what is the blood test to look for infection in knee replacements
Clin Orthop Relat Res. 2008 Nov; 466(11): 2628–2633.
Diagnosis of Infected Total Knee: Findings of a Multicenter Database
Javad Parvizi, MD, FRCS,1 Elie Ghanem, MD,1 Peter Sharkey, Dr.,1 Ajay Aggarwal, MD,2 R. Stephen J. Burnett, Doctor, FRCS(C),2 and Robert L. Banter, Physician 
2, three
Javad Parvizi
1Rothman Constitute of Orthopedics, Thomas Jefferson University Hospital, Philadelphia, PA USA
Elie Ghanem
1Rothman Institute of Orthopedics, Thomas Jefferson University Infirmary, Philadelphia, PA USA
Peter Sharkey
1Rothman Institute of Orthopedics, Thomas Jefferson University Hospital, Philadelphia, PA U.s.
Ajay Aggarwal
2Department of Orthopaedic Surgery, Washington University Schoolhouse of Medicine, St. Louis, MO Usa
R. Stephen J. Burnett
twoDepartment of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO United states of america
Robert 50. Barrack
2Department of Orthopaedic Surgery, Washington University Schoolhouse of Medicine, St. Louis, MO Usa
3Charles F. and Joanne Knight Distinguished Professor of Orthopaedic Surgery, Washington Academy School of Medicine, Chief of Staff for Orthopaedic Surgery, Barnes-Jewish Infirmary, One Barnes-Jewish Hospital Plaza, 11300 West Pavilion, St. Louis, MO 63110 USA
Received 2007 October nineteen; Accepted 2008 Aug 7.
Abstract
Although total knee arthroplasty (TKA) is an effective and successful procedure, the outcome is occasionally compromised by complications including periprosthetic joint infection (PJI). Authentic and early diagnosis is the showtime step in effectively managing patients with PJI. At the present time, diagnosis remains dependent on clinical judgment and reliance on standard clinical tests including serologic tests, analysis of aspirated joint fluid, and interpretation of intraoperative tissue and fluid examination results. Although reports regarding sensitivity and specificity of all diagnostic tests in the literature are abundant, the estimation of the bachelor information has been hampered past the low sample size of these studies. In view of the scope of this important problem and the limitations of previous reports, a large database was assembled of all revision TKA performed at three academic referral centers in order to decide the current status of diagnosis of the infected TKA utilizing normally available tests. Intraoperative cultures should non be used as a gilded standard for PJI attributable to high percentages of fake-negative and fake-positive cases. When combined with clinical judgment, total white cell count and percentage of neutrophils in the synovial fluid more accurately reflects PJI and when combined with hematologic exams safely excludes or confirms infection.
Level of Prove: Level II, prognostic report. See Guidelines for Authors for a complete description of levels of testify.
Introduction
Total articulatio genus arthroplasty (TKA) is performed in the United states of america on over 400,000 patients annually with the number of procedures projected to double within 10 years [5, 14]. Though effective and successful, the outcome of TKA is occasionally compromised by complications [3, ix, 10, nineteen]. Periprosthetic articulation infection (PJI) is one such complication that occurs afterwards one% to 3% of TKA translating to around 10,000 cases per yr in the Usa [8, 18].
It appears that despite all efforts for prevention, PJI will continue to pose challenges to the orthopaedic community. Ane of the problems associated with PJI relates to timely diagnosis of this complication [4, xvi]. Accurate and early diagnosis is the first step in effectively managing patients with PJI [7, 8]. At the present time diagnosis remains dependent on clinical judgment and reliance on standard clinical tests including serologic tests such as sedimentation rate (ESR), C-reactive protein (CRP), white blood cell count (WBC), assay of aspirated joint fluid, and interpretation of intraoperative tissue and fluid test results. Typically the diagnosis will be based on a combination of findings, rather than a unmarried one [one, twenty].
However, PJI may occasionally escape diagnosis considering of a multitude of reasons. First, the clinical presentation of PJI tin be innocuous and mimic other atmospheric condition. Second, the radiographic workup in the diagnosis of PJI is rarely informative and cannot distinguish between septic and aseptic failures. More importantly, there is no unmarried examination with absolute accuracy for diagnosis of PJI. Although reports regarding sensitivity and specify of numerous diagnostic tests in the literature grow, the interpretation of the available information has been hampered by the depression sample size of these studies. One such instance is the analysis of synovial fluid for leukocyte count and neutrophil percentage; a loftier sensitivity of 94% and 97% and a specificity of 88% and 98% respectively have been reported [21]. Nevertheless, the cutoff values for the fluid cell count and neutrophil differential [11, 16] are not agreed upon.
We conceived our investigation to ostend current concepts in the diagnosis of PJI and introduce new ones based on information available from multiple joint arthroplasty centers. Our goal was to investigate the role and efficacy of serological tests and synovial fluid analysis during the preoperative evaluation of patients with suspected PJI. Based on past literature we presumed combining tests can lead to superior diagnostic value in terms of sensitivity, specificity, and predictive value [7, 15, 16]. We believed the efficacy of Gram stain in diagnosing PJI intraoperatively tin exist improved by analyzing both the number of stained white blood cells and looking for the presence of organisms. Although intraoperative culture has been accounted equally the gold standard for diagnosing PJI, some investigators take challenged this notion [2, 4, 6, 8]. A review of our pooled data was performed to make up one's mind the false negative incidence of intraoperative culture, and the role that prophylactic antibiotics given prior to revision surgery may have on civilization results. Finally, we explored the clinical fate of patients with a simulated positive unexpected intraoperative culture.
Materials and Methods
We assembled a unmarried database comprised of detailed information on all patients undergoing revision TKA for all reasons in three academic centers from 2000 to 2005. There were a total of 889 patients in this cohort with a mean age of 67 years (range, 43–94 years). Patients were diagnosed with periprosthetic infection if they fulfilled ane of the post-obit criteria: (1) an abscess or sinus tract was found communicating with the joint infinite; (ii) positive preoperative aspiration culture on solid media; or (three) two or more positive intraoperative cultures or ane positive culture on solid media in conjunction with the presence of gross intracapsular purulence or aberrant histology [12]. Intraoperative culture results were classified as fake positives if a unmarried positive civilization occurred in the absenteeism of other signs of infection described above. Of the 889 patients 197 (22%) met 1 of these criteria. The incidence of PJI was similar among the three institutions. Data routinely collected on this cohort included prophylactic antibiotic administration; preoperative ESR, CRP, and WBC; analysis of aspirated articulation fluid (when performed) for accented cell count; percentage of neutrophils; gram stain and civilization; and analysis of intraoperative gram stain and culture results.
We identified the 171 TKA patients from the 197 with an infection who had a positive preoperative articulation aspiration culture. We documented the details of any antibiotics given preoperatively. The outcome of intraoperative culture samples was and then correlated with the preoperative articulation aspiration findings to determine the imitation negative charge per unit. We further adamant the influence of administration of prophylactic antibiotics on isolation of an organism(s) from the intraoperative cultures.
We identified 296 total knee revisions performed at one of the participating institutions from the total of 889 patients revised who had both an ESR and CRP drawn as role of the preoperative workup. The serology tests from a single institution were included in order to forestall a confounding variable that may have been introduced by including lab values from dissimilar institutions. The sensitivity, specificity, and predictive values were calculated for each test lone and when combined together. The cost of the serological tests was compared to that of other preoperative diagnostic modalities including Indium scans, FDG-PET imaging, and articulation fluid assay.
We divers a positive gram stain as the visualization of bacterial cells or "many leukocytes" (> 5 per high-power field) nether the smear. The sensitivity, specificity, and predictive values of visualizing bacterial cells or stained white cells in diagnosing PJI according to these criteria were determined separately and in combination. One prepare of combinations performed required both bacteria and "many leukocytes" to be positive to confirm infection. The second set of combinations required both bacteria to be absent and < 5 leukocytes per high-power field were visualized to be negative to dominion out infection.
To ascertain cutoff values for fluid leukocyte count and neutrophil percentage we used synovial fluid analysis performed on 429 TKA (161 infected; 268 hygienic) at the three institutions. The sensitivity, specificity, and predictive values were calculated for the above cutoff values using receiver operating curves. The ESR and CRP cutoff values of 30 mm/hr and 10 mg/L respectively were combined with the above determined cutoff values for fluid leukocyte count and neutrophil percentage to ameliorate the diagnostic value of each test when used separately.
To appraise the accuracy of intraoperative cultures in isolating an infecting organism, the rate of false-negative and simulated-positive intraoperative culture was determined. False negative was defined as the absence of isolation of any organisms from intraoperative samples in patients with "proven" PJI based on a positive preoperative aspirate, elevated serology, and/or elevated cell count/differential. False positives were determined based on the isolation of organisms from intraoperative culture samples in patients who did not showroom signs of infection for at least 2 years following revision TKA, despite receiving no handling for infection.
The estimated sensitivity, specificity, predictive values, and likelihood ratios were calculated for the different preoperative and intraoperative variables, and the 95% conviction intervals (CI) were reported. A p value of < 0.05 (2-sided) was considered meaning. All analyses were performed using SPSS, version 13 (SPSS, Inc., Chicago, IL). Receiver operating characteristic (ROC) curves which describe the relation between true-positive (sensitivity) and false-negative (1-specificity) cases were constructed for the fluid leukocyte count and neutrophil percentage (Fig.1A–B). The area under the curve was calculated for each of the in a higher place variables and compared. An area under the curve of 1 demonstrates an platonic exam with a 100% sensitivity and specificity, while an expanse under the curve less than 0.five indicates that the diagnostic test is less useful. The cut-off values of fluid leukocyte count and neutrophil percentage for optimal diagnosis of PJI were determined. The sensitivity, specificity, and predictive values were calculated for each of the cutoff values. We performed a pair-wise comparing of the expanse under the bend for the fluid leukocyte count and neutrophil per centum to decide which diagnostic examination is all-time suited for diagnosing PJI.
Receiver operating curves for predicting periprosthetic infection are illustrated. An expanse under the curve of i demonstrates an ideal exam with a 100% sensitivity and specificity, while an area under the curve less than 0.v indicates that the diagnostic has poor discriminatory value. (A) The cutoff value for optimal accuracy in diagnosis of PJI was 1100 cells/μL for fluid leukocyte count. (B) The cutoff value for optimal accurateness for fluid neutrophil differential was 64%. When both tests yielded results below their cutoff values, the negative predictive value of the combination increased to 99.6%, while if both tests were greater than their cutoff values the positive predictive value improved to 100%.
Results
Of the 296 patients with preoperative ESR and CRP performed at one of the participating institutions, 116 patients (39%) were classified as infected and 180 patients (61%) were considered noninfected. The hateful ESR and CRP of the infected patients at 85 mm/hr and 110 mg/L were higher (p < 0.001) than the corresponding values at 22 mm/hr and seven mg/L for the noninfected knees. 5 patients (iv%) in the infected group had a normal ESR (< twenty mm/hr) and CRP (< 10 mg/L). Infection was suspected in all v patients and an organism was cultured on solid media in iv of the 5 cases.
The evaluation of the joint aspirate from 429 TKA (161 infected; 268 aseptic) using receiver operating curves revealed that the cutoff values for optimal accuracy in diagnosis of PJI were 1100 cells/μL for fluid leukocyte count and 64% for neutrophil differential. When both tests yielded results below their cutoff values, the negative predictive value of the combination increased to 99.six%, while if both tests were greater than their cutoff values the positive predictive value improved to 100%. Similarly, when both the neutrophil per centum and CRP were less than 64% and x mg/L respectively ane tin rule out PJI in the majority of cases.
The analysis of tissue cultures in 453 TKA patients revealed that the presence of organisms and "many" neutrophils on a gram smear had high specificity (98%–100%) and positive predictive value (89%–100%). Still, the sensitivities (30%–50%) and negative predictive values (70%–79%) of the two tests were depression. When the 2 tests were combined in series the specificity and positive predictive value were accented (100%) with slightly improved sensitivity (43%–64%) and negative predictive value (82%).
Analysis of the results of intraoperative cultures revealed that there was a x% incidence of fake negative rate in patients with strong clinical suspicion for infection. This was despite the presence of gross pus in some of the cases. On the other manus, of a consecutive serial of 692 revision TKAs, intraoperative cultures were unexpectedly positive in 41 cases (5.9%). Of these 41, 29 cases had a single positive intraoperative culture and were judged a probable fake positive based on absence of any other prove of infection, of which five were treated with an extended course of intravenous antibiotics after hospital discharge and the remaining 24 received no further treatment. None of these 29 patients manifested any sign of infection at a minimum followup of 24 months (boilerplate, 46 months; range, 24–74 months). Twelve patients were determined to accept probable acute periprosthetic infection, 11 of whom were treated with a form of antibiotics. Two of these patients became reinfected within 1 year. The remaining ten patients had no farther sequelae.
Among the accomplice of 171 patients with positive preoperative aspirate, 72 patients received prophylactic antibiotics within one hr of revision TKA. Intraoperative culture was negative in nine of 72 patients who received antibiotics corresponding to a false-negative rate of 12.five%. In contrast, an organism could not be isolated from intraoperative samples in eight of 99 patients who did non receive prophylactic antibiotics, corresponding to a fake-negative rate of eight%. We found no divergence (p = 0.34) in the incidence of false-negative cultures between those who did and those who did non receive perioperative antibiotics. In over ninety% of cases administering antibiotics did not change the ability to observe a pathogen. A new organism was rarely discovered and when it was, it rarely had an touch on treatment.
Word
Periprosthetic joint infection has ascended to the highest rank as the crusade of failure following articulation arthroplasty [23]. Further, one study suggests a big number of what was once idea hygienic loosening may actually be due to undiagnosed infection and thus the rate of PJI might be an underestimate of the actual cases of infection [22]. Some studies suggest combining the results of several tests volition yield a more accurate diagnosis of infection. Based on that literature nosotros presumed combining tests can lead to superior sensitivity, specificity, and predictive value.
Although our study population included patients from multiple referral centers and is the largest cohort to appointment, we recognize some limitations. Because of the involvement of multiple centers some variability in information collection and analysis may accept existed that could confound these findings. In that location may have also been differences among institutions with regard to interpretation of histological findings, Gram stain, and cell counts that could have likewise influenced the results. In social club to minimize the variability nosotros ensured that the aforementioned standardized units were used when examining laboratory tests such equally the ESR, CRP, and prison cell counts. This study is also on patients undergoing revision TKA and its findings could non and should not be generalized to other joints. In add-on, the analyses excluded patients with inflammatory arthropathy including rheumatoid arthritis, systemic lupus erythematosus, and gout because of their inherently elevated levels of fluid cell count, neutrophil percentage, and serological values. Nevertheless, these limitations do not detract from our conclusions given that our large patient population affords us adequate power to reach deductions that reflect those present in the literature.
Periprosthetic joint infection, besides its psychological and financial burden on the patient and guild, poses a major diagnostic challenge to the orthopaedic community [iv]. Despite availability of various diagnostic modalities, confirmation of PJI can exist difficult in some patients [six, 13, 15, 20]. Farther, at that place is no consensus as to what constitutes a PJI, making its diagnosis very challenging [17]. Although literature abounds with reports on the accuracy of various tests for diagnosis of PJI [8, 13, fifteen, 16, 20], the small sample size and the conflicting findings of studies hinder the interpretation of the available information.
This multicenter study amassing a relatively large population of patients with and without PJI demonstrated some important findings. Perhaps ane of the near important findings of the study was that administration of prophylactic antibody did not seem to interfere with isolation of an infecting organism. Infecting organisms could still be isolated from the intraoperative civilisation of over 90% of patients who received preoperative antibiotics. The incidence of negative cultures was not unlike betwixt patients who received antibiotics versus those who did not. Thus the beneficial effect of prophylactic antibiotics should not be withheld from patients undergoing revision TKA. This is especially important equally TKA is often performed under tourniquet and a filibuster in assistants of antibiotic until tissue culture samples are obtained is more concerning. One of import caveat of this report should be remembered: the findings of the written report only apply to patients in whom an infecting organism has been isolated preoperatively.
Our data propose intraoperative cultures cannot and should not be used as gold standards for diagnosis of PJI as there is a relatively loftier per centum of both false-negative and imitation-positive cases. Although the latter betoken has been expressed past several studies [two, 16, 20], others continue to advocate intraoperative cultures as the unmarried nearly important test [8, 20]. We interpret our information as suggesting the joint aspirate fluid, with respect to total white cell count and per centum of neutrophils, is more accurate for diagnosis of infected TKA than intraoperative cultures. Once again this was the example when a definite cutoff value for total prison cell count and the neutrophil percent using receiver operating curve analysis had been performed and the prison cell analysis findings were combined with ESR and CRP values. Although Trampuz et al. [21] were the first to report cutoff values for fluid cell count and differential, they did not advise the clinical importance of a state of affairs when both tests reveal a positive or negative outcome. Spangehl et al. [twenty] also reported improved sensitivity, specificity, and predictive value when combining the examination values of ESR and CRP. However, there is little information in the literature describing the combination of serological tests with aspiration fluid cell count or neutrophil differential. We establish the clinical utility of fluid analysis in diagnosing infection can be improved by combining this test with serology findings. Combinations of cell count and differential and serology safely excluded or confirmed the presence of infection during the preoperative assessment of the patients with failed knees.
Our data also demonstrated that simple serological tests, namely ESR and CRP, are excellent screening tools and we believe they should be obtained in every patient with a painful TKA. Elevated ESR and/or CRP were highly predictive of PJI and should prompt further evaluation such as joint aspiration. This study could not evaluate the function of preoperative os scan every bit an insufficient number of these tests had been performed in the accomplice. The study, yet, revealed that intraoperative gram stain and cell count carried a low sensitivity and negative predictive value. The latter tests should therefore non be used as screening tools. However, these fast and simple intraoperative test have a valuable part in reaching a diagnosis for cryptic cases [4, 16].
Accurate and early diagnosis is the commencement step in finer managing patients with PJI. At the present fourth dimension, diagnosis remains dependent on clinical judgment and reliance on standard clinical tests including serologic tests, analysis of aspirated joint fluid, and interpretation of intraoperative tissue and fluid test results. In view of the scope of this important problem and the limitations of previous reports, nosotros take determined the current condition of diagnosis of the infected TKA utilizing commonly available tests.
Footnotes
Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity involvement, patent/licensing arrangements, etc) that might pose a conflict of involvement in connection with the submitted article.
Each author certifies that his or her institution has approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the report was obtained.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2565043/