Orthopedics

Feature Article 

Commercially Available Polymerase Chain Reaction Has Minimal Utility in the Diagnosis of Periprosthetic Joint Infection

Beau J. Kildow, MD; Sean P. Ryan, MD; Richard Danilkowicz, MD; Alexander L. Lazarides, MD; Tyler J. Vovos, MD; Michael P. Bolognesi, MD; William A. Jiranek, MD; Thorsten M. Seyler, MD, PhD

Abstract

The use of genetic sequencing modalities in the diagnosis of periprosthetic joint infection (PJI) and the identification of organisms has gained popularity recently. Polymerase chain reaction (PCR) offers timely results for common organisms. The purpose of this study was to compare the accuracy of broad-range PCR, conventional culture, the Musculoskeletal Infection Society (MSIS) criteria, and the recently proposed criteria by Parvizi et al in the diagnosis of PJI. In this retrospective study, aspirate or tissue samples were collected in 104 revision and 86 primary arthroplasties for routine diagnostic workup for PJI and sent to the laboratory for PCR. Concordance along with statistical differences between diagnostic studies were calculated using chi-square test for categorical data. On comparison with the MSIS criteria, concordance was significantly lower for PCR at 64.7% compared with 86.3% for culture (P<.001). There was no significant difference based on diagnosis of prior infection (P=.706) or sample collection method (tissue swab or synovial fluid) (P=.316). Of the 87 patients who met MSIS criteria, only 20 (23.0%) PCR samples had an organism identified. In this series, PCR had little utility as a stand-alone test for the diagnosis of PJI, with a sensitivity of only 23.0% when using MSIS criteria as the gold standard. Polymerase chain reaction also appears to be significantly less accurate than culture in the diagnosis of PJI. Currently, several laboratory tests used for either criteria for PJI diagnosis should be obtained along with the overall clinical picture to help guide decision-making for PJI treatment. [Orthopedics. 2020;43(6):333–338.]

Abstract

The use of genetic sequencing modalities in the diagnosis of periprosthetic joint infection (PJI) and the identification of organisms has gained popularity recently. Polymerase chain reaction (PCR) offers timely results for common organisms. The purpose of this study was to compare the accuracy of broad-range PCR, conventional culture, the Musculoskeletal Infection Society (MSIS) criteria, and the recently proposed criteria by Parvizi et al in the diagnosis of PJI. In this retrospective study, aspirate or tissue samples were collected in 104 revision and 86 primary arthroplasties for routine diagnostic workup for PJI and sent to the laboratory for PCR. Concordance along with statistical differences between diagnostic studies were calculated using chi-square test for categorical data. On comparison with the MSIS criteria, concordance was significantly lower for PCR at 64.7% compared with 86.3% for culture (P<.001). There was no significant difference based on diagnosis of prior infection (P=.706) or sample collection method (tissue swab or synovial fluid) (P=.316). Of the 87 patients who met MSIS criteria, only 20 (23.0%) PCR samples had an organism identified. In this series, PCR had little utility as a stand-alone test for the diagnosis of PJI, with a sensitivity of only 23.0% when using MSIS criteria as the gold standard. Polymerase chain reaction also appears to be significantly less accurate than culture in the diagnosis of PJI. Currently, several laboratory tests used for either criteria for PJI diagnosis should be obtained along with the overall clinical picture to help guide decision-making for PJI treatment. [Orthopedics. 2020;43(6):333–338.]

Periprosthetic joint infection (PJI) results in significant morbidity and mortality following total joint arthroplasty.1,2 To date, there is no single test or combination of tests providing complete accuracy in diagnosing PJI.3,4 Several biomarkers have been identified as helping aid in the diagnosis of PJI; however, given their inability to identify an organism, they are not ideal.5–8 Therefore, the focus has recently shifted toward the use of DNA sequencing modalities for both PJI diagnosis and organism identification.9–11

Several genetic techniques have been reported since the early 1990s, but none has proven to be more accurate than the gold standard of culture.9,12–17 Various polymerase chain reaction (PCR) techniques9,16–18 are used to detect organisms; however, these techniques only detect a small set of microbes. Broad-range PCR introduced optimism, as it amplifies a highly conserved region in the bacterial genome, thus allowing for detection of nearly all bacteria. Unfortunately, it has yielded low sensitivities (67.1% to 73.3%) similar to those of culture.14,16,18

Next-generation sequencing (NGS) appears more reliable because it involves sequencing and identification of all 16s amplicons in a sample, thus circumventing the limitations of prior genetic techniques.19 Currently, this technology is commercially available for approximately $200 per test. Clinical application of NGS has shown promising results, especially in diagnosing culture-negative infections.10,11

An advantage to PCR and NGS includes the ability to obtain results from a synovial fluid sample prior to operative management. Results can be obtained in less than 24 hours with PCR, but in 3 to 5 days with NGS. This technology can also help in tailoring treatment regimens for patients, mitigating the need for potential long periods of culture growth and thus decreasing the length of hospitalization. Thus, these tests have the potential to improve diagnostic accuracy for PJI at a low cost.

The purpose of this study was to compare the diagnostic accuracy of PCR prior to NGS relative to the gold standard for PJI diagnosis, the Musculoskeletal Infection Society (MSIS) criteria,20 and the recently proposed criteria by Parvizi et al.21 Furthermore, the authors sought to evaluate the utility of PCR as a stand-alone diagnostic test. They hypothesized that PCR would be as sensitive as culture and could potentially impact subsequent sequencing.

Materials and Methods

This retrospective review involved patients being evaluated for and/or having existing PJI from January 2017 to July 2019 at a single academic tertiary referral center. This study was approved by the institution's human subject review board. Patients were included if they had a primary or revision total hip or knee arthroplasty and were being evaluated for a possible acute or chronic PJI, had a prior successful reimplantation and were being evaluated for infection, had prior irrigation and debridement and were being evaluated for persistent infection, or were being treated for PJI with a two-stage spacer and were being considered for reimplantation. All patients were included regardless of type of implant, type of antibiotic spacer, current use of intravenous antibiotics, surgical approach, or history of prior PJI. For statistical analysis, patients with prior irrigation and debridement, an antibiotic spacer, or reimplantation from a prior spacer were categorized as the infection cohort. Patients were excluded only if they did not have a sample or refused that one be obtained for evaluation using PCR or NGS.

Two different cohorts of patients were evaluated based on the presence of a past infection. Patients who presented with a painful primary or revision total joint arthroplasty first had an erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) laboratory test. If these results were within normal limits, patients did not undergo further testing for PJI. If one or both laboratory values were elevated, a joint aspiration was performed. For patients being evaluated for an acute infection (less than 6 weeks from the index procedure), ESR/CRP thresholds for abnormal values were defined as outlined by Yi et al.22 The fluid from the aspirate was sent for cell count, polymorphonuclear (PMN) cell percentage, and culture and to MicroGen Dx Laboratory, Lubbock, Texas, for PCR. These patients constituted the “non-infection history” cohort. For patients being evaluated for reimplantation from two-stage antibiotic spacer, with prior successful reimplantation, or with prior irrigation and debridement with a liner exchange procedure—the “infection history” cohort—ESR/CRP tests were conducted. If the results were within normal limits, patients returned to the operating room, where tissue samples were collected and sent to MicroGen Dx Laboratory for PCR. Aspiration was performed if the patient had an elevated ESR or CRP prior to reimplantation consideration and evaluated as stated above. For the purposes of this study, PCR results were evaluated without results from NGS, which were reported by MicroGen Dx Laboratory 2 to 4 days after the PCR results.

All patient charts were manually reviewed to analyze the following data from the electronic medical records: patient age, sex, American Society of Anesthesiologists score,23 and body mass index. Data collected for PJI workup included ESR, CRP, cell count, PMN cell percentage, culture results, presence of sinus tract, D-dimer, presence of acute inflammation on intraoperative histopathology tissue samples, positive result on leukocyte esterase test, and PCR results. Organisms that can be identified through PCR are listed in Table 1. Infection was defined according to the MSIS criteria20 and the recently proposed criteria by Parvizi et al.21

Microbe Profile Identified by Polymerase Chain Reactiona

Table 1:

Microbe Profile Identified by Polymerase Chain Reaction

Results of PCR, culture, and PJI defined by recently proposed criteria by Parvizi et al21 were compared with the current gold standard for infection diagnosis, MSIS criteria, by calculating concordance (agreement in PJI diagnosis), specificity, sensitivity, positive predictive value, and negative predictive value, in the usual fashion. These calculations were applied to the entire cohort as well as the sub-cohorts as defined above. Statistical analysis was performed using Excel, version 16.16.13 (Microsoft) and JMP Pro, version 14.0.0 (SAS Institute Inc) software.

Results

A total of 190 patients underwent infection evaluation, including having results from PCR. Mean age of the patients was 68.1 years (range, 38.0–93.4 years). The majority, 147 (77%), of the cases involved the knee, while 43 (23%) involved the hip (Table 2). The two main cohorts were identified based on history of prior infection. There were 86 (45.3%) primary and 30 (15.8%) revision total joint arthroplasties in the non-infection history cohort. In the prior infection cohort, 39 (20.5%) patients were currently being treated with an antibiotic spacer and under consideration for reimplantation, 21 (11.1%) had a history of prior irrigation and debridement with modular component exchange, and 14 (7.4%) had a prior reimplantation (Figure 1).

Patient Demographics

Table 2:

Patient Demographics

Number of patients in each cohort. Primary and past revision cohorts had no history of infection. Past infection-spacer were patients currently with a spacer being considered for reimplantation. Abbreviations: inf, infection; I&D, irrigation and debridement.

Figure 1:

Number of patients in each cohort. Primary and past revision cohorts had no history of infection. Past infection-spacer were patients currently with a spacer being considered for reimplantation. Abbreviations: inf, infection; I&D, irrigation and debridement.

Using the MSIS criteria as the gold standard to diagnose PJI, the sensitivity and specificity of PCR were 23.0% and 100%, respectively. The recently proposed criteria by Parvizi et al21 nearly matched the current MSIS criteria, having sensitivity of 98.8% and specificity of 98.9%. When compared with the MSIS criteria, concordance was significantly lower for PCR at 64.7% compared with 86.3% for culture (P<.001). There was no significant difference based on prior infection (P=.706) or method of sample collection (tissue swab or synovial fluid) (P=.316). In the prior infection cohort, the sensitivity and specificity of PCR were 27.0% and 100%, respectively (Table 3). The overall concordance between PCR and culture was 72.1%. A total of 87 samples met MSIS criteria. Eighty-two samples met criteria set forth by Parvizi et al,21 with 5 being “inconclusive.” Only 1 sample did not meet MSIS criteria.

Sensitivity, Specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of Polymerase Chain Reaction (PCR), Culture, and Criteria Set Forth by Parvizi et al21 Compared With Musculoskeletal Infection Society Criteria for Periprosthetic Joint Infection

Table 3:

Sensitivity, Specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of Polymerase Chain Reaction (PCR), Culture, and Criteria Set Forth by Parvizi et al21 Compared With Musculoskeletal Infection Society Criteria for Periprosthetic Joint Infection

PCR Versus Culture

Polymerase chain reaction did not identify an organism in 53 samples that were culture positive. Thirty-six samples grew an organism in culture that was not included in the panel of organisms detected by PCR. However, 17 samples grew an organism that theoretically should have been identified by PCR. A total of 20 samples were PCR positive and culture positive, all of which met both MSIS criteria and criteria set forth by Parvizi et al.21 Polymerase chain reaction and culture had organism mismatch in 1 sample. Polymerase chain reaction identified Cuti-bacterium acnes, while culture identified Staphylococcus aureus. There were 117 samples that were culture and NGS negative; 20 of these samples met both criteria for PJI. Of the 53 samples that were culture positive/PCR negative, 50 met both criteria (Figure 2).

Concordance of polymerase chain reaction (PCR), culture, Musculoskeletal Infection Society (MSIS) criteria, and criteria by Parvizi et al.21

Figure 2:

Concordance of polymerase chain reaction (PCR), culture, Musculoskeletal Infection Society (MSIS) criteria, and criteria by Parvizi et al.21

Discussion

To date, this is the largest series comparing PCR results with other diagnostic criteria, including culture. The purpose was to identify the accuracy of PCR compared with common modalities used to diagnose PJI. The PCR technology evaluated in this study is the only commercially available test on the market and is becoming an increasingly popular tool in PJI diagnosis. To the authors' knowledge, there are no studies examining the clinical utility of this test compared with current diagnostic modalities. The overall concordance of PCR and culture was 72.1%. Compared with the current gold standard (MSIS criteria), PCR had a sensitivity of 23.0% and a specificity of 100%. The authors' reported sensitivity of PCR was lower than what has been previously described; however, overall, the efficacy of PCR is not promising, despite previous optimism in culture-negative infections.12 Fihman et al16 reported a sensitivity of 53.8% for patients with PJIs in a prospective study of 76 samples. A large meta-analysis by Jun et al24 identified an overall sensitivity of 76% and specificity of 94% from pooled data of 20 studies with 2526 participants. This meta-analysis included a wide array of PCR techniques and concluded that no single PCR test was better than reported sensitivities for alpha- defensin.24

There have been many PCR techniques described in the literature when applying this technology to PJI. The original technique commonly described was broad-range 16s rDNA. This technique involved identifying and amplifying the conserved 16s rDNA from bacteria within a sample. This would then be sequenced to identify specific bacteria and potential resistant genes. This technology revealed sensitivities ranging from 50% to 92% and 65% to 94%.25 This process has been modified in an attempt to increase diagnostic accuracy. Lausmann et al26 reported a sensitivity and specificity of 78.8% and 100%, respectively, when analyzing 60 samples using multiplex PCR. This technique involves using smaller, specific primers to target a preselected set of bacteria and possibly antibiotic-resistant genes. The use of smaller, more specific primers was thought to have the advantages of increased sensitivity and specificity and results within 24 hours. Portillo et al15 demonstrated an increased sensitivity of 96% when using multiplex PCR on 86 samples that underwent implant sonication. However, this study evaluated implants postoperatively, which may not translate to fluid or tissue samples obtained for diagnosis prior to operative management. Multiplex PCR appears promising, especially when combined with sonication; however, results vary and it is currently not performed routinely by arthroplasty surgeons.24,27

Recently, Moshirabadi et al28 reported the highest sensitivity and specificity in the literature (97.4% and 100%, respectively) using PCR technology for PJI diagnosis. This technique, known as PCR-restriction fragment length polymorphism, involves using microbe-specific enzymatic cleavage of the PCR products to help increase detection and identification of microbes, theoretically increasing sensitivity. Moshirabadi et al28 also noted that this process is faster than conventional PCR and NGS; however, this technique has yet to be validated and is not yet commercially available.

The PCR evaluated in this study was performed by MicroGen Dx Laboratory. This is the same laboratory that has made both PCR and NGS commercially available for organism identification in PJI diagnosis. In general, the process involves an enzymatic and mechanical isolation of bacterial DNA within a sample. Broad-spectrum PCR is performed, which uses a primer that targets the conserved 16s rDNA sequence in the microbe genome. Once the conserved region has been identified by the primer, an amplification process is initiated. Within 24 hours, results from the PCR can identify organisms that are listed in Table 1. This amplified sample is then sequenced in parallel, known as NGS. Theoretically, NGS has the potential to identify any microbe that is present in the original sample, assuming PCR correctly identified and amplified microbial DNA. This technology costs approximately $200, which is less expensive than the face-value cost of obtaining ESR, CRP, and cultures at the authors' institution ($250). In a cost-effectiveness model performed by Torchia et al,29 NGS was more cost-effective than culture when the pretest probability of PJI was greater than 45.5%, and the sensitivity of NGS was above 70.0%. Although the current authors did not evaluate the accuracy of NGS, applying this model to results of PCR would not be cost-effective because of the poor sensitivity of 23.0%.

The current results indicate that the sensitivity of PCR is not as high as previously reported.14,15,28 As indicated above, PCR did not identify an organism in 53 samples that were culture positive, of which 50 met MSIS criteria. There are two plausible explanations for these findings. The sample and/or microbe concentration could be too small to be identified and extracted prior to the DNA amplification process. Bergin et al30 identified a detection limit for Staphylococcus aureus and Escherichia coli of 590 and 2900 CFU/mL, respectively, using rRNA qPCR.30 Samples being sent may not meet threshold concentrations for respective organisms, decreasing the sensitivity. Another plausible explanation could be in the technique used to amplify DNA sequences of a given sample. If the primer sequences are significantly longer than the shorter sequences that are needed to be amplified, the specific DNA sequences that are needed for organism identification may not be effectively amplified. This would significantly reduce the sensitivity of both PCR. This is especially important if this PCR technology is used to amplify the sample DNA that is used for organism sequencing for NGS. This may have a propagating effect, limiting the sensitivity of NGS. Finally, the authors indicated that there was no significant difference in the type of sample obtained (tissue vs fluid aspirate) when comparing results of PCR with culture and both criteria used to define PJI. The authors also found no significant difference in PCR results compared with culture and both PJI criteria for patients who were presumably taking antibiotics or had an antibiotic spacer in place (infection vs non-infection cohorts) at the time of sampling.

There were several notable limitations to this study. Due to the retrospective nature of this study, there was no documentation of the amount of synovial fluid or quantity of tissue that was sent for PCR. Per manufacturer instructions, a minimum of 2 mL of synovial fluid should be obtained for analysis. Additionally, the inability to accurately assess prior antibiotic administration may have resulted in higher false-negative PCR readings. However, this technology is capable of amplifying DNA from dead bacteria, so antibiotics should not alter results. The authors' institution does not routinely obtain synovial alpha-defensin or synovial CRP. Although these two tests are part of the criteria set forth by Parvizi et al,21 the authors thought that the validity of these criteria was not sacrificed because they paralleled the MSIS criteria almost exactly. There is also bias when comparing culture with PCR using MSIS as the gold standard. Because culture is an integrated criteria marker for MSIS, the sensitivity and specificity of culture will be inherently higher. The authors believe that this does not sacrifice the findings of this study because the sensitivity of PCR was poor despite the comparison with other diagnostic techniques. Finally, patient outcomes, specifically infection eradication after treatment based on PCR, could not be reported at this time.

Conclusion

There is no single reliable test for PJI diagnosis and organism identification. Despite having relatively low sensitivity and a potential for contamination, culture continues to be the conventional modality for aiding in diagnosis and organism identification. Theoretically, commercially available 16s rRNA PCR appears to be a promising tool; however, the authors' data suggest that it has poor sensitivities. Currently, laboratory tests used for either criteria for PJI diagnosis should be obtained regardless of PCR along with the overall clinical picture to help guide decision-making for PJI treatment. Genetic techniques should continue to be explored, given their potential to be a single tool used in PJI diagnosis and organism/antimicrobial gene identification.

References

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  28. Moshirabadi A, Razi M, Arasteh P, et al. Polymerase chain reaction assay using the restriction fragment length polymorphism technique in the detection of prosthetic joint infections: a multi-centered study. J Arthroplasty. 2019;34(2):359–364. doi:10.1016/j.arth.2018.10.017 [CrossRef]. PMID:30471785
  29. Torchia MT, Austin DC, Kunkel ST, Dwyer KW, Moschetti WE. Next-generation sequencing vs culture-based methods for diagnosing periprosthetic joint infection after total knee arthroplasty: a cost-effectiveness analysis. J Arthroplasty. 2019;34(7):1333–1341. doi:10.1016/j.arth.2019.03.029 [CrossRef]. PMID:31005439
  30. Bergin PF, Doppelt JD, Hamilton WG, et al. Detection of periprosthetic infections with use of ribosomal RNA-based polymerase chain reaction. J Bone Joint Surg Am. 2010;92(3):654–663. doi:10.2106/JBJS.I.00400 [CrossRef]. PMID:20194324

Microbe Profile Identified by Polymerase Chain Reactiona

Enterococcus faecalisStreptococcus pyogenesStaphylococcus aureusKlebsiella pneumoniaeEnterococcus faeciumCutibacterium acnesStreptococcus agalactiaePseudomonas aeruginosaCandida albicans

Patient Demographics

CharacteristicValue
Age, mean (range), y68.1 (38.0–93.4)
Female, No.98 (51.6%)
Male, No.92 (48.4%)
Knee, No.147 (77.4%)
Hip, No.43 (22.6%)
BMI, mean (range), kg/m232.7 (19.7–53.4)
ASA score, No.
  234 (17.9%)
  3147 (77.4%)
  49 (4.7%)

Sensitivity, Specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of Polymerase Chain Reaction (PCR), Culture, and Criteria Set Forth by Parvizi et al21 Compared With Musculoskeletal Infection Society Criteria for Periprosthetic Joint Infection

Diagnostic testSensitivitySpecificityPPVNPV
PCR23.00%100%100%60.60%
Culture77.00%94.20%91.80%82.90%
Parvizi et al2198.80%98.90%98.80%98.90%
Authors

The authors are from the Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina.

Drs Kildow, Ryan, Danilkowicz, Lazarides, and Vovos have no relevant financial relationships to disclose. Dr Bolognesi is a paid presenter for TJO and Zimmer; has received research support from Biomet, DePuy, Exactech, Inc, KCI, and Zimmer; has received financial or material support from Acelity, AOA Omega, and Smith & Nephew; holds stock in Amedica and TJO; and receives royalties from TJO and Zimmer. Dr Jiranek receives royalties from DePuy. Dr Seyler is a paid consultant for Haraeus, Smith & Nephew, and TJO; has received research support from KCI, Medblue Incubator Inc, Next Science, Samumed, and Zimmer; and receives royalties from Pattern Health, Restor3d, and TJO.

Correspondence should be addressed to: Beau J. Kildow, MD, Department of Orthopaedic Surgery, Duke University Medical Center, Box 3000, Durham, NC 27710 ( kildow06@gmail.com).

Received: May 08, 2020
Accepted: August 10, 2020
Posted Online: October 01, 2020

10.3928/01477447-20200923-01

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