan
Intraoperative cultures
Mixed (45 hip, 11
knee)
34.89 (2.12,
573.23)
0.56 (0.37, 0.84)
0.44 (0.22, 0.69)
1 (0.91, 1) 8 0 10 38
II Benitez Segura 77
Tc-99m HMPAO leukocyte
scintigraphy
Intraoperative cultures
Mixed (48 hip, 29
knee)
1.39 (1.14, 1.7)
0.12 (0.02, 0.84)
0.96 (0.82, 1)
0.31 (0.18, 0.45)
27 34 1 15
135
Table 52. Indium-111-labeled-Leukocyte Imaging
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Glithero 25 In-111
leukocyte scan
Intraoperative cultures Hip
14 (0.81,
242.78)
0.63 (0.37, 1.06)
0.38 (0.09, 0.76)
1 (0.8, 1) 3 0 5 17
II Rand 38 In-111
leukocyte scan
at least 2 of: 1)positive
culture results 2)acute
inflammatory histologic findings 3)clinical
sepsis with pus within the joint
Knee 5.56
(1.92, 16.09)
0.2 (0.07, 0.56)
0.83 (0.59, 0.96)
0.85 (0.62, 0.97)
15 3 3 17
II Magnuson 98 In-111
leukocyte scan
Intraoperative cultures or histology
Mixed 3.25 (2.02, 5.23)
0.16 (0.08, 0.36)
0.88 (0.76, 0.95)
0.73 (0.58, 0.85)
44 13 6 35
II Johnson 29 In-111
leukocyte scan
Intraoperative cultures Mixed 1.9
(1.21, 2.98) 0.1
(0.01, 1.54) 1
(0.66, 1)
0.5 (0.27, 0.73)
9 10 0 10
II Pring 40 In-111
granulocyte scan
Intraoperative cultures or
histology or deep abscess
Mixed8.96
(2.77, 28.94)
0.03 (0, 0.46)
1 (0.81, 1)
0.91 (0.71, 0.99)
18 2 0 20
136
Table 53. Combined Leukocyte/Bone Imaging
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
II Pons 78
Tc-99m MDP, Tc-99
HMPAO leukocyte
scintigraphy
Intraoperative cultures and
histology Hip
6.3 (2.65, 14.98)
0.44 (0.24, 0.83)
0.6 (0.32, 0.84)
0.9 (0.8, 0.96) 9 6 6 57
II Scher 91*
Tc-99m HDP/In-111
leukocyte scan
At least 2 of: 1)positive
intraoperative cultures (either broth or plate)
2)intraoperative findings of gross purulence within the joint 3)final
permanent histologic section incidcating acute
inflammation based on ≥10
PMN/HPF in 5 areas
Hip 8.1
(3.22, 20.35)
0.43 (0.2, 0.93)
0.6 (0.26, 0.88)
0.93 (0.85, 0.97)
6 6 4 75
137
Table 53. Combined Leukocyte/Bone Imaging (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
II Scher 40*
Tc-99m HDP/In-
111 leukocyte
scan
At least 2 of: 1)positive
intraoperative cultures (either broth or plate)
2)intraoperative findings of gross purulence within the joint 3)final
permanent histologic section incidcating acute
inflammation based on ≥10
PMN/HPF in 5 areas
Knee 4.06 (1.83, 8.98)
0.15 (0.04, 0.56)
0.88 (0.64, 0.99)
0.78 (0.56, 0.93)
15 5 2 18
I Teller 166
Tc-99m HPD/In-
111 leukocyte
scan
Intraoperative cultures of frank
purulence Mixed 2.86
(1.85, 4.44)0.47
(0.27, 0.82)
0.64 (0.41, 0.83)
0.78 (0.7, 0.84) 14 32 8 112
II Johnson 29
Tc-99m HDP/In-
111 leukocyte
scan
Intraoperative cultures Mixed
17.78 (2.6,
121.78)
0.12 (0.02, 0.74)
0.89 (0.52, 1)
0.95 (0.75, 1) 8 1 1 19
*Three hip scans and one knee scan regarded as equivocal were excluded from the analysis
138
Table 54. Combined Leukocyte/Bone Marrow Imaging
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Joseph 36
In-111 leukocyte/Tc-
99m sulfur colloid scans
at least 2 of: 1)positive
intraoperative culture 2)final histology (>10 PMN/HPF in 5
areas) 3)intraoperative findings of gross purulence within
the joint
Hip 19.6
(1.11, 347.03)
0.66 (0.42, 1.05)
0.33 (0.07, 0.7)
1 (0.87, 1) 3 0 6 27
I Joseph 36
In-111 leukocyte/Tc-
99m sulfur colloid scans
and with blood pooling
and flow phase data
at least 2 of: 1)positive
intraoperative culture 2)final histology (>10 PMN/HPF in 5
areas) 3)intraoperative findings of gross purulence within
the joint
Hip 30.8
(1.87, 508.31)
0.46 (0.23, 0.91)
0.56 (0.21, 0.86)
1 (0.87, 1) 5 0 4 27
139
Table 54. Combined Leukoycte/Bone Marrow Imaging (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Joseph 58
In-111 leukocyte/Tc-
99m sulfur colloid scans
at least 2 of: 1)positive
intraoperative culture 2)final histology (>10 PMN/HPF in 5
areas) 3)intraoperative
findings of gross purulence within the joint
Mixed (36 hip, 22
knee)
41.25 (2.5,
681.7)
0.54 (0.34, 0.85)
0.47 (0.21, 0.73)
1 (0.92, 1) 7 0 8 43
I Joseph 58
In-111 leukocyte/Tc-
99m sulfur colloid scans
and with blood pooling
and flow phase data
at least 2 of: 1)positive
intraoperative culture 2)final histology (>10 PMN/HPF in 5
areas) 3)intraoperative
findings of gross purulence within the joint
Mixed (36 hip, 22
knee)
28.67 (4, 205.52)
0.34 (0.17, 0.7)
0.67 (0.38, 0.88)
0.98 (0.88, 1) 10 1 5 42
II Mulamba 30
In-111 leukocyte/Tc-
99m sulfur colloid scans
Intraoperative cultures Hip
32.14 (2.08,
497.33)
0.11 (0.02, 0.5)
0.92 (0.64, 1)
1 (0.8, 1) 12 0 1 17
140
Table 54. Combined Leukoycte/Bone Marrow Imaging (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
II Benitez Segura 77
Tc-99m HMPAO
leukocyte/Tc-99m stannous microcolloid bone marrow
scan
Intraoperative cultures
Mixed (48 hip, 29
knee)
45.5 (6.52,
317.44)
0.07 (0.02, 0.28)
0.93 (0.76, 0.99)
0.98 (0.89, 1) 26 1 2 48
II Benitez Segura 77
Tc-99m HMPAO
leukocyte/Tc-99m stannous microcolloid bone marrow scan/Tc-99m MDP bone
scan
Intraoperative cultures
Mixed (48 hip, 29
knee)
45.5 (6.52,
317.44)
0.07 (0.02, 0.28)
0.93 (0.76, 0.99)
0.98 (0.89, 1) 26 1 2 48
II Love 59
In-111 leukocyte/Tc-
99m sulfur colloid scans
Intraoperative cultures or histology
Mixed (40 hip, 19
knee)
9.81 (3.62, 26.54)
0.02 (0, 0.33)
1 (0.86, 1)
0.91 (0.76, 0.98)
25 3 0 31
141
Table 55. Gallium-67 Imaging
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
II Reing 79 Ga-67 scan
Intraoperative cultures
Mixed (67
hips, 12
knee, 1 elbow)
111 (7.0, 1765)
0.07 (0.02, 0.34)
0.95 (0.75, 1)
1 (0.94, 1) 19 0 1 59
II Kraemer 43
Sequential Tc-99m
bone scan/Ga-67 scan
Intraoperative cultures Hip 24.36
(1.44, 410) 0.62
(0.4, 0.94)
0.38 (0.14, 0.68)
1 (0.88, 1) 5 0 8 30
II Kraemer 33 Sequential
scan or aspiration
Intraoperative cultures Hip 14
(1.96, 100) 0.38
(0.17, 0.84)
0.64 (0.31, 0.89)
0.95 (0.77, 1) 7 1 4 21
142
Table 56. FDG-PET Imaging
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Chryssikos 127
FDG-PET - increased
FDG uptake at prosthesis-
bone interface
At least 1 of: 1)an open wound or
sinus communicating with the joint 2)
systemic infection with pain in the hip and purulent fluid
within the joint 3)positive result on
at least 3 tests (ESR, CRP, joint
aspiration, intraoperative
frozen section, and intraoperative
culture)
Hip 11.39 (5.51, 23.58)
0.16 (0.07, 0.37)
0.85 (0.68, 0.95)
0.93 (0.85, 0.97)
28 7 5 87
II Delank 27
FDG-PET - FDG uptake
in the periprosthetic
soft tissue
Intraoperative Macroscopic,
Microbiological, and
Histopathological examinations
Mixed (22
hip, 5 knee)
19.17 (1.05, 348)
0.6 (0.3, 1.18)
0.4 (0.05, 0.85)
1 (0.85, 1) 2 0 3 22
143
Table 56. FDG-PET Imaging (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood Ratio (95%
CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
II Love 59 FDG-PET - activity at bone-prosthesis
interface
Intraoperative cultures or histology
Mixed (40
hip, 19 knee)
0.93 (0.58, 1.5)
1.09 (0.62, 1.9)
0.52 (0.31, 0.72)
0.44 (0.27, 0.62)
13 19 12 15
II Love 59 FDG-PET - any periprosthetic
activity
Intraoperative cultures or histology
Mixed (40
hip, 19 knee)
1.09 (0.96, 1.23)
0.19 (0.01, 3.56)
1 (0.86, 1)
0.09 (0.02, 0.24)
25 31 0 3
II Love 59
FDG-PET - semiquantitative analysis of bone-
prosthesis interface activity (target-
background ratio)
Intraoperative cultures or histology
Mixed (40
hip, 19 knee)
12.24 (1.66, 90.5)
0.66 (0.49, 0.89)
0.36 (0.18, 0.57)
0.97 (0.85, 1) 9 1 16 33
II Love 59
FDG-PET/WBC marrow - any perisprosthetic
activity on FDG image without corresponding
activity on marrow image
Intraoperative cultures or histology
Mixed (40
hip, 19 knee)
1.48 (1.14, 1.93)
0.11 (0.02, 0.82)
0.96 (0.8, 1)
0.35 (0.2, 0.54) 24 22 1 12
144
Table 57. Technetium-99m Bone Imaging
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Nagoya 46 Tc-99m 3-phase bone scintigraphy
at least 1 of: 1)intraoperative or open biopsy tissue culture, 2)histology,
3)visibly purulent
synovial fluid
Hip 8.53
(2.88, 25.25)
0.13 (0.04, 0.49)
0.88 (0.64, 0.99)
0.9 (0.73, 0.98)
15 3 2 26
II Bernay 31
Tc-99m MDP 3-phase
scintigraphy
Pathological and gross operative findings
Hip 3.36
(1.47, 7.67)
0.26 (0.07, 0.93)
0.8 (0.44, 0.97)
0.76 (0.53, 0.92)
8 5 2 16
II Benitez Segura 77
Tc-99m MDP 2-
phase bone scintigraphy
Intraoperative cultures
Mixed (48 hip, 29
knee)
0.99 (0.94, 1.05)
1.72 (0.04, 84.59)
1 (0.88, 1)
0 (0, 0.07) 28 49 0 0
II Levitsky 58*
Tc-99m MDP 3-
phase bone scintigraphy
Intraoperative cultures and gross sepsis
Mixed (63
hip, 9 knee)
2.33 (0.74, 7.37)
0.78 (0.48, 1.25)
0.33 (0.07, 0.7)
0.86 (0.73, 0.94)
3 7 6 42
II Levitsky 54*
Tc-99m MDP 3-
phase bone scintigraphy
and plain radiographs
Intraoperative cultures and gross sepsis
Mixed (63
hip, 9 knee)
4.31 (1.18, 15.75)
0.68 (0.4, 1.18)
0.38 (0.09, 0.76)
0.91 (0.79, 0.98)
3 4 5 42
*Analysis excludes 14 indeterminate results (positive cultures or sepsis, but not both)
145
Table 58. Other Nuclear Imaging tests
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Klett 28
Antigranulocyte antibody BW
250/183 scintigraphy
Histology Knee4.41
(1.74, 11.19)
0.05 (0, 0.7)
1 (0.75, 1)
0.8 (0.52, 0.96)
13 3 0 12
II Bernay 31 Tc-99m
nanocolloid scintigraphy
Pathological and gross operative findings
Hip 6
(2.28, 15.82)
0.05 (0, 0.82)
1 (0.69, 1)
0.86 (0.64, 0.97)
10 3 0 18
146
RECOMMENDATION 10 We are unable to recommend for or against computed tomography (CT) or magnetic resonance imaging (MRI) as a diagnostic test for periprosthetic joint infection.
Strength of Recommendation: Inconclusive
Rationale
Computed Tomography (CT)
One included study indicated that some CT findings are possibly useful in the diagnosis of periprosthetic infection, but more study is needed (range of positive LR: 0.3-46; range of negative LR: 0.04-1.3).19 The evidence indicates that CT may be a good “rule in” test but not as good a “rule out” test. This evidence is insufficient and does not allow a recommendation for or against the use of this modality.
Magnetic Resonance Imaging (MRI)
There is insufficient evidence to address the diagnostic efficacy of MRI for diagnosing periprosthetic infections. Based on the lack of evidence, we cannot recommend for or against the use of MRI.
Supporting Evidence
CT: We included one study of hip patients with reliable data which examined computed tomography (CT).19 Of the findings on CT that were studied, fluid collections in muscles and perimuscular fat, joint distention, and soft-tissue abnormalities each produced statistically significant positive and negative likelihood ratios. Findings of periostitis and fluid-filled bursae each produced a statistically significant positive likelihood ratio. The other findings did not produce statistically significant results. The results are presented in Table 62.
No MRI studies met the inclusion criteria for this recommendation.
SUMMARY OF EVIDENCE Table 59. CT and MRI Summary of Evidence
Test Number
of Studies
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)
CT imaging – various measures
(range) 1 0.29 – 45.7 0.04 – 1.28 0.08 - 1 0.3 - 1
147
EXCLUDED ARTICLES Table 60. Excluded Articles - Recommendation 10
Author Title Reason for Exclusion
Cooper, et al. 2008
Magnetic Resonance Imaging in the Diagnosis and Management of Hip Pain After Total Hip Arthroplasty <25 patients
Reinus, et al. 1996
Evaluation of femoral prosthetic loosening using CT imaging <25 patients
Sofka, et al. 2003 Magnetic resonance imaging of total knee arthroplasty Insufficient
Data
148
STUDY QUALITY Table 61. Study Quality - CT
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Cyteval 65
CT - asymmetric position of
femoral head
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65
CT - bone abnormalities
(focal or nonfocal low attenuation, periostitis)
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65
CT - fluid collections in muscles and perimuscular
fat
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65 CT - fluid-filled bursae I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
149
Table 61. Study Quality – CT (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Cyteval 65
CT - fluid-filled bursae
- greater trochanter
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65 CT - fluid-
filled bursae - iliopsoas
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65 CT - focal
low attenuation
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65 CT - joint distention I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65 CT -
nonfocal low attenuation
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65 CT - periostitis I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Cyteval 65 CT - soft-
tissue abnormalities
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
150
STUDY RESULTS Figure 20. CT Imaging Results - Likelihood Ratios
StudyId
Cyteval - fluid bursae - iliopsoas
Cyteval - fluid bursae - greater trochanter
Cyteval - fluid-filled bursae
Cyteval - fluid collections
Cyteval - bone abnormalities
Cyteval - soft-tissue abnormalities
Cyteval - joint distention
Cyteval - nonfocal low attenuation
Cyteval - focal low attenuation
Cyteval - periostitis
Cyteval - femoral head asymmetry
1 2 510
DLR POSITIVE
StudyId
Cyteval - fluid bursae - iliopsoas
Cyteval - fluid bursae - greater trochanter
Cyteval - fluid-filled bursae
Cyteval - fluid collections
Cyteval - bone abnormalities
Cyteval - soft-tissue abnormalities
Cyteval - joint distention
Cyteval - nonfocal low attenuation
Cyteval - focal low attenuation
Cyteval - periostitis
Cyteval - femoral head asymmetry
0 .1 .2 .5 1
DLR NEGATIVE
151
Table 62. CT Imaging
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Cyteval 65
CT - asymmetric position of
femoral head
Intraoperative Cultures (≥2) Hip 0.29
(0.04, 2.02) 1.28
(1.01, 1.63) 0.08
(0, 0.38) 0.72
(0.58, 0.83) 1 15 11 38
I Cyteval 65 CT - periostitis
Intraoperative Cultures (≥2) Hip 20.77
(1.06, 407) 0.82
(0.62, 1.06) 0.17
(0.02, 0.48) 1
(0.93, 1) 2 0 10 53
I Cyteval 65 CT - fluid-
filled bursae - iliopsoas
Intraoperative Cultures (≥2) Hip 2.65
(0.73, 9.6) 0.83
(0.59, 1.16) 0.25
(0.05, 0.57) 0.91
(0.79, 0.97) 3 5 9 48
I Cyteval 65 CT - focal
low attenuation
Intraoperative Cultures (≥2) Hip 1.47
(0.57, 3.78) 0.86
(0.56, 1.32) 0.33
(0.1, 0.65) 0.77
(0.64, 0.88) 4 12 8 41
I Cyteval 65
CT - fluid-filled bursae
- greater trochanter
Intraoperative Cultures (≥2) Hip 17.67
(2.16, 144) 0.68
(0.45, 1.02) 0.33
(0.1, 0.65) 0.98
(0.9, 1) 4 1 8 52
I Cyteval 65 CT -
nonfocal low attenuation
Intraoperative Cultures (≥2) Hip 0.88
(0.43, 1.83) 1.1
(0.64, 1.9) 0.42
(0.15, 0.72) 0.53
(0.39, 0.67) 5 25 7 28
I Cyteval 65 CT - fluid-filled bursae
Intraoperative Cultures (≥2) Hip
3.68 (1.34, 10.08)
0.66 (0.4, 1.07)
0.42 (0.15, 0.72)
0.89 (0.77, 0.96) 5 6 7 47
152
Table 62. CT Imaging (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Cyteval 65
CT - fluid collections in muscles and perimuscular
fat
Intraoperative Cultures (≥2) Hip 45.69
(2.69, 775) 0.58
(0.37, 0.93)
0.42 (0.15, 0.72)
1 (0.93, 1) 5 0 7 53
I Cyteval 65 CT - bone abnormalities
Intraoperative Cultures (≥2) Hip 1.07
(0.74, 1.56) 0.83
(0.29, 2.4)
0.75 (0.43, 0.95)
0.3 (0.18, 0.44)
9 37 3 16
I Cyteval 65 CT - joint distention
Intraoperative Cultures (≥2) Hip
22.08 (5.54, 88.03)
0.17 (0.05, 0.61)
0.83 (0.52, 0.98)
0.96 (0.87, 1) 10 2 2 51
I Cyteval 65 CT - soft-
tissue abnormalities
Intraoperative Cultures (≥2) Hip
6.92 (3.53, 13.57)
0.04 (0, 0.68)
1 (0.74, 1)
0.87 (0.75, 0.95)
12 7 0 46
153
RECOMMENDATION 11 We recommend against the use of intraoperative Gram stain to rule out periprosthetic joint infection.
Strength of Recommendation: Strong
Rationale
Our systematic review included three studies of Gram stain in the diagnosis of periprosthetic joint infection.3, 78, 100 Negative likelihood ratios suggest this is not a good “rule out” test (values >0.5). Comparatively, negative likelihood ratios for synovial fluid white blood cell count and differential tests (Recommendation 4) are much lower (<0.1). Thus, Gram stain is not a useful test for ruling out periprosthetic infection.
Supporting Evidence
Three included studies addressed the diagnostic utility of intraoperative Gram stains (one hip, one knee, one hip and knee).3, 78, 100 Data from the knee study were of moderate reliability, while the data from the other two studies were reliable. The test is fairly good at ruling in infection (positive likelihood ratios greater than 10) but not as good at ruling out infection (negative likelihood ratios greater than 0.5). Results are summarized in Table 63.
SUMMARY OF EVIDENCE Table 63. Gram Stain Summary of Evidence
Test Number of Studies
Positive Likelihood Ratio (95%
CI)
Negative Likelihood Ratio (95%
CI)
Sensitivity (95% CI)
Specificity (95% CI)
Gram Stain (range) 3 10.8 – 42.3 0.56 – 0.83 0.19 – 0.44 0.97 -1
*Range presented because fewer than four studies
154
EXCLUDED ARTICLES Table 64. Excluded Articles - Recommendation 11
Author Title Reason for Exclusion Atkins, et al.
1998 Prospective evaluation of criteria for microbiological diagnosis of prosthetic-joint infection
at revision arthroplasty. The OSIRIS Collaborative Study Group Not best available
evidence Barrack, et al.
1997 The Coventry Award. The value of preoperative aspiration before total knee revision Not best available evidence
Chimento, et al. 1996 Gram stain detection of infection during revision arthroplasty Not best available
evidence Della Valle, et al.
1999 The role of intraoperative Gram stain in revision total joint arthroplasty >10% prostheses already removed
Ghanem, et al. 2009 Periprosthetic infection: where do we stand with regard to Gram stain? Not best available
evidence Ko, et al.
2005 The role of intraoperative frozen section in decision making in revision hip and knee
arthroplasties in a local community hospital Not best available
evidence Kraemer, et al.
1993 Bone scan, gallium scan, and hip aspiration in the diagnosis of infected total hip
arthroplasty Not best available
evidence Spangehl, et al.
1999 Prospective analysis of preoperative and intraoperative investigations for the diagnosis of
infection at the sites of two hundred and two revision total hip arthroplasties Not best available
evidence
155
STUDY QUALITY Table 65. Gram Stain - Quality
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Spangehl 202 Gram stain I ? ● ● ● ● ● ● ● ● ● ? ● ● ● Banit 63 Gram stain I ● ● ● ● ● ● ● ● ● ? ● ● ● ● Banit 55 Gram stain I ● ● ● ● ● ● ● ● ● ? ● ● ● ●
Parvizi 70 Gram stain - tissue II ● ● ● ● ● ● ● ○ ○ ? ? ● ● ●
Parvizi 70 Gram stain - fluid II ● ● ● ● ● ● ● ○ ○ ? ? ● ● ●
156
STUDY RESULTS Figure 21. Gram Stain Results - Likelihood Ratios
StudyId
Parvizi - fluid
Parvizi - tissue
Banit
Spangehl
1 2 5 10DLR POSITIVE
StudyId
Parvizi - fluid
Parvizi - tissue
Banit
Spangehl
1.1 .2 .5DLR NEGATIVE
157
Table 66. Intraoperative Gram Stain Results
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Spangehl 202 Gram stain
At least 1 of: 1)open wound or sinus
communicating with the joint 2)purulent
fluid within the joint 3)positive
investigations in a minumum of 3 of the following: ESR >30
mm/h, CRP >10mg/L,
preoperative aspiration ≥1 positive
culture, frozen section >5 PMNs/hpf, intraoperative culture >1/3 positive cultures
Hip 10.8 (2.74, 42.6)
0.83 (0.69, 0.99)
0.19 (0.06, 0.38)
0.98 (0.95, 1) 5 3 22 172
I Banit 63 Gram stain
Intraoperative cultures Hip
39.75 (2.29, 689.8)
0.63 (0.41, 0.98)
0.36 (0.11, 0.69)
1 (0.93, 1) 4 0 7 52
I Banit 55 Gram stain
Intraoperative cultures Knee
42.3 (2.47, 724.7)
0.56 (0.32, 0.97)
0.44 (0.14, 0.79)
1 (0.92, 1) 4 0 5 46
158
Table 66. Intraoperative Gram Stain Results (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood Ratio (95%
CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
II Parvizi 70 Gram stain - tissue
at least 3 of: 1)CRP >1mg/dL 2)ESR
>30mm/hr 3)positive joint aspiration
culture 4)purulent intraoperative tissue
appearance 5)positive intraoperative culture
Knee13.6
(0.82, 226.8)
0.8 (0.68, 0.95)
0.21 (0.09, 0.36)
1 (0.89, 1) 8 0 31 31
II Parvizi 70 Gram stain - fluid
at least 3 of: 1)CRP >1mg/dL 2)ESR
>30mm/hr 3)positive joint aspiration
culture 4)purulent intraoperative tissue
appearance 5)positive intraoperative culture
Knee 11.13 (1.55, 80.1)
0.66 (0.52, 0.85)
0.36 (0.21, 0.53)
0.97 (0.83, 1) 14 1 25 30
159
RECOMMENDATION 12 We recommend the use of frozen sections of peri-implant tissues in patients who are undergoing reoperation for whom the diagnosis of periprosthetic joint infection has not been established or excluded.
Strength of Recommendation: Strong
Rationale
Eight Level I studies were identified that evaluated the use of frozen sections to help diagnose peri-implant infection.3, 21, 30, 32, 54, 59, 75, 96 Three studies excluded patients with known underlying inflammatory arthropathy.30, 54, 96 Six of the eight studies used intraoperative cultures, while two studies used a combination of test results as the gold standard for diagnosis against which the frozen sections were compared. All studies based the histologic diagnosis of probable infection on the tissue concentration of acute inflammatory cells, usually defined by two variables: 1) the number of neutrophils in a high magnification (400X) microscopic field, and 2) the minimum number of fields containing that concentration of neutrophils. At least three studies excluded neutrophils entrapped in superficial fibrin. Four studies used 10 or more neutrophils per high power field, and three of the four required 10 more neutrophils in at least 5 fields. The remaining study required 10 or more neutrophils in any given area. Our meta-analysis of these studies indicated that frozen section is a very good “rule in” test (i.e., a positive result has a high likelihood of infection; LR+: 23), but is a relatively low value “rule out” test (i.e. a negative result does not have a high likelihood of absent infection; LR-: 0.23). Four other studies used 5 or more neutrophils per high power field; several of these specified at least 5 microscopic fields but the other studies did not. Meta-analysis indicated that when compared to a 10 PMN/HPF criterion this lower inflammation threshold may have similar sensitivity, but slightly lower specificity (i.e. a higher frequency of false positive results). There is insufficient information to distinguish 5 from 10 neutrophils per high power field as the best threshold needed for diagnosis. Insufficient information is available to determine the efficacy of frozen sections in patients with an underlying inflammatory arthropathy.
160
Supporting Evidence
We included eight studies with reliable data (two hip, one knee, two each, three mixed) that addressed the diagnostic utility of frozen sections.3, 21, 30, 32, 54, 59, 75, 96 Meta-analysis of these studies indicated between-study heterogeneity (I2=64%), possibly due to one study which did not have a quantitative definition of infection seen on frozen section.30 Four studies used 10 or more neutrophils in five fields as a threshold. Meta-analysis of these latter studies indicated that frozen section using this threshold was a very good “rule in” test (positive LR = 23.4) and not as good as a “rule out” test (negative LR = 0.23). Four studies used a threshold of 5 PMN/HPF; meta-analysis of these studies indicated a moderately good “rule in” test and not as good of a “rule out” test (positive LR = 9.1, negative LR = 0.22). Five studies reported sampling suspicious-appearing sites, and three reported excluding the histology of fibrin.
SUMMARY OF EVIDENCE Table 67. Frozen Section Summary of Evidence
Test Number
of Studies
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)
Frozen section - threshold of 10 PMN in 5 HPF
(I2=0%) 4 23.4
(11.7, 47.1) 0.23
(0.14, 0.36) 0.78
(0.66, 0.86) 0.97
(0.94, 0.98)
Frozen section - threshold of 5
PMN/HPF (I2=0%)
4 9.1 (4.8, 17.2)
0.22 (0.13, 0.36)
0.80 (0.68, 0.88)
0.91 (0.84, 0.95)
161
EXCLUDED ARTICLES Table 68. Excluded Articles - Recommendation 12
Author Title Reason for Exclusion Abdul-Karim, et al.
1998 Frozen section biopsy assessment for the presence of polymorphonuclear leukocytes in
patients undergoing revision of arthroplasties Not best available
evidence Athanasou, et al.
1995 Diagnosis of infection by frozen section during revision arthroplasty Not best available evidence
Bori, et al. 2006
Low sensitivity of histology to predict the presence of microorganisms in suspected aseptic loosening of a joint prosthesis
Not best available evidence
Charosky, et al. 1973 Total hip replacement failures. A histological evaluation <25 patients
Della Valle, et al. 1999
Analysis of frozen sections of intraoperative specimens obtained at the time of reoperation after hip or knee resection arthroplasty for the treatment of infection
>10% prostheses already removed
Fehring, et al. 1996 Aspiration as a guide to sepsis in revision total hip arthroplasty Not best available
evidence Feldman, et al.
1995 The role of intraoperative frozen sections in revision total joint arthroplasty Not best available evidence
Kanner, et al. 2008 Reassessment of the usefulness of frozen section analysis for hip and knee joint revisions Not best available
evidence
Kataoka, et al. 2002
An assessment of histopathological criteria for infection in joint arthroplasty in rheumatoid synovium
Not relevant - not specific to revision
surgery
Mirra, et al. 1976 The pathology of the joint tissues and its clinical relevance in prosthesis failure Not best available
evidence Mirra, et al.
1982 The pathology of failed total joint arthroplasty Not best available evidence
162
Table 68. Excluded Articles (Continued) Author Title Reason for Exclusion
Musso, et al. 2003 Role of frozen section histology in diagnosis of infection during revision arthroplasty >10% prostheses
already removed Pons, et al.
1999 Infected total hip arthroplasty--the value of intraoperative histology Not best available evidence
Rosas, et al. 1998
Contribution of laboratory tests, scintigraphy, and histology to the diagnosis of lower limb joint replacement infection
<25 patients/insufficient
data Spangehl, et al.
1999 Prospective analysis of preoperative and intraoperative investigations for the diagnosis of
infection at the sites of two hundred and two revision total hip arthroplasties Not best available
evidence Wong, et al.
2005 Intraoperative frozen section for detecting active infection in failed hip and knee
arthroplasties Not best available
evidence
163
STUDY QUALITY Table 69. Frozen Section - Quality
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Banit 63 Frozen section: >10 PMNs/high
power field in any of the sampled areas
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Banit 55 Frozen section: >10 PMNs/high
power field in any of the sampled areas
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Banit 121 Frozen section: >5 PMNs/high power field in any of the sampled areas I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Della Valle 94
Frozen section: avg. of >10 PMN seen within tissue (not fibrin) in the 5
most cellular fields seen I ● ● ● ● ● ● ● ● ● ● ? ? ● ●
Fehring 97
Frozen section: acute inflammation characterized by the presence of
PMNs (specific criteria of number per field not established)
I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Frances Borrego 83 Frozen section: >10 PMNs/hpf in 5
fields I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
164
Table 69. Frozen Section – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Frances Borrego 63 Frozen section: >10 PMNs/hpf in
5 fields I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Ko 40 Frozen section: >5 PMNs/HPF I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Lonner 175 Frozen section: ≥10PMNs/hpf in 5 fields I ● ● ● ● ● ● ● ● ● ● ● ? ● ●
Lonner 175 Frozen section: ≥5 PMNs/hpf in 5 fields I ● ● ● ● ● ● ● ● ● ● ● ? ● ●
Nunez 136 Frozen section: ≥5 PMNs/hpf (looked at 10 fields) I ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Schinsky 201 Frozen section: avg. of >10PMN in the 5 most cellular HPF I ● ● ● ● ● ● ● ● ● ? ? ● ● ●
165
STUDY RESULTS Figure 22. Frozen Section Meta-Analysis – Threshold of 10 PMN in 5 Fields
StudyId
COMBINED
Schinsky
Della Valle
Lonner
Frances Borrego
1 2 5 10DLR POSITIVE
StudyId
COMBINED
Schinsky
Della Valle
Lonner
Frances Borrego
1.1 .2 .5DLR NEGATIVE
Figure 23. Frozen Section Meta-Analysis – Threshold of 5 PMN/HPF
StudyId
COMBINED
Nunez
Ko
Lonner
Banit
1 2 5 10DLR POSITIVE
StudyId
COMBINED
Nunez
Ko
Lonner
Banit
1.1 .2 .5DLR NEGATIVE
166
Figure 24. Frozen Section Results - Likelihood Ratios – Mixed Thresholds
StudyId
Fehring
Ko
Nunez
Banit
Frances Borrego
Schinsky
Della Valle
Lonner
1 2 5 10DLR POSITIVE
StudyId
Fehring
Ko
Nunez
Banit
Frances Borrego
Schinsky
Della Valle
Lonner
1.1 .2 .5DLR NEGATIVE
167
Table 70. Frozen Section Results
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Banit 63
Frozen Section
(>10 PMNs/HPF in any of the
sampled areas)
Intraoperative Cultures Hip
5.91 (1.88, 18.52)
0.59 (0.34, 1.02)
0.45 (0.17, 0.77)
0.92 (0.81, 0.98)
5 4 6 48
I Frances Borrego 83
Frozen Section
(>10 PMNs/HPF in 5 fields)
Intraoperative Cultures Hip
76 (4.45,
1299.33)
0.5 (0.26, 0.97)
0.5 (0.16, 0.84)
1 (0.95, 1) 4 0 4 75
I Schinsky 201
Frozen Section
(avg. of >10 PMNs in the
5 most cellular HPF)
At least 2 of: 1)a positive
intraoperative culture (on solid media) 2)gross
purulence 3)final histopathology
(avg. of >10 PMNs in the 5 most cellular
HPF)
Hip 11.8
(6.14, 22.67)
0.29 (0.19, 0.45)
0.73 (0.59, 0.84)
0.94 (0.89, 0.97)
40 9 15 137
168
Table 70. Frozen Section Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Nunez 136
Frozen Section (≥5 PMN/HPF; looked at 10
fields)
Intraoperative Cultures Hip
6.78 (3.86, 11.92)
0.16 (0.08, 0.33)
0.86 (0.73, 0.94)
0.87 (0.79, 0.94)
42 11 7° 76
I Banit 55
Frozen Section
(>10 PMNs/HPF in any of the
sampled areas)
Intraoperative Cultures Knee
17.86 (5.3,
60.16)
0.05 (0, 0.79)
1 (0.66, 1)
0.96 (0.85, 0.99)
9 2 0 44
169
Table 70. Frozen Section Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Della Valle 94
Frozen Section
(avg. of >10 PMNs in the
5 most cellular HPF)
At least 2 of 3 positive
intraoperative cultures on
solid media or 2 of following: 1)one positive culture 2)final histopathology consistent with
infection 3)gross
purulence seen at time of revision
Knee 23.27 (5.95, 91.05)
0.13 (0.06, 0.29)
0.88 (0.74, 0.96)
0.96 (0.87, 1) 36 2 5 51
I Frances Borrego 63
Frozen Section
(>10 PMNs/hpf in 5 fields)
Intraoperative Cultures Knee
6.5 (2.46, 17.16)
0.37 (0.21, 0.66)
0.67 (0.45, 0.84)
0.90 (0.76, 0.97)
16 4 8 35
I Banit 63
Frozen Section (>5 PMNs/HPF in any of the
sampled areas)
Intraoperative Cultures
Mixed (63 hip, 55 knee,
3 shoulder)
4.17 (2.42, 7.16)
0.40 (0.22, 0.73)
0.67 (0.43, 0.85)
0.84 (0.75, 0.910
14 16 7 84
170
Table 70. Frozen Section Results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Fehring 97
Frozen Section
(Presence of PMNs (no
specific criteria of
number per field)
Intraoperative Cultures Mixed
1.74 (0.43, 7.03)
0.91 (0.69, 1.22)
0.18 (0.02, 0.52)
0.90 (0.81, 0.95)
2 9* 9 77
I Ko 40 Frozen
Section (>5 PMNs/HPF)
Intraoperative Cultures
Mixed (34 hip, 6 knee)
20.67 (2.85, 150.1)
0.34 (0.14, 0.87)
0.67 (0.3, 0.93)
0.97 (0.83, 1) 6 1 3 30
I Lonner 175
Frozen Section
(≥10 PMN/HPF in 5 fields)
Intraoperative Cultures
Mixed (142 hip, 33 knee)
65.7 (16.4, 264)
0.16 (0.06, 0.45)
0.84 (0.60, 0.97)
0.99 (0.95, 1) 16 2 3 154
I Lonner 175
Frozen Section (≥5 PMN/HPF in 5 fields)
Intraoperative Cultures
Mixed (142 hip, 33 knee)
18.8 (8.87, 39.7)
0.17 (0.06, 0.47)
0.84 (0.60, 0.97)
0.96 (0.91, 0.98)
16 7 3 149
°Three of seven positive cultures considered possible contaminants due to negative clinical and intraoperative findings
*Study noted 6 cases with negative cultures but high clinical suspicion of infection; 3 cases with indeterminate results not included
171
RECOMMENDATION 13 We recommend that multiple cultures be obtained at the time of reoperation in patients being assessed for periprosthetic joint infection.
Strength of Recommendation: Strong
Rationale
Four Level I studies compared the effects of using one as opposed to more than one positive culture as a threshold for diagnosing infection, with histology of peri-implant tissue as the gold standard.2, 94, 104, 105 Two of these studies obtained at least three cultures per patient and two of these studies obtained at least two cultures per patient. Compared to histology, more than one positive culture result had a higher positive likelihood ratio for diagnosing infection than a single positive culture result.
Assessing infection using multiple cultures increases the chances of identifying infection. Cultures are easily performed during the procedure and provide reliable results as indicated by the postive likelihood ratio. Obtaining more than one culture decreases the likelihood of false negative result and may assist the clinician in clarifying a result that may be deemed a false positive based on the results of other tests.
Supporting Evidence
Four studies presented reliable data on the effects of using one or more than one positive culture as a threshold for infection.2, 94, 104, 105 In these studies, authors sampled from the “most suspicious areas” or “areas that appear to be most infected or inflamed”. In these studies, cultures were compared to histologic findings or a combination of histologic findings, visible purulence, and a sinus tract communicating with the prosthesis. There was between-study heterogeneity in each category. Samples were taken for aerobic and anaerobic culture in each study.
One study with moderately reliable data compared swab vs. tissue,99 and another study with less reliable data compared fluid vs. tissue.78 In each study, the differences between the two techniques were not statistically significant.
SUMMARY OF EVIDENCE Table 71. Summary of Evidence
Test Number
of Studies
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)
Intraoperative Cultures (≥1
positive culture) – range
4 2.87 – 8.1 0.09 – 0.29 0.73 – 0.94 0.67 – 0.91
Intraoperative Cultures (≥2 4 11.5 – 76.6 0.25 – 0.47 0.54 – 0.77 0.93 – 0.99
172
positive cultures) – range
*Range presented because meta-analysis indicated heterogeneity
173
EXCLUDED ARTICLES Table 72. Excluded Articles - Recommendation 13
Author Title Reason for Exclusion Baker, et al.
1994 Use of Sentinel blood culture system for analysis of specimens from potentially infected
prosthetic joints Does not address recommendation
Bare, et al. 2006 Preoperative evaluations in revision total knee arthroplasty Not best available
evidence Barrack, et al.
2007 The fate of the unexpected positive intraoperative cultures after revision total knee
arthroplasty Not best available
evidence Barrack, et al.
1993 The value of aspiration of the hip joint before revision total hip arthroplasty Not best available evidence
Berend, et al. 2007
Unexpected positive intraoperative cultures and gram stain in revision total hip arthroplasty for presumed aseptic failure
Not best available evidence
Cune, et al. 2008
A Superficial Swab Culture is Useful for Microbiologic Diagnosis in Acute Prosthetic Joint Infections
Not best available evidence
Duff, et al. 1996 Aspiration of the knee joint before revision arthroplasty Not best available
evidence Dupont,
1986 Significance of operative cultures in total hip arthroplasty Insufficient Data
Fehring, et al. 1996 Aspiration as a guide to sepsis in revision total hip arthroplasty Not best available
evidence Feldman, et al.
1995 The role of intraoperative frozen sections in revision total joint arthroplasty Not best available evidence
Fitzgerald, et al. 1973 Bacterial colonization of wounds and sepsis in total hip arthroplasty Does not address
recommendation Ince, et al.
2004 Is 'aseptic' loosening of the prosthetic cup after total hip replacement due to nonculturable
bacterial pathogens in patients with low-grade infection? <25 patients
174
Table 72. Excluded Articles (Continued) Author Title Reason for Exclusion
Levine, et al. 2001 Use of blood culture vial specimens in intraoperative detection of infection <25 patients
Marculescu, et al. 2005 Prosthetic joint infection diagnosed postoperatively by intraoperative culture Does not address
recommendation Mehra, et al.
2006 Bacteriology swab in primary total hip arthroplasty-- does it have a role? Does not address recommendation
Mikkelsen, et al. 2006 Culture of multiple peroperative biopsies and diagnosis of infected knee arthroplasties Not best available
evidence Moojen, et al.
2007 Identification of orthopaedic infections using broad-range polymerase chain reaction and
reverse line blot hybridization Not best available
evidence
Muller, et al. 2008
Diagnosis of periprosthetic infection following total hip arthroplasty - evaluation of the diagnostic values of pre- and intraoperative parameters and the associated strategy to
preoperatively select patients with a high probability of joint infection
Not best available evidence
Neut, et al. 2003 Detection of biomaterial-associated infections in orthopaedic joint implants <25 patients
Padgett, et al. 1995 Efficacy of intraoperative cultures obtained during revision total hip arthroplasty Not best available
evidence
Pandey, et al. 2000
Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection
Research and Intervention Service
Not best available evidence
Panousis, et al. 2005
Poor predictive value of broad-range PCR for the detection of arthroplasty infection in 92 cases
Not best available evidence
Picado, et al. 2008 Accuracy of intraoperative cultures in primary total hip arthroplasty Does not address
recommendation Pipino, et al.
1989 Bacteriological and histological study of 40 loose cemented hip prostheses Insufficient Data
175
Table 72. Excluded Articles (Continued) Author Title Reason for Exclusion
Pizzoferrato, et al. 1980 Microbiological investigation of 161 cases of hip endo-arthroprosthesis failure Insufficient Data
Ringberg, et al. 1998
Bacteriologic evidence of infection caused by coagulase-negative staphylococci in total hip replacement
Does not address recommendation
Schinsky, et al. 2008
Perioperative testing for joint infection in patients undergoing revision total hip arthroplasty
Not best available evidence
Spangehl, et al. 1999
The role of intraoperative gram stain in the diagnosis of infection during revision total hip arthroplasty
Not best available evidence
Tietjen, et al. 1977 The significance of intracapsular cultures in total hip operations Not best available
evidence
176
STUDY QUALITY Table 73. Intraoperative Cultures - Quality
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Atkins 297 Intraoperative Cultures (≥3) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Atkins 213 Intraoperative Cultures (≥3) I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
Atkins 239 Intraoperative Cultures (≥3) I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
Atkins 297 Intraoperative Cultures (≥1, solid or broth) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Atkins 213 Intraoperative Cultures (≥1, solid or broth) I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
Atkins 239 Intraoperative Cultures (≥1, solid or broth) I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
Atkins 297 Intraoperative Cultures (≥2) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Atkins 213 Intraoperative Cultures (≥2) I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
Atkins 239 Intraoperative Cultures (≥2) I ? ● ● ● ● ● ● ● ● ● ? ● ● ●
Schafer 284 Intraoperative Cultures (≥1) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Schafer 284 Intraoperative Cultures (≥2) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
177
Table 73. Intraoperative Cultures – Quality (Continued)
● = Yes ○ = No
? = Unclear
Author N Index Test Level of Evidence
Spec
trum
bia
s avo
ided
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as
avoi
ded
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Trampuz 2006 78 Intraoperative Cultures (≥1) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Trampuz 2006 78 Intraoperative Cultures (≥2) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Trampuz 2007 331 Intraoperative Cultures (≥1) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Trampuz 2007 331 Intraoperative Cultures (≥2) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
Spangehl 180 Intraoperative culture of tissue (>1/3 of sample positive) III ● ● ● ● ● ● ○ ● ● ● ? ● ● ●
Spangehl 168 Intraoperative swab culture (>1/3 of samples positive) III ● ● ● ● ● ● ○ ● ● ● ? ● ● ●
Parvizi 70 Intraoperative fluid culture IV ● ● ● ● ● ● ○ ○ ○ ● ? ● ● ●
Parvizi 70 Intraoperative tissue culture IV ● ● ● ● ● ● ○ ○ ○ ● ? ● ● ●
178
STUDY RESULTS Figure 25. Intraoperative Cultures Results - Threshold of 1 vs. 2 Positive Cultures
StudyId
Trampuz (2007) - 2
Atkins - 2
Trampuz (2006) - 2
Schafer - 2
Trampuz (2007) - 1
Atkins - 1
Trampuz (2006) - 1
Schafer - 1
1 2 5 10DLR POSITIVE
StudyId
Trampuz (2007) - 2
Atkins - 2
Trampuz (2006) - 2
Schafer - 2
Trampuz (2007) - 1
Atkins - 1
Trampuz (2006) - 1
Schafer - 1
1.1 .2 .5DLR NEGATIVE
Figure 26. Intraoperative Cultures Results - Tissue or Swab or Fluid
StudyId
Parvizi - fluid
Parvizi - tissue
Spangehl - tissue
Spangehl - swab
1 2 5 10DLR POSITIVE
StudyId
Parvizi - fluid
Parvizi - tissue
Spangehl - tissue
Spangehl - swab
1.1 .2 .5DLR NEGATIVE
179
Table 74. Overall and number of cultures results
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Schafer 284 Intraoperative Cultures (≥1) Histology
Mixed (145 hip, 139
knee)
2.87 (2.32, 3.56)
0.09 (0.04, 0.19)
0.94 (0.88, 0.98)
0.67 (0.6, 0.74) 98 59 6 121
I Trampuz 2006 78 Intraoperative
Cultures (≥1)
At least 1 of: 1)visible
purulence of synovial fluid
or area surrounding the
prosthesis 2)acute
inflammation on
histopathologic exam of
permanent periprosthetic tissue sections 3)a sinus tract
communicating with the
prosthesis
Mixed (68
knee, 10
hip)
8.1 (3.41, 19.26)
0.28 (0.14, 0.55)
0.75 (0.53, 0.9)
0.91 (0.8, 0.97) 18 5 6 49
180
Table 74. Overall and number of cultures results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Atkins (all) 297 Intraoperative
Cultures (≥1) Histology
Mixed (253 hip, 44
knee)
4.33 (3.25, 5.78)
0.21 (0.11, 0.42)
0.83 (0.68, 0.93)
0.81 (0.75, 0.85)
34 49 7 207
I
Atkins (patients with 3-6 samples)
213 Intraoperative Cultures (≥1) Histology
Mixed (253 hip, 44
knee)
4.01 (2.89, 5.56)
0.22 (0.1, 0.48)
0.83 (0.64, 0.94)
0.79 (0.73, 0.85)
24 38 5 146
I
Atkins (patients operated
on by most
consistent sureons)
239 Intraoperative Cultures (≥1) Histology
Mixed (253 hip, 44
knee)
4.37 (3.19, 5.98)
0.19 (0.08, 0.42)
0.85 (0.68, 0.95)
0.81 (0.75, 0.86)
28 40 5 166
181
Table 74. Overall and number of cultures results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Trampuz 2007 331 Intraoperative
Cultures (≥1)
At least 1 of: 1)visible
purulence of synovial fluid
or area surrounding
the prosthesis 2)acute
inflammation on
histopathologic exam of
permanent periprosthetic tissue sections 3)a sinus tract
communicating with the
prosthesis
Mixed (207 knee, 124 hip)
8.04 (5.33, 12.14)
0.29 (0.2, 0.42)
0.73 (0.62, 0.83)
0.91 (0.87, 0.94)
58 23 21 229
I Schafer 284 Intraoperative Cultures (≥2) Histology
Mixed (145 hip, 139
knee)
11.54 (6.61, 20.13)
0.25 (0.17, 0.35)
0.77 (0.68, 0.85)
0.93 (0.89, 0.97)
80 12 24 168
182
Table 74. Overall and number of cultures results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Trampuz 2006 78 Intraoperative
Cultures (≥2)
At least 1 of: 1)visible
purulence of synovial fluid
or area surrounding
the prosthesis 2)acute
inflammation on
histopathologic exam of
permanent periprosthetic tissue sections 3)a sinus tract
communicating with the
prosthesis
Mixed (68
knee, 10
hip)
29.25 (4.05, 211)
0.47 (0.3, 0.72)
0.54 (0.33, 0.74)
0.98 (0.9, 1) 13 1 11 53
I Atkins (all) 297 Intraoperative
Cultures (≥2) Histology
Mixed (253 hip, 44
knee)
25.87 (12.1, 55.1)
0.3 (0.19, 0.48)
0.71 (0.54, 0.84)
0.97 (0.94, 0.99)
29 7 12 249
183
Table 74. Overall and number of cultures results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I
Atkins (patients with 3-6 samples)
213 Intraoperative Cultures (≥2) Histology
Mixed (253 hip, 44
knee)
24.11 (9.76, 59.54)
0.35 (0.21, 0.59)
0.66 (0.46, 0.82)
0.97 (0.94, 0.99)
19 5 10 179
I
Atkins (patients operated
on by most
consistent sureons)
239 Intraoperative Cultures (≥2) Histology
Mixed (253 hip, 44
knee)
25.0 (11.1, 56.5)
0.28 (0.16, 0.49)
0.73 (0.54, 0.87)
0.97 (0.94, 0.99)
24 6 9 200
184
Table 74. Overall and number of cultures results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I Trampuz 2007 331 Intraoperative
Cultures (≥2)
At least 1 of: 1)visible
purulence of synovial fluid
or area surrounding
the prosthesis 2)acute
inflammation on
histopathologic exam of
permanent periprosthetic tissue sections 3)a sinus tract
communicating with the
prosthesis
Mixed (207 knee, 124 hip)
76.6 (19.0, 308)
0.4 (0.3, 0.52)
0.61 (0.49, 0.72)
0.99 (0.97, 1) 48 2 31 250
I Atkins (all) 297 Intraoperative
Cultures (≥3) Histology
Mixed (253 hip, 44
knee)
168 (23.6, 1207)
0.34 (0.22, 0.52)
0.66 (0.49, 0.8)
1 (0.98, 1) 27 1 142 255
185
Table 74. Overall and number of cultures results (Continued)
Level of Evidence Author N Test Reference
Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
I
Atkins (patients with 3-6 samples)
213 Intraoperative Cultures (≥3) Histology
Mixed (253 hip, 44
knee)
114 (15.8, 823)
0.38 (0.24, 0.61)
0.62 (0.42, 0.79)
0.99 (0.97, 1) 18 1 11 183
I
Atkins (patients operated
on by most
consistent sureons)
239 Intraoperative Cultures (≥3) Histology
Mixed (253 hip, 44
knee)
144 (20.1, 1028)
0.3 (0.18, 0.51)
0.7 (0.51, 0.84)
1 (0.97, 1) 23 1 10 205
186
Table 75. Tissue vs. Swab vs. Fluid
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
III Spangehl 168
Intraoperative Swab
Cultures (>1/3 of samples positive)
At least 1 of: 1)open wound of sinus in
communication with the joint 2)systemic
infection with pain in the joint and purulent fluid within the joint 3)positive result on at
least 3 investigations(ESR>30, CRP>10, preoperative aspiration with at least
1 positive culture, frozen section with
>5PMN/HPF, intraoperative culture
(>1/3 of cultures positive)
Hip 115 (16.1, 829)
0.24 (0.1, 0.56)
0.76 (0.5, 0.93)
0.99 (0.96, 1) 13 1 4 150
187
Table 75. Tissue vs. Swab vs. Fluid (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
III Spangehl 180
Intraoperative Tissue
Cultures (>1/3 of sample
positive)
At least 1 of: 1)open wound of sinus in
communication with the joint 2)systemic
infection with pain in the joint and purulent fluid within the joint 3)positive result on at
least 3 investigations(ESR>30, CRP>10, preoperative aspiration with at least
1 positive culture, frozen section with
>5PMN/HPF, intraoperative culture
(>1/3 of cultures positive)
Hip 30.6
(12.8, 73.1)
0.06 (0.01, 0.39)
0.94 (0.73, 1)
0.97 (0.93, 0.99)
17 5 1 157
188
Table 75. Tissue vs. Swab vs. Fluid (Continued)
Level of Evidence Author N Test Reference Standard Joint
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) TP FP FN TN
IV Parvizi 70 Intraoperative
Tissue Culture
At least 3 of: 1)CRP >1mg/dL 2)ESR
>30mm/hr 3)positive joint aspiration culture
4)purulent intraoperative tissue
appearance 5)positive intraoperative culture
Knee 53.6 (3.41, 841)
0.17 (0.08, 0.33)
0.85 (0.69, 0.94)
1 (0.89, 1) 33 0 6 31
IV Parvizi 70 Intraoperative Fluid Culture
At least 3 of: 1)CRP >1mg/dL 2)ESR
>30mm/hr 3)positive joint aspiration culture
4)purulent intraoperative tissue
appearance 5)positive intraoperative culture
Knee 27.8 (4.03, 191)
0.11 (0.04, 0.27)
0.9 (0.76, 0.97)
0.97 (0.83, 1) 35 1 4 30
189
RECOMMENDATION 14 We recommend against initiating antibiotic treatment in patients with suspected periprosthetic joint infection until after cultures from the joint have been obtained.
Strength of Recommendation: Strong
Rationale
One Level I study addressed whether administration of antibiotic therapy prior to obtaining cultures from the joint affected the sensitivity of the cultures in diagnosing periprosthetic infections.105 The study found a false negative rate of 55% in patients receiving antibiotics within the previous 14 days compared to 23% in patients not receiving antibiotics during the same time period. The difference was statistically significant. Hence, there is a concern that antibiotics can interfere with isolation of the infecting organism leading to confusion regarding the diagnosis or inability to use organism specific antibiotics subsequently when infection is confirmed. Thus, administration of oral or intravenous antibiotics to patients with suspected diagnosis of periprosthetic joint infection is discouraged, until aspiration of the joint is performed or samples for culture are obtained. The finding of only one Level I study supporting this recommendation would be evaluated as moderate strength. However, because of the severity of the potential harm to the patient in getting a false negative culture result, the strength of the recommendation was elevated to strong. Supporting Evidence
One included study with reliable data addressed whether antibiotic therapy decreases the sensitivity of intraoperative cultures in diagnosing periprosthetic infection.105 The group of patients who had received antimicrobial therapy within 14 days of surgery had a statistically significantly higher rate of false-negative culture results than those who had not. In this study, a positive result was defined as growth from at least two specimens.
190
EXCLUDED ARTICLES Table 76. Excluded Articles - Recommendation14
Author Title Reason for Exclusion Barrack, et al.
1997 The Coventry Award. The value of preoperative aspiration before total knee revision <25 patients/arm
Datz, et al. 1986 Effect of antibiotic therapy on the sensitivity of indium-111-labeled leukocyte scans Not relevant - not
specific to pji Spangehl, et al.
1999 Prospective analysis of preoperative and intraoperative investigations for the diagnosis of
infection at the sites of two hundred and two revision total hip arthroplasties <25 patients/arm
Spangehl, et al. 1999
The role of intraoperative gram stain in the diagnosis of infection during revision total hip arthroplasty <25 patients/arm
Trampuz, et al. 2006
Sonication of explanted prosthetic components in bags for diagnosis of prosthetic joint infection is associated with risk of contamination <25 patients
191
STUDY QUALITY Table 77. Preoperative Antibiotic Therapy - Quality
● = Yes ○ = No
? =Unclear
Author N Index Test Level of Evidence Sp
ectru
m b
ias a
void
ed
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as a
void
ed
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Trampuz 78 Intraoperative Cultures (≥2) I ● ● ● ● ● ● ● ● ● ● ? ● ● ●
192
STUDY RESULTS Table 78. Preoperative Antibiotics and False-Negative Cultures Level of Evidence Author N Joint Reference Standard False Negatives Risk Ratio p-
value
I Trampuz 79 Mixed
At least 1 of: 1)visible purulence of synovial fluid or area surrounding the prosthesis
2)acute inflammation on histopathologic exam of permanent periprosthetic tissue
sections 3)a sinus tract communicating with the prosthesis
Antibiotics within 14 days: 55% No antibiotics within 14 days: 23%
2.38 (1.26, 4.51)
0.004
193
RECOMMENDATION 15 We suggest that prophylactic pre-operative antibiotics not be withheld in patients at lower probability for periprosthetic infection and those with an established diagnosis of periprosthetic joint infection who are undergoing reoperation.
Strength of Recommendation: Moderate
Rationale
Two Level II studies and two joint registry studies found that the administration of perioperative antibiotics significantly decreased the risk of postoperative infection.14, 26, 28, 43 These studies however, do not address whether or not the administration of preoperative antibiotics interfere with intraoperative cultures. One Level III study did not find a significant difference in the false negative rate of intraoperative knee cultures in patients receiving perioperative antibiotic prophylaxis (12.5 vs. 8.1%; p=0.34).34
Patients who contract periprosthetic infection face catastrophic complications including additional surgery, increased cost and prolonged treatment, as well as possible permanent loss of the prosthesis. The important role of antibiotic prophylaxis in helping to prevent these catastrophic events outweighs the potential risks.
Supporting Evidence
Two RCTs, neither specific to patients undergoing revision, compared preoperative antibiotics to placebo.14, 26 Two joint registry studies, one of which was specific to patients undergoing revision, compared antibiotic prophylaxis (systemic and/or cement) to no antibiotic prophylaxis.28, 43 The two RCTs and one of the joint registry studies were of hip patients; the other joint registry study was of knee patients. The studies’ results indicated a higher risk of infection when antibiotics were not used. The results are presented in Table 84 and Table 85.
One included study with moderately reliable data addressed whether administration of preoperative antibiotics decreases the sensitivity of intraoperative cultures in diagnosing periprosthetic infection.34 Among patients in whom the infecting organism had been isolated from the preoperative aspiration, the rate of false-negative intraoperative culture results was not statistically significantly different between the group of patients who had received antibiotics and the group who had not.
194
EXCLUDED ARTICLES Table 79. Excluded Articles - Recommendation 15
Author Title Reason for Exclusion Akre, et al.
2000 Risk for gastric cancer after antibiotic prophylaxis in patients undergoing hip replacement Does not address recommendation
AlBuhairan, et al. 2008 Antibiotic prophylaxis for wound infections in total joint arthroplasty: a systematic review Systematic review,
bibliography screened Bratzler, et al.
2004 Antimicrobial prophylaxis for surgery: An advisory statement from the national surgical
infection prevention project Narrative review,
bibliography screened Chodak, et al.
1977 Use of systemic antibiotics for prophylaxis in surgery: a critical review Systematic review, bibliography screened
de Lalla, et al. 1993
Regional and systemic prophylaxis with teicoplanin in monolateral and bilateral total knee replacement procedures: study of pharmacokinetics and tissue penetration
Not best available evidence
Ericson, et al. 1973 Cloxacillin in the prophylaxis of postoperative infections of the hip Duplicate data
Eshkenazi, et al. 2001
Serum and synovial vancomycin concentrations following prophylactic administration in knee arthroplasty
Not best available evidence
Espehaug, et al. 1997 Antibiotic prophylaxis in total hip arthroplasty Duplicate data
Gillespie, et al. 2001
Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures
Does not address recommendation
Glenny, et al. 1999 Antimicrobial prophylaxis in total hip replacement: a systematic review Systematic review,
bibliography screened Hill, et al.
1981 Prophylactic cefazolin versus placebo in total hip replacement. Report of a multicentre
double-blind randomised trial Duplicate data
Hughes, et al. 1979
Treatment of subacute sepsis of the hip by antibiotics and joint replacement. Criteria for diagnosis with evaluation of twenty-six cases
Does not address recommendation
195
Table 79. Excluded Articles (Continued) Author Title Reason for Exclusion
Isacson, et al. 1984
Renal impairment after high doses of dicloxacillin-prophylaxis in joint replacement surgery
Does not address recommendation
Johnson, 1987 Antibiotic prophylaxis with cefuroxime in arthroplasty of the knee <25 patients
Klenerman, et al. 1991
Combined prophylactic effect of ultraclean air and cefuroxime for reducing infection in prosthetic surgery
Not best available evidence
Lidwell, et al. 1987
Ultraclean air and antibiotics for prevention of postoperative infection. A multicenter study of 8,052 joint replacement operations Duplicate data
Lidwell, et al. 1984
Infection and sepsis after operations for total hip or knee-joint replacement: influence of ultraclean air, prophylactic antibiotics and other factors Duplicate data
Lidwell, et al. 1982
Effect of ultraclean air in operating rooms on deep sepsis in the joint after total hip or knee replacement: a randomised study
Not best available evidence
Mannien, et al. 2006 Effect of optimized antibiotic prophylaxis on the incidence of surgical site infection Not best available
evidence Marotte, et al.
1987 Infection rate in total hip arthroplasty as a function of air cleanliness and antibiotic prophylaxis. 10-year experience with 2,384 cementless Lord madreporic prostheses
Not best available evidence
McQueen, et al. 1987
A comparison of systemic cefuroxime and cefuroxime loaded bone cement in the prevention of early infection after total joint replacement
Does not address recommendation
Mini, et al. 2001
Preliminary results of a survey of the use of antimicrobial agents as prophylaxis in orthopedic surgery
Does not address recommendation
Nelson, et al. 1993
A comparison of gentamicin-impregnated polymethylmethacrylate bead implantation to conventional parenteral antibiotic therapy in infected total hip and knee arthroplasty
Does not address recommendation
Nelson, et al. 1980
The effect of previous surgery, operating room environment, and preventive antibiotics on postoperative infection following total hip arthroplasty
Not best available evidence
Norden, 1983 A critical review of antibiotic prophylaxis in orthopedic surgery Narrative review,
bibliography screened
196
Table 79. Excluded Articles (Continued) Author Title Reason for Exclusion
Parvizi, et al. 2008 Diagnosis of infected total knee: findings of a multicenter database Duplicate Data
Schulitz, et al. 1980
The prophylactic use of antibiotics in alloarthroplasty of the hip joint for coxarthrosis. A randomized study
Antibiotics not given preoperatively
Van Kasteren, et al. 2007
Antibiotic prophylaxis and the risk of surgical site infections following total hip arthroplasty: Timely administration is the most important factor
Does not address recommendation
197
STUDY QUALITY Table 80. Preoperative Antibiotics - Diagnostic Study Quality
● = Yes ○ = No
? =Unclear
Author N Index Test Level of Evidence Sp
ectru
m b
ias a
void
ed
Sele
ctio
n cr
iteria
des
crib
ed
App
ropr
iate
refe
renc
e st
anda
rd
Dis
ease
pro
gres
sion
bia
s avo
ided
Parti
al v
erifi
catio
n bi
as a
void
ed
Diff
eren
tial v
erifi
catio
n bi
as a
void
ed
Inco
rpor
atio
n bi
as a
void
ed
Inde
x te
st e
xecu
tion
desc
ribed
Ref
eren
ce st
anda
rd e
xecu
tion
desc
ribed
Test
revi
ew b
ias a
void
ed
Dia
gnos
tic re
view
bia
s avo
ided
Clin
ical
revi
ew b
ias a
void
ed
Uni
nter
pret
able
/Inte
rmed
iate
test
re
sult(
s) re
porte
d
With
draw
als e
xpla
ined
Ghanem 171 Intraoperative Cultures (≥1) III ? ● ● ● ● ● ○ ● ● ● ○ ● ● ●
198
Table 81. Preoperative Antibiotics - Randomized Trial Quality
● = Yes ○ = No
? = Not Reported
Author Treatment Control N Level of Evidence St
ocha
stic
Ran
dom
izat
ion
Allo
catio
n C
once
alm
ent
Subj
ects
Blin
d
Ass
esso
r Blin
d
>80%
Fol
low
-Up
Sim
ilar i
n O
utco
me
at
Bas
elin
e
Carlsson Cloxacillin Placebo 171 II ? ○ ● ? ○ ● Carlsson Cloxacillin Placebo 118 II ? ○ ● ? ○ ● Doyon Cefazolin Placebo 2137 II ? ● ● ○ ● ● Doyon Cefazolin Placebo 1069 II ? ● ● ○ ○ ●
Table 82. Preoperative Antibiotics - Joint Registry Quality
● = Yes ○ = No
? = Not Reported n/a = not applicable
Author Treatment Control N Level of Evidence
Man
dato
ry D
ata
Subm
issi
on
Popu
latio
n-B
ased
Reg
istry
Val
idat
ed D
ata
>90%
of p
atie
nts c
aptu
red
Stat
istic
al Q
ualit
y C
ontro
l Mea
sure
s Pe
rfor
med
En
sure
s cor
rect
dia
gnos
is
Engesaeter Cephalosporin or Penicillin
No antibiotic 22170 II ○ ● ● ● ● ●
Jamsen Not specified (most often cefuroxime)
No antibiotic 43149 II ● ● ○ ● ? ●
199
STUDY RESULTS Table 83. Preoperative Antibiotics and False-Negative Cultures Level of Evidence Author N Joint Reference Standard False Negatives Risk
Ratio p-
value
III Ghanem 171 Knee
Aspiration culture on solid media, or on
liquid media if intraoperative culture
positive, if CRP, ESR, and aspirate
leukocyte cell count and/or neutrophil percentage were
elevated in presence of intraoperative purulent material
Antibiotics: 12.5%
No antibiotics: 8.1%
1.55 (0.63, 3.81)
0.34
Table 84. Relative Risk of Infection - Placebo vs. Preoperative Antibiotics
Level of Evidence Author N Joint Duration
(years)
Relative Risk* (95% CI)
Positive Likelihood
Ratio (95% CI)
Negative Likelihood
Ratio (95% CI)
Number Needed to Treat
II Carlsson 171 Hip 0.5
∞ (no infections
in antibiotic
group)
1.99 (1.71, 2.31)
0 22
II Carlsson 118 Hip 5 7.2
(1.7, 30.5)
2.03 (1.52, 2.71)
0.22 (0.06, 0.81)
5
II Doyon 2137 Hip 2 3.5 (1.7, 7.1)
1.58 (1.34, 1.85)
0.44 (0.25, 0.76)
43
II Doyon 1069 Hip 5 4.9 (2.5, 9.6)
1.73 (1.52, 1.97)
0.33 (0.18, 0.57)
14
* RR > 1 indicates greater risk in placebo group
200
Table 85. Registry Data – Hazard Ratio of Revision due to Infection
Level of Evidence Author N Type of
Surgery Joint Adjusted Hazard Ratio*
II
Jamsen (<25 patients in the no antibiotic
group)
2166 Revision Knee
systemic + cement: 1 systemic only: 2.1 (1.1, 3.9) cement only: 1.9 (0.5, 7.7) neither: 3.4 (0.8, 14.5)
II Engesaeter 22170 Primary Hip
systemic + cement: 1 systemic only: 1.8 (1.1, 3.0) cement only: 2.7 (0.8, 8.7) neither: 4.9 (1.2, 20.2)
*Jamsen adjusted for age, gender, diagnosis, type of implanted prosthesis; Engesaeter adjusted for age, sex, cement and prosthesis brand, type of operating theatre, operating time
201
FUTURE RESEARCH While many of the recommendations in this guideline are supported by high quality evidence, certain areas are still lacking in high quality evidence. A number of diagnostic tests exist and no single test has yet been identified that consistently allows the clinician to rule in or rule out the presence of a periprosthetic infection in all patients. Given the potential problems with instituting treatment and missing this diagnosis, future research in the area of diagnosing a periprosthetic joint infection is warranted.
Specifically, further studies that characterize facets of the patient’s history and physical examination as well as the presence of comorbidities that may affect the probability of a periprosthetic joint infection are needed to help guide diagnostic algorithms.
Molecular techniques to aid in the diagnosis of PJI are currently under investigation. This includes the use of microarrays, the polymerase chain reaction (PCR), proteomics, and ELISA for measuring various cytokines, enzymes, IL-6, and neutrophil enzymes.The routine role of sonification of removed implants and cement spacers also needs to be clarified. At the time of publication of these guidelines, there are inconclusive results to recommend the use or cost-effectiveness of these tests in clinical practice. Thus, further studies are needed to determine their utility.
While there was strong evidence to support the use of an erythrocyte sedimentation rate and c-reactive protein as initial screening tests for infection, the value of these tests for patients with inflammatory arthritis (such as rheumatoid arthritis) or other systemic diseases associated with increased ESR and CRP levels is unclear.
There is currently inadequate evidence to support or refute the role of wound swab in management of patients with suspected periprosthetic joint infection. The efficacy of various tests at the second stage of a two-stage operation for known periprosthetic infection also requires clarification.
Patients who present with a painful total hip or total knee arthroplasty, who do not otherwise have a clear indication for reoperation or revision, also present a diagnostic challenge as cultures from the joint may be difficult or impossible to obtain. Further, analysis of the value of non-invasive testing modalities, that do not rely on direct sampling from around the prosthesis (such as advance imaging studies) would be of value.
Finally, the effect that antibiotic treatment has on the utility of many of the commonly used tests for diagnosing a periprosthetic joint infection is incompletely understood. Many patients suspected of a periprosthetic joint infection may have received prior treatment with antibiotics and the temporal effect of such treatment is unclear. While the work group issued a strong recommendation against the administration of antibiotics prior to obtaining a culture from the joint, many patients unfortunately have had such treatment by the time they are evaluated by an Orthopaedic surgeon adding to the diagnostic challenge. Finally, while the benefits of prophylactic antibiotics prior to the surgical incision for preventing surgical site infections is clear, the benefit of withholding such antibiotic prophylaxis prior to obtaining deep cultures at the time of re-operation or
202
revision is unclear, and future studies that examine the effect of a single prophylactic dose of antibiotics on the sensitivity of operative cultures are warranted.
203
V. APPENDIXES
204
APPENDIX I WORK GROUP Craig Della Valle MD, Chair Rush University Medical Center 1611 W Harrison St # 300 Chicago, IL 60612-4861 Javad Parvizi, MD, Vice-Chair Rothman Institute 925 Chestnut St - 5th Fl Philadelphia, PA 19107 Thomas W Bauer, MD PhD Cleveland Clinic Foundation Department of Pathology 9500 Euclid Ave Desk L25 Cleveland, OH 44195 Paul E DiCesare, MD UC Davis Medical Center Department of Orthopaedic Surgery 4860 Y St Ste 3800 Sacramento, CA 95817 Richard Parker Evans, MD University of Arkansas for Medical Sciences Department of Orthopedics 4301 W Markham, #531 Little Rock, AR 72205 John Segreti, MD Rush University Medical Center 600 S Paulina St. Ste 143 Chicago, Il 60612 Mark Spangehl, MD Mayo Clinic 5777 East Mayo Blvd Phoenix, AZ 85054
Guidelines and Technology Oversight Chair: William C. Watters III MD 6624 Fannin #2600 Houston, TX 77030 Evidence Based Practice Committee Chair: Michael Keith, MD 2500 Metro Health Drive Cleveland, OH 44109-1900 AAOS Staff: Charles M. Turkelson, PhD Director of Research and Scientific Affairs 6300 N River Road Rosemont, IL 60018 Janet L. Wies MPH AAOS Clinical Practice Guideline Mgr Patrick Sluka MPH AAOS Lead Research Analyst Kristin Hitchcock AAOS Medical Librarian Special Acknowledgements Sara Anderson MPH Kevin Boyer Laura Raymond, MA
205
APPENDIX II AAOS BODIES THAT APPROVED THIS CLINICAL PRACTICE GUIDELINE Guidelines and Technology Oversight Committee The AAOS Guidelines and Technology Oversight Committee (GTOC) consists of sixteen AAOS members. The overall purpose of this Committee is to oversee the development of the clinical practice guidelines, performance measures, health technology assessments and utilization guidelines.
Evidence Based Practice Committee The AAOS Evidence Based Practice Committee (EBPC) consists of ten AAOS members. This Committee provides review, planning and oversight for all activities related to quality improvement in orthopaedic practice, including, but not limited to evidence-based guidelines, performance measures, and outcomes.
Council on Research, Quality Assessment, and Technology To enhance the mission of the AAOS, the Council on Research, Quality Assessment, and Technology promotes the most ethically and scientifically sound basic, clinical, and translational research possible to ensure the future care for patients with musculoskeletal disorders. The Council also serves as the primary resource to educate its members, the public, and public policy makers regarding evidenced-based medical practice, orthopaedic devices and biologics, regulatory pathways and standards development, patient safety, occupational health, technology assessment, and other related areas of importance.
The Council is comprised of the chairs of the AAOS Biological Implants, Biomedical Engineering, Evidence Based Practice, Guidelines and Technology Oversight, Occupational Health and Workers’ Compensation, Patient Safety, Research Development, and US Bone and Joint Decade committees. Also on the Council are the AAOS second vice-president, representatives of the Diversity Advisory Board, the Women's Health Issues Advisory Board, the Board of Specialty Societies (BOS), the Board of Councilors (BOC), the Communications Cabinet, the Orthopaedic Research Society (ORS), the Orthopedic Research and Education Foundation (OREF), and three members at large.
Board of Directors The 17 member AAOS Board of Directors manages the affairs of the AAOS, sets policy, and determines and continually reassesses the Strategic Plan.
206
DOCUMENTATION OF APPROVAL
AAOS Work group Draft Completed November 25, 2009
Peer Review Completed December 28, 2009
Public Commentary Completed April 15, 2010
AAOS Guidelines and Technology Oversight Committee April 24, 2010
AAOS Evidence Based Practice Committee April 24, 2010
AAOS Council on Research Quality Assessment May 17, 2010
and Technology
AAOS Board of Directors June 18, 2010
207
APPENDIX III STUDY ATTRITION FLOWCHART
6873 abstracts screened for inclusion
459 articles recalled for full text review
6414 abstracts excluded
105 articles recalled from bibliography screening
473 articles excluded
91 articles included
208
APPENDIX IV LITERATURE SEARCHES Search Strategy for PubMed
(periprosthetic[tiab] OR "Arthroplasty, Replacement, Hip"[Mesh] OR "Arthroplasty, Replacement, Knee"[Mesh] OR "Hip Prosthesis"[mh] OR "Knee Prosthesis"[mh]
OR ((hip[tiab] OR "Hip Joint"[mh] OR knee[tiab] OR "Knee Joint"[mh] OR acetabular[tiab] OR femoral[tiab] OR tibial[tiab] OR patellar[tiab])
AND (arthroplasty[tiab] OR implant[tiab] OR implants[tiab] OR "total joint"[tiab] OR unicompartment*[tiab] OR replacement[tw] OR resurfacing[tiab] OR hemiarthroplasty[tiab] OR component[tiab] OR (cup[tiab] AND stem[tiab]) OR revision[tiab] OR resection[tiab] OR prosthesis[tiab] OR prostheses[tiab] OR prosthetic[tiab] OR "Joint Prosthesis"[mh] OR "Prosthesis Failure"[mh]))) AND (("Prosthesis-Related Infections"[mh] OR infection[tiab] OR infected[tiab] OR "Sepsis"[mh] OR sepsis[tiab] OR septic[tiab] OR "Bacterial Infections"[mh] OR "Bacteria"[mh] OR staphylococcus[tw] OR bacteria*[tiab] OR mycobacteria*[tw] OR fungal[tw] OR fungus[tw] OR "Mycoses"[mh] OR coagulase negative staph[tw] OR streptococcus[tw] OR acid-fast bacillus[tw] OR afb[tiab] OR gram positive[tw] OR gram negative[tw] OR staphylococcus epidermidis[tw] OR pus[tw] OR "Suppuration"[mh:noexp] OR purulence[tw]) OR ((pain[tiab] OR painful[tiab] OR "Pain"[mh:noexp] OR stiffness[tw] OR warmth[tw] OR effusion[tw] OR redness[tw] OR swelling[tw] OR bacteremia[tw] OR candidemia[tw]) AND ("Postoperative Complications/radiography"[mh] OR "Postoperative Complications/pathology"[mh]OR x-ray[tiab] OR "Blood Cell Count"[mh] OR cbc[tw] OR "Blood Sedimentation"[mh] OR sedimentation rate[tw] OR "Erythrocyte Aggregation"[mh] OR "C-Reactive Protein"[mh] OR "c-reactive protein"[tw] OR serology[tw] OR "Biopsy, Needle"[mh] OR aspiration[tiab] OR "frozen section*"[tw] OR histology[tw] OR "Diagnostic Imaging"[mh] OR "Radiopharmaceuticals/diagnostic use"[mh] OR sulfur colloid[tw] OR gallium[tw] OR indium-111[tw] OR fdg-pet[tw] OR technetium-99[tw] OR MRI[tw] OR (ct[tiab] AND scan[tiab])))) AND English[lang] AND 1970:2009/08/10[dp] NOT (comment[pt] OR editorial[pt] OR letter[pt] OR addresses[pt] OR news[pt] OR "newspaper article"[pt] OR "case reports"[pt] OR "historical article"[pt])
Sorted by study type
#1 Systematic[sb]
#2 (randomized controlled trial[pt] OR controlled clinical trial[pt] OR "randomized controlled trials as topic"[mh] OR random allocation[mh] OR double-blind method[mh] OR single-blind method[mh] OR clinical trial[pt] OR "clinical trials as topic"[mh] OR "clinical trial"[tw] OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw] OR tripl*[tw]) AND (mask*[tw] OR blind*[tw])) OR "latin square"[tw] OR placebos[mh] OR placebo*[tw] OR random*[tw] OR research design[mh:noexp] OR "comparative study "[pt] OR "evaluation studies as topic"[mh] OR "evaluation studies "[pt] OR "follow-Up
209
studies"[mh] OR "prospective studies"[mh] OR "cross-over studies"[mh] OR control*[tw] OR prospectiv*[tw] OR volunteer*[tw])
NOT #1 OR #2
Search strategy for EMBASE
(‘hip arthroplasty’/de OR ‘total hip prosthesis’/de OR ‘acetabuloplasty’/de OR ‘knee arthroplasty’/de OR ‘total knee replacement’/de) AND
((‘infection’/de OR ‘gram negative infection’/de OR ‘gram negative sepsis’/de OR ‘staphylococcus infection’/de OR ‘streptococcus infection’/de OR ‘mycosis’/exp OR ‘infection control’/de OR ‘infection rate’/de OR ‘infection prevention’/de OR ‘infection risk’/de OR ‘bacterial infection’/exp OR ‘postoperative infection’/de OR ‘prosthesis infection’/de)
OR ((pain OR painful OR stiffness OR warmth OR effusion OR redness OR swelling OR bacteremia/de OR candidemia/de) AND (‘hip radiography’/de OR ‘knee radiography’/de OR ‘frozen section’/de OR ‘blood cell count’/de OR ‘erythrocyte sedimentation rate’/de OR ‘c reactive protein’/de OR ‘aspiration biopsy’/de OR ‘joint aspiration’/de OR ‘nuclear magnetic resonance’/exp OR ‘computer assisted tomography’/exp OR ‘diagnostic imaging’/de OR ‘radiopharmaceutical agent’/exp)))
AND ([article]/lim OR [conference paper]/lim OR [review]/lim) AND [english]/lim AND [embase]/lim
Sorted by study type
#1 'meta analysis' OR 'systematic review' OR medline
#2 random* OR 'clinical trial' OR 'health care quality'/exp
NOT #1 OR #2
Search strategy for CINAHL
((MM “Arthroplasty, Replacement, Hip” or MM “Arthroplasty, Replacement, Knee” or ((hip or knee) and (replacement* or prosthesis or prostheses or implant*))) AND (infection or infected or MM infection+ or MM mycoses+ or MM “Prosthesis-Related Infections” or MM “Bacterial Infections+” or MM Streptococcus+ or MM Staphylococcus+ or MM “Staphylococcal Infections” or MM “Streptococcal Infections+” or MM Sepsis+ or MM Suppuration))
and PT “research” and LA English and PY 1970-2009
NOT
PT “editorial” or PT “letter” or PT “case study” or MM “case studies”
210
Sorted by study type
#1 (MM “meta analysis” or MM “systematic review” or PT “systematic review”)
NOT (#1)
Search strategy for Cochrane Central
(joint):ti,ab,kw and (arthroplasty OR prosthesis OR prosthetic OR replacement OR implant):ti,ab,kw and (hip OR knee OR acetabular):ti,ab,kw and (infection OR infected):ti,ab,kw
211
APPENDIX V DATA EXTRACTION ELEMENTS The data elements below were extracted into electronic forms in Microsoft® Excel. The extracted information includes: Study Characteristics
• Selection criteria • Reference standard details • Index test details • Blinding of index test results when interpreting reference standard • Blinding of reference standard results when interpreting index test • Withdrawals from study
Results
• True positives • True negatives • False positives • False negatives • Uninterpretable/intermediate results
212
APPENDIX VI JUDGING THE QUALITY OF DIAGNOSTIC STUDIES The QUADAS tool108-110 is used to identify sources of bias, variability, and the quality of reporting in studies of diagnostic accuracy. Fourteen questions answered “yes”, “no”, or “unclear” contribute to the QUADAS tool. There is no score derived from the use of the QUADAS tool.
Was the spectrum of patient’s representative of the patients who will receive the test in practice?
Were selection criteria clearly described?
Is the reference standard likely to correctly classify the target condition?
Is the time period between ref. standard and index test short enough to be reasonably sure that the target condition did not change between the two tests?
Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis?
Did patients receive the same reference standard regardless of the index test result?
Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)?
Was the execution of the index test described in sufficient detail to permit replication of the test?
Was the execution of the reference standard described in sufficient detail to permit its replication?
Were the index test results interpreted without knowledge of the results of the reference standard?
Were the reference standard results interpreted without knowledge of the results of the index test?
Were the same clinical data available when test results were interpreted as would be available when the test is used in practice?
Were uninterpretable/intermediate test results reported?
Were withdrawals from the study explained?
213
JUDGING THE QUALITY OF PROGNOSTIC STUDIES Were the variables of interest clearly identified in the Methods section?
Were all variables of interest discussed in the Results section?
Were there sufficient patients per variable?
Were there sufficient events per variable?
If coding of variables is used, is the coding scheme described or unambiguous?
Collinearity has been tested or there is no obvious potential for collinearity?
Was the fitting procedure explicitly stated?
Were any goodness-of-fit statistics reported?
Was the model subjected to a test of validation?
JUDGING THE QUALITY OF TREATMENT STUDIES RANDOMIZED CONTROLLED TRIALS
Did the study employ stochastic randomization?
Was there concealment of allocation?
Were subjects blinded to the treatment they received?
Were those who assessed/rated the patient’s outcomes blinded to the group to which the patients were assigned?
Was there more than 80% follow-up for all patients in the control group and the experimental group on the outcome of interest?
Did patients in the different study groups have similar levels of performance on ALL of the outcome variables at the time they were assigned to groups?
For randomized crossover studies, was there evidence that the results obtained in the study’s two experimental groups (in period 1 and 2) did not differ?
For randomized crossover studies, was there evidence that the results of the two control groups (in period 1 and 2) did not differ?
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APPENDIX VII FORM FOR ASSIGNING STRENGTH OF RECOMMENDATION (INTERVENTIONS) GUIDELINE RECOMMENDATION___________________________________
PRELIMINARY STRENGTH OF RECOMMENDATION: ________________
STEP 1: LIST BENEFITS AND HARMS
Please list the benefits (as demonstrated by the systematic review) of the intervention.
Please list the harms (as demonstrated by the systematic review) of the intervention.
Please list the benefits for which the systematic review is not definitive.
Please list the harms for which the systematic review is not definitive.
STEP 2: IDENTIFY CRITICAL OUTCOMES
Please circle the above outcomes that are critical for determining whether the intervention is beneficial and whether it is harmful.
Are data about critical outcomes lacking to such a degree that you would lower the preliminary strength of the recommendation?
What is the resulting strength of recommendation?
STEP 3: EVALUATE APPLICABILITY OF THE EVIDENCE
Is the applicability of the evidence for any of the critical outcomes so low that substantially worse results are likely to be obtained in actual clinical practice?
Please list the critical outcomes backed by evidence of doubtful applicability.
Should the strength of recommendation be lowered because of low applicability?
What is the resulting strength of recommendation?
STEP 4: BALANCE BENEFITS AND HARMS
Are there trade-offs between benefits and harms that alter the strength of recommendation obtained in STEP 3?
What is the resulting strength of recommendation?
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STEP 5 CONSIDER STRENGTH OF EVIDENCE
Does the strength of the existing evidence alter the strength of recommendation obtained in STEP 4?
What is the resulting strength of recommendation?
NOTE: Because we are not performing a formal cost analyses, you should only consider costs if their impact is substantial.
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APPENDIX VIII VOTING BY THE NOMINAL GROUP TECHNIQUE Voting on guideline recommendations will be conducted using a modification of the nominal group technique (NGT), a method previously used in guideline development.71 Briefly each member of the guideline workgroup ranks his or her agreement with a guideline recommendation on a scale ranging from 1 to 9 (where 1 is “extremely inappropriate” and 9 is “extremely appropriate”). Consensus is obtained if the number of individuals who do not rate a measure as 7, 8, or 9 is statistically non-significant (as determined using the binomial distribution). Because the number of workgroup members who are allowed to dissent with the recommendation depends on statistical significance, the number of permissible dissenters varies with the size of the workgroup. The number of permissible dissenters for several workgroup sizes is given in the table below:
Workgroup Size Number of Permissible Dissenters
≤ 3 Not allowed, statistical significance cannot be obtained
4-5 0
6-8 1
9 1 or 2
The NGT is conducted by first having members vote on a given recommendation without discussion. If the number of dissenters is “permissible”, the recommendation is adopted without further discussion. If the number of dissenters is not permissible, there is further discussion to see whether the disagreement(s) can be resolved. Three rounds of voting are held to attempt to resolve disagreements. If disagreements are not resolved after three voting rounds, no recommendation is adopted.
OPINION-BASED RECOMMENDATIONS A guideline can contain recommendations that are backed by little or no data. Under such circumstances, work groups often issue opinion-based recommendations. Although doing so is sometimes acceptable in an evidence-based guideline (expert opinion is a form of evidence), it is also important to avoid constructing a guideline that liberally uses expert opinion; research shows that expert opinion is often incorrect.
Opinion-based recommendations are developed only if they address a vitally important aspect of patient care. For example, constructing an opinion-based recommendation in favor of taking a history and physical is warranted. Constructing an opinion-based recommendation in favor of a specific modification of a surgical technique is seldom warranted. To ensure that an opinion-based recommendation is absolutely necessary, the
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AAOS has adopted rules to guide the content of the rationales that underpin such recommendations. These rules are based on those outlined by the US Preventive Services Task Force (USPSTF).81 Specifically, rationales based on expert opinion must:
• Not contain references to or citations from articles not included in the systematic review that underpins the recommendation.
• Not contain the AAOS guideline language “We Recommend”, “We suggest” or “treatment x is an option”.
• Contain an explanation of the potential preventable burden of disease. This involves considering both the incidence and/or prevalence of the disease, disorder, or condition and considering the associated burden of suffering. To paraphrase the USPSTF, when evidence is insufficient, provision of a treatment (or diagnostic) for a serious condition might be viewed more favorably than provision of a treatment (or diagnostic) for a condition that does not cause as much suffering. The AAOS (like the USPSTF) understand that evaluating the “burden of suffering” is subjective and involves judgment. This evaluation should be informed by patient values and concerns. The considerations outlined in this bullet make it difficult to recommend new technologies. It is not appropriate for a guideline to recommend widespread use of a technology backed by little data and for which there is limited experience. Such technologies are addressed in the AAOS’ Technology Overviews.
• Address potential harms. In general, “When the evidence is insufficient, an intervention with a large potential for harm (such as major surgery) might be viewed less favorably than an intervention with a small potential for harm (such as advice to watch less television).”81
• Address apparent discrepancies in the logic of different recommendations. Accordingly, if there are no relevant data for several recommendations and the work group chooses to issue an opinion-based recommendation in some cases but chooses not to make a recommendation in other cases, the rationales for the opinion-based recommendations must explain why this difference exists. Information garnered from the previous bullet points will be helpful in this regard.
• Consider current practice. The USPSTF specifically states that clinicians justifiably fear that not doing something that is done on a widespread basis will lead to litigation.81The consequences of not providing a service that is neither widely available nor widely used are less serious than the consequences of not providing a treatment accepted by the medical profession and thus expected by patients. Discussions of available treatments and procedures rely on mutual communication between the patient’s guardian and physician, and on weighing the potential risks and benefits for a given patient. The patient’s “expectation of treatment” must be tempered by the treating
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physician’s guidance about the reasonable outcomes that the patient can expect.
• Justify, why a more costly device, drug, or procedure is being recommended over a less costly one whenever such an opinion-based recommendation is made.
Work group members write the rationales for opinion based recommendations on the first day of the final work group meeting. When the work group re-convenes on the second day of its meeting, it will vote on the rationales. The typical voting rules will apply. If the work group cannot adopt a rationale after three votes, the rationale and the opinion-based recommendation will be withdrawn, and a “recommendation” stating that the group can neither recommend for or against the recommendation in question will appear in the guideline.
Discussions of opinion-based rationales may cause some members to change their minds about whether to issue an opinion-based recommendation. Accordingly, at any time during the discussion of the rationale for an opinion-based recommendation, any member of the work group can make a motion to withdraw that recommendation and have the guideline state that the work group can neither recommend for or against the recommendation in question.
CHECKLIST FOR VOTING ON OPINION-BASED RECOMMENDATIONS When voting on the rationale, please consider the following:
1. Does the recommendation affect a substantial number of patients or address treatment (or diagnosis) of a condition that causes death and/or considerable suffering?
2. Does the recommendation address the potential harms that will be incurred if it is implemented and, if these harms are serious, does the recommendation justify;
a. why the potential benefits outweigh the potential harms and/or
b. why an alternative course of treatment (or diagnostic workup) that involves less serious or fewer harms is not being recommended?
3. Does the rationale explain why the work group chose to make a recommendation in the face of minimal evidence while, in other instances, it chose to make no recommendation in the face of a similar amount of evidence?
4. Does the rationale explain that the recommendation is consistent with current practice?
5. If relevant, does the rationale justify why a more costly device, drug, or procedure is being recommended over a less costly one?
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APPENDIX IX STRUCTURED PEER REVIEW FORM Review of any AAOS confidential draft allows us to improve the overall guideline but does not imply endorsement by any given individual or any specialty society who participates in our review processes. The AAOS review process may result in changes to the documents; therefore, endorsement cannot be solicited until the AAOS Board of Directors officially approves the final guideline. Reviewer Information: Name of Reviewer_________________________________________ Address_________________________________________________ City___________________ State_________________ Zip Code___________ Phone _____________________Fax ________________________ E-mail_______________________ Specialty Area/Discipline: _______________________________________ Work setting: _________________________________________________ Credentials: _________________________________________________ May we list you as a Peer Reviewer in the final Guidelines? Yes No Are you reviewing this guideline as Yes No a representative of a professional society? If yes, may we list your society as a reviewer Yes No of this guideline? Reviewer Instructions Please read and review this Draft Clinical Practice Guideline and its associated Evidence Report with particular focus on your area of expertise. Your responses are confidential and will be used only to assess the validity, clarity, and accuracy of the interpretation of the evidence. If applicable, please specify the draft page and line numbers in your comments. Please feel free to also comment on the overall structure and content of the guideline and Evidence Report. If you need more space than is provided, please attach additional pages. Please complete and return this form electronically to [email protected] or fax the form back to Jan Wies at (847) 823-9769. Thank you in advance for your time in completing this form and giving us your feedback. We value your input and greatly appreciate your efforts. Please send the completed form and comments by Month/Day/Year.
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COMMENTS Please provide a brief explanation of both your positive and negative answers in the preceding section. If applicable, please specify the draft page and line numbers in your comments. Please feel free to also comment on the overall structure and content of the guideline and Evidence Report OVERALL ASSESSMENT Would you recommend these guidelines for use in practice? (check one) Strongly recommend _______ Recommend (with provisions or alterations) _______ Would not recommend _______ Unsure _______ COMMENTS: Please provide the reason(s) for your recommendation.
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APPENDIX X PEER REVIEW PANEL Participation in the AAOS peer review process does not constitute an endorsement of this guideline by the participating organization.
Peer review of the draft guideline is completed by an outside Peer Review Panel. Outside peer reviewers are solicited for each AAOS guideline and consist of experts in the guideline’s topic area. These experts represent professional societies other than AAOS and are nominated by the guideline workgroup prior to beginning work on the guideline. For this guideline, 14 outside peer review organizations were invited to review the draft guideline and all supporting documentation. Eight of these societies participated in the review of the guideline draft and five explicitly consented to be listed as a peer review organization in this appendix.
The organizations that reviewed the document and consented to be listed as a peer review organization are listed below:
American Association of Hip and Knee Surgeons
European Bone and Joint Infection Society
Knee Society
Musculoskeletal Infection Society
Society of Nuclear Medicine
Individuals who participated in the peer review of this document and gave their consent to be listed as reviewers of this document are:
Thomas K. Fehring MD
Kevin L. Garvin MD
Arlen D. Hanssen MD
James I. Huddleston MD
Douglas R. Osmon MD
Christopher J. Palestro MD
Geert H.I.M. Walenkamp MD, PhD.
Barbara Weissman MD
The Society for Nuclear Medicine Standards Committee
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PUBLIC COMMENTARY A period of public commentary follows the peer review of the draft guideline. If significant non-editorial changes are made to the document as a result of public commentary, these changes are also documented and forwarded to the AAOS bodies that approve the final guideline. Public commentators who gave explicit consent to be listed in this document include the following: William Jiranek MD Andrew H. Schmidt MD, Orthopaedic Trauma Association Participation in the AAOS guideline public commentary review process does not constitute an endorsement of the guideline by the participating organizations or the individual listed nor does it is any way imply the reviewer supports this document.
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APPENDIX XI INTERPRETING THE FOREST PLOTS Throughout the guideline we use descriptive diagrams or forest plots to present data from studies comparing a diagnostic test to a reference standard. In the example below, the positive and negative likelihood ratios are the effect measures used to depict study results. The horizontal line running through each point represents the 95% confidence interval for that point. In this graph, the solid vertical line represents “no effect” where the likelihood ratio is equal to one. The dashed line represents the value of a likelihood ratio that indicates a large and conclusive change in the probability of disease.
For example, in the figure below the summary estimate (diamond) indicates a positive likelihood ratio close to 10 and a negative likelihood ratio of between 0.2 and 0.5. This result is statistically significant because the 95% Confidence Interval does not cross the “no effect” line. Please note that summary measures are not reported in the plot if high heterogeneity (>50%) was present.
StudyId
COMBINED
Lachiewicz
Williams
Mulcahy
Eisler
Malhotra
Barrack
Fink
Della Valle
Glithero
1 2 5 10DLR POSITIVE
StudyId
COMBINED
Lachiewicz
Williams
Mulcahy
Eisler
Malhotra
Barrack
Fink
Della Valle
Glithero
1.1 .2 .5DLR NEGATIVE
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APPENDIX XII CONFLICT OF INTEREST All members of the AAOS workgroup disclosed any conflicts of interest prior to the development of the recommendations for this guideline. Conflicts of interest are disclosed in writing with the American Academy of Orthopaedic Surgeons via a private on-line reporting database and also verbally at the recommendation approval meeting. Disclosure Items: (n) = Respondent answered 'No' to all items indicating no conflicts. 1=Board member/owner/officer/committee appointments; 2= Medical/Orthopaedic Publications; 3= Royalties; 4= Speakers bureau/paid presentations;5A= Paid consultant; 5B= Unpaid consultant; 6= Research or institutional support from a publisher; 7= Research or institutional support from a company or supplier; 8= Stock or Stock Options; 9= Other financial/material support from a publisher; 10= Other financial/material support from a company or supplier.
Thomas W Bauer, MD, PhD: (Cleveland, OH): 2 (Journal of Bone and Joint Surgery - American); 5A (Musculoskeletal Transplant Foundation; Osteotech; Smith & Nephew; Stryker). Submitted on: 08/27/2008.
Craig J Della Valle, MD: 2 (Clinical Orthopaedics and Related Research; Journal of the American Academy of Orthopedic Surgeons; SLACK Incorporated); 4 (Angiotech); 5A (Zimmer); 5B (Biomet; Kinamed); 7 (Zimmer); 10 (Smith & Nephew; Stryker). Submitted on: 08/17/2008.
Paul E DiCesare, MD: 5A (Stryker); 7 (Stryker). Submitted on: 08/11/2008.
Richard Parker Evans, MD: 1 (American Academy of Orthopedic Surgeons); 4 (DePuy, A Johnson & Johnson Company; Smith & Nephew; Cubist); 5A (DePuy, A Johnson & Johnson Company; Smith & Nephew; Cubist); 5B (3M); 7 (National Institutes of Health (NIAMS & NICHD); Biomet; Cubist). Submitted on: 12/07/2007 and last confirmed as accurate on 04/17/2008.
Michael Warren Keith, MD: (n). Submitted on: 10/10/2007 at 08:42 AM and last confirmed as accurate on 04/09/2008.
Javad Parvizi, MD: 1 (Smarttech LLC); 2 (Clinical Orthopaedics and Related Research; Journal of Arthroplasty; Journal of Bone and Joint Surgery - American; Journal of Bone and Joint Surgery - British; Journal of Orthopaedic Research; Journal of the American Academy of Orthopedic Surgeons); 4 (Johnson & Johnson); 5A (Stryker; Smith & Nephew); 7 (Stryker). Submitted on: 10/10/2007.
John Segreti, MD: (Chicago, IL): 4 (Johnson & Johnson; Merck; Pfizer; Wyeth; Cubist); 5A (Johnson & Johnson; Pfizer; Wyeth); 5B (Medtronic); 7 (Abbott; Bristol-Myers Squibb; Health and Human Services; Merck; Cubist); 8 (Pfizer; Zimmer). Submitted on: 08/12/2008.
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Mark J Spangehl, MD (Phoenix, AZ): (n). Submitted on: 08/12/2008.
William Charles Watters III, MD: 1 (North American Spine Society; Work Loss Data Institute); 2 (The Spine Journal); 5A (Stryker; Intrinsic Therapeutics; MeKessen Health Care Solutions). Submitted on: 10/09/2007 at 08:09 PM and last confirmed as accurate on 04/23/2008.
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APPENDIX XIII REFERENCES
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