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Difficult-to-Detect Low-Grade Infections Responsible for Poor Outcomes in Total Knee Arthroplasty
Take-Home Points
- Despite standardization of diagnostic criteria by the MSIS for the diagnosis of PJI, some low-grade inflections create a diagnostic challenge for clinicians.
- P acnes infection following TJA can be present despite patients having normal serum inflammatory marker levels and synovial fluid aspirations.
- Patients with a PJI with low virulence organisms can present with painful, arthrofibrotic joints that do not appear to be clinically infected.
- Biopsy for pathology and culture can aid in the diagnosis of suspected PJI in patients who fail to meet MSIS criteria.
- If detected and accurately diagnosed, PJI with P acnes can be successfully eradicated with IV antibiotics and 2-stage revision arthroplasty with a good functional outcome.
Total joint arthroplasty (TJA) is a routinely performed, highly efficacious procedure for patients with degenerative osteoarthritis.1,2 In the United States in 2003, more than 450,000 total knee arthroplasties (TKAs) were performed, and this number is projected to increase by more than 673% by 2030, as America’s population continues to age.3 With the increase in primary TJAs has come an increase in revision TJAs. The most common cause of revision TJA is infection (25.2%), which has a rate of 1% to 4% after primary TJA.1,4 Despite advancements in implant technology, preoperative preventive strategies, perioperative techniques, and postoperative management, a recent meta-analysis of patient follow-up data revealed that 15% to 20% of patients remained dissatisfied after TJA, despite having technically well-placed implants.5,6
Recent studies have suggested that prosthetic joint infection (PJI) may be underreported because of the difficulty in diagnosis, which may be one of the reasons why patients remain dissatisfied after TJA.7 As a result, new efforts have been made to develop uniform criteria for PJI diagnosis.8 In 2011, the Musculoskeletal Infection Society (MSIS) developed a new definition for the PJI diagnosis, based on clinical and laboratory criteria, in order to increase diagnostic accuracy. However, MSIS acknowledged that PJI may be present even if these criteria are not met, particularly in the case of low-grade infections, as patients may not present with clinical signs of infection and may have normal inflammatory markers and joint aspirates. The biofilm-forming bacteria Propionibacterium acnes and Staphylococcus epidermidis are 2 such low-virulence organisms—once commonly considered contaminants but now recognized as potential pathogens for postoperative joint infections.9 In a review performed at a major orthopedic hospital, Bjerke-Kroll and colleagues10 found that the rate of PJI with P acnes has been increasing linearly over the past 14 years. According to reports in the literature,11-13P acnes has been isolated in 2% to 4% of all cases of PJI, and Zappe and colleagues13 found a P acnes PJI rate of 6% in a retrospective analysis performed at their institution. Given the high rate of P acnes colonization of the axilla, this organism is now increasingly recognized as a cause of infection after shoulder surgery, as found in a case series of 10 patients with P acnes PJI after total shoulder arthroplasty (TSA).14 However, there is still limited data on the role of P acnes in lower extremity PJI.
Although patients with P acnes PJI can present with overt signs of infection, more often they lack systemic or local signs of infection, making the diagnosis difficult.15 Surgeons may not consider PJI as a cause of TJA failure in patients who do not meet diagnostic criteria.7 In a case series of patients with P acnes PJI after TSA, Millett and colleagues14 concluded that erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are not always reliable indicators of infection with low-virulence organisms. Eighty percent of patients in their study had normal ESR and CRP level before surgery. Zappe and colleagues13 reported on P acnes PJI diagnoses in 4 total hip arthroplasties (THAs), 3 TKAs, and 1 TSA. Of the 8 patients, 6 (75%) had borderline elevated CRP levels, and 4 (50%) had normal synovial fluid analysis and cultures from joint aspirations. In a study using electron microscopy and fluorescence in situ hybridization (FISH) labeling, Stoodley and colleagues16 found, in 8 polyethylene liners removed from culture-negative THA patients for aseptic loosening, extensive biofilm colonization with S epidermidis.
Reports of PJI cases misdiagnosed as aseptic loosening also suggest that screening and diagnostic tools are not sensitive enough to detect all infections and that PJI likely is underdiagnosed. In a prospective cohort study, Portillo and colleagues17 categorized patients who were undergoing revision surgery after TJA by cause of failure: aseptic loosening, mechanical failure, or PJI based on current MSIS guidelines. Intraoperative cultures were taken during the revisions. P acnes was isolated in 2 (3%) of the 63 cases classified as PJI and in 12 (19%) of the 63 classified as aseptic loosening. Tsukayama and colleagues18 reported an 11% rate of positive intraoperative cultures for P acnes during revision surgery in cases that the operating surgeon considered aseptic, based on white blood cell (WBC) count, ESR, and CRP level. Rasouli and colleagues19 used an Ibis biosensor to perform polymerase chain reaction (PCR) on synovial fluid from 44 patients who underwent aseptic revision of TKA failures. The authors detected a pathogen in 17 (38%) of the 44 presumed aseptic patients and concluded some aseptic loosening cases are actually chronic low-grade organism PJIs not diagnosed according to current PJI criteria.
In this article, we present the case of a patient with a stiff, painful knee after TKA and with ESR, CRP level, and synovial fluid analysis within normal limits. Open biopsy for cultures showed P acnes PJI, which was successfully treated with 2-stage revision. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 69-year-old man with a past medical history of hypertension underwent left primary TKA in 2012. In 2014, he presented to our office complaining of chronic left knee pain and stiffness that had developed insidiously over the first 3 months after surgery and never improved, despite rigorous physical therapy (Table). 
Despite not meeting MSIS diagnostic criteria, the patient elected to undergo open biopsy for synovial culture as a last resort. During surgery, there was no purulence in the joint, and frozen section showed <5 neutrophils per high-power field. All cultures from 5 separate synovial tissue samples grew P acnes, confirming the PJI diagnosis. Cultures turned positive after being incubated an average of 12.2 days (range, 10-14 days). Sensitivities showed the organism was responsive to oxacillin. The risks and benefits of 2-stage revision surgery were discussed with the patient at the next office visit, and he decided on 2-stage revision. On November 4, 2014, he underwent open synovectomy, irrigation and débridement with iodine and Dakin solution, hardware removal, and cement antibiotic spacer placement without complication (Figures 3A, 3B). 
Just before stage 2 revision on January 6, 2015, preoperative inflammatory markers were within normal limits. During surgery, additional cultures were taken from synovial tissue. At 15 days, these cultures showed no growth, confirming eradication of the infection. The patient underwent reimplantation without complication and had an uneventful postoperative course with no wound-healing issues (Figures 4A, 4B). 
Discussion
Because PJIs with low-virulence organisms can present with normal levels of inflammatory markers and negative fluid analysis and culture from joint aspirations, they pose a diagnostic challenge for arthroplasty surgeons. In this case report, there was a low index of suspicion for PJI based on radiographic, physical examination, and laboratory findings. Our patient did not meet MSIS diagnostic criteria for PJI before undergoing open biopsy. Initial cultures from joint aspiration of synovial fluid were negative, and inflammatory markers were within normal limits. However, all 5 synovial tissue biopsy specimens that were cultured confirmed a low-grade periprosthetic infection with P acnes—likely the reason for the poor outcome. This case supports Zappe and colleagues13 and Millett and colleagues,14 who found that a subset of patients with a low-grade organism PJI had normal to mildly elevated inflammatory markers and negative fluid analysis and cultures from joint aspirations.
Hardware-involved orthopedic infections are often caused by bacteria that form a biofilm, which can be difficult to culture. Biofilm matrix binds cells into aggregates, which grow only a single colony on culture media, decreasing positive yield. Therefore, synovial fluid cultures are often negative, because of the low number of planktonic cells removed by aspirate. Using FISH and PCR, Stoodley and colleagues16 found biofilm on hardware removed for “culture-negative aseptic loosening.” This is especially important for low-grade organism infections that lack a strong inflammatory response in the joint and that may be missed with traditional screening. This may be one reason our patient’s synovial fluid cultures and inflammatory markers were negative.
Another reason these low-grade infections can be missed is that P acnes is notoriously difficult to culture—it may take up to 15 days to grow in a special medium.20 Intraoperative cultures may be read as false-negative if not incubated the right amount of time. In many hospitals, aerobic and anaerobic cultures are discarded if there is no growth after 3 to 5 days. In our patient’s case, the earliest that cultures turned positive was on day 10—which is consistent with other reports, including one by Butler-Wu and colleagues,15 who suggested a minimum incubation of 13 days for optimal recovery of organisms. Our case highlights the importance of lengthening incubation to allow for growth of low-virulent organisms. Given the different types of management used for PJI and aseptic loosening, it is imperative that surgeons take cultures during revision TJA and that cultures are held up to 14 days to allow enough time for low-virulence organisms to grow.
Fortunately, PJI with low-virulence organisms can be treated successfully. Treating P acnes PJI with exchange arthroplasty and IV antibiotics has documented success rates as high as 92%.21 Again, we emphasize the importance of obtaining intraoperative cultures to determine antibiotic sensitivities, which can guide treatment. Our patient’s infection was eradicated with 2-stage revision and IV antibiotics, and his symptoms, ROM, and function improved significantly.
Diagnosing PJI after TJA can be challenging, as there is no definitive test that is sensitive, specific, rapid, and minimally invasive. Researchers have looked for novel serum or synovial fluid biomarkers that may be elevated in PJI. Synovial interleukin 6 (IL-6) and synovial α-defensin show great promise. In 2 separate studies, elevated IL-6 levels strongly correlated with infection.22,23 Jacovides and colleagues23 found that a synovial IL-6 level higher than 4270 pg/mL had a 100% positive predictive value and a 91% negative predictive value for diagnosing PJI. In some trials, synovial α-defensin has shown up to 100% sensitivity and specificity for PJI diagnosis. Most notably, in a trial by Frangiamore and colleagues,24 α-defensin levels were elevated to statistically significant levels in P acnes PJI, indicating this test may help in diagnosing PJI with low-virulence organisms. Finally, PCR has also shown promise in detecting low-grade joint infections. PCR uses 16 primers that allow not only for the identification of pan-genomic bacterial markers, specific bacterial organisms, and Candida, but also for the presence of antibiotic resistance markers. Use of pan-genomic PCR also allows for detection of a wider variety of pathogens, including organisms commonly missed by conventional culture methods.25Early intervention can significantly improve outcomes in PJI. Therefore, we recommend maintaining a high index of suspicion for low-virulence PJI in patients with chronic pain and decreased functionality after TJA with well-placed implants, despite their not meeting current MSIS diagnostic criteria for PJI. As new microbiological tools for detecting PJI with low-grade organisms are developed, use of these technologies can be incorporated into the diagnosis algorithm. Screening tools more sensitive in detecting low-grade organisms can help avoid the morbidity associated with interoperative synovial biopsies for culture and can allow for more efficient surgical planning. These tools, along with increased clinical awareness of potential PJIs, ultimately will lead to earlier detection, accurate diagnosis, and optimal treatment.
Am J Orthop. 2017;46(3):E148-E153. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
1. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
2. Kamath AF, Ong KL, Lau E, et al. Quantifying the burden of revision total joint arthroplasty for periprosthetic infection. J Arthroplasty. 2015;30(9):1492-1497.
3. Kurtz SM, Ong KL, Schmier J, et al. Future clinical and economic impact of revision total hip and knee arthroplasty. J Bone Joint Surg Am. 2007;89(suppl 3):144-151.
4. Zmistowski B, Restrepo C, Huang R, Hozack WJ, Parvizi J. Periprosthetic joint infection diagnosis: a complete understanding of white blood cell count and differential. J Arthroplasty. 2012;27(9):1589-1593.
5. Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
6. Djahani O, Rainer S, Pietsch M, Hofmann S. Systematic analysis of painful total knee prosthesis, a diagnostic algorithm. Arch Bone Jt Surg. 2013;1(2):48-52.
7. Parvizi J, Suh DH, Jafari SM, Mullan A, Purtill JJ. Aseptic loosening of total hip arthroplasty: infection always should be ruled out. Clin Orthop Relat Res. 2011;469(5):1401-1405.
8. Della Valle C, Parvizi J, Bauer TW, et al. Diagnosis of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg. 2010;18(12):760-770.
9. Dramis A, Aldlyami E, Grimer RJ, Dunlop DJ, O’Connell N, Elliott T. What is the significance of a positive Propionibacterium acnes culture around a joint replacement? Int Orthop. 2009;33(3):829-833.
10. Bjerke-Kroll BT, Christ AB, Mclawhorn AS, Sculco PK, Jules-Elysée KM, Sculco TP. Periprosthetic joint infections treated with two-stage revision over 14 years: an evolving microbiology profile. J Arthroplasty. 2014;29(5):877-882.
11. Pandey R, Berendt AR, Athanasou NA. Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service. Arch Orthop Trauma Surg. 2000;120(10):570-574.
12. Segawa H, Tsukayama DT, Kyle RF, Becker DA, Gustilo RB. Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. J Bone Joint Surg Am. 1999;81(10):1434-1445.
13. Zappe B, Graf S, Ochsner PE, Zimmerli W, Sendi P. Propionibacterium spp. in prosthetic joint infections: a diagnostic challenge. Arch Orthop Trauma Surg. 2008;128(10):1039-1046.
14. Millett PJ, Yen YM, Price CS, Horan MP, van der Meijden OA, Elser F. Propionibacterium acnes infection as an occult cause of postoperative shoulder pain: a case series. Clin Orthop Relat Res. 2011;469(10):2824-2830.
15. Butler-Wu SM, Burns EM, Pottinger PS, et al. Optimization of periprosthetic culture for diagnosis of Propionibacterium acnes prosthetic joint infection. J Clin Microbiol. 2011;49(7):2490-2495.
16. Stoodley P, Ehrlich GD, Sedghizadeh PP, et al. Orthopaedic biofilm infections. Curr Orthop Pract. 2011;22(6):558-563.
17. Portillo ME, Salvadó M, Alier A, et al. Prosthesis failure within 2 years of implantation is highly predictive of infection. Clin Orthop Relat Res. 2013;471(11):3672-3678.
18. Tsukayama DT, Strada R, Gustilo RB. Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections. J Bone Joint Surg Am. 1996;78(4):512-523.
19. Rasouli MR, Harandi AA, Adeli B, Purtill JJ, Parvizi J. Revision total knee arthroplasty: infection should be ruled out in all cases. J Arthroplasty. 2012;27(6):1239-1243.e1-e2.
20. Schäfer P, Fink B, Sandow D, Margull A, Berger I, Frommelt L. Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy. Clin Infect Dis. 2008;47(11):1403-1409.
21. Zeller V, Ghorbani A, Strady C, Leonard P, Mamoudy P, Desplaces N. Propionibacterium acnes: an agent of prosthetic joint infection and colonization. J Infect. 2007;55(2):119-124.
22. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
23. Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J Arthroplasty. 2011;26(6 suppl):99-103.e1.
24. Frangiamore SJ, Gajewski ND, Saleh A, Farias-Kovac M, Barsoum WK, Higuera CA. α-Defensin accuracy to diagnose periprosthetic joint infection—best available test? J Arthroplasty. 2016;31(2):456-460.
25. Hartley JC, Harris KA. Molecular techniques for diagnosing prosthetic joint infections. J Antimicrob Chemother. 2014;69(suppl 1):i21-i24.
Take-Home Points
- Despite standardization of diagnostic criteria by the MSIS for the diagnosis of PJI, some low-grade inflections create a diagnostic challenge for clinicians.
- P acnes infection following TJA can be present despite patients having normal serum inflammatory marker levels and synovial fluid aspirations.
- Patients with a PJI with low virulence organisms can present with painful, arthrofibrotic joints that do not appear to be clinically infected.
- Biopsy for pathology and culture can aid in the diagnosis of suspected PJI in patients who fail to meet MSIS criteria.
- If detected and accurately diagnosed, PJI with P acnes can be successfully eradicated with IV antibiotics and 2-stage revision arthroplasty with a good functional outcome.
Total joint arthroplasty (TJA) is a routinely performed, highly efficacious procedure for patients with degenerative osteoarthritis.1,2 In the United States in 2003, more than 450,000 total knee arthroplasties (TKAs) were performed, and this number is projected to increase by more than 673% by 2030, as America’s population continues to age.3 With the increase in primary TJAs has come an increase in revision TJAs. The most common cause of revision TJA is infection (25.2%), which has a rate of 1% to 4% after primary TJA.1,4 Despite advancements in implant technology, preoperative preventive strategies, perioperative techniques, and postoperative management, a recent meta-analysis of patient follow-up data revealed that 15% to 20% of patients remained dissatisfied after TJA, despite having technically well-placed implants.5,6
Recent studies have suggested that prosthetic joint infection (PJI) may be underreported because of the difficulty in diagnosis, which may be one of the reasons why patients remain dissatisfied after TJA.7 As a result, new efforts have been made to develop uniform criteria for PJI diagnosis.8 In 2011, the Musculoskeletal Infection Society (MSIS) developed a new definition for the PJI diagnosis, based on clinical and laboratory criteria, in order to increase diagnostic accuracy. However, MSIS acknowledged that PJI may be present even if these criteria are not met, particularly in the case of low-grade infections, as patients may not present with clinical signs of infection and may have normal inflammatory markers and joint aspirates. The biofilm-forming bacteria Propionibacterium acnes and Staphylococcus epidermidis are 2 such low-virulence organisms—once commonly considered contaminants but now recognized as potential pathogens for postoperative joint infections.9 In a review performed at a major orthopedic hospital, Bjerke-Kroll and colleagues10 found that the rate of PJI with P acnes has been increasing linearly over the past 14 years. According to reports in the literature,11-13P acnes has been isolated in 2% to 4% of all cases of PJI, and Zappe and colleagues13 found a P acnes PJI rate of 6% in a retrospective analysis performed at their institution. Given the high rate of P acnes colonization of the axilla, this organism is now increasingly recognized as a cause of infection after shoulder surgery, as found in a case series of 10 patients with P acnes PJI after total shoulder arthroplasty (TSA).14 However, there is still limited data on the role of P acnes in lower extremity PJI.
Although patients with P acnes PJI can present with overt signs of infection, more often they lack systemic or local signs of infection, making the diagnosis difficult.15 Surgeons may not consider PJI as a cause of TJA failure in patients who do not meet diagnostic criteria.7 In a case series of patients with P acnes PJI after TSA, Millett and colleagues14 concluded that erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are not always reliable indicators of infection with low-virulence organisms. Eighty percent of patients in their study had normal ESR and CRP level before surgery. Zappe and colleagues13 reported on P acnes PJI diagnoses in 4 total hip arthroplasties (THAs), 3 TKAs, and 1 TSA. Of the 8 patients, 6 (75%) had borderline elevated CRP levels, and 4 (50%) had normal synovial fluid analysis and cultures from joint aspirations. In a study using electron microscopy and fluorescence in situ hybridization (FISH) labeling, Stoodley and colleagues16 found, in 8 polyethylene liners removed from culture-negative THA patients for aseptic loosening, extensive biofilm colonization with S epidermidis.
Reports of PJI cases misdiagnosed as aseptic loosening also suggest that screening and diagnostic tools are not sensitive enough to detect all infections and that PJI likely is underdiagnosed. In a prospective cohort study, Portillo and colleagues17 categorized patients who were undergoing revision surgery after TJA by cause of failure: aseptic loosening, mechanical failure, or PJI based on current MSIS guidelines. Intraoperative cultures were taken during the revisions. P acnes was isolated in 2 (3%) of the 63 cases classified as PJI and in 12 (19%) of the 63 classified as aseptic loosening. Tsukayama and colleagues18 reported an 11% rate of positive intraoperative cultures for P acnes during revision surgery in cases that the operating surgeon considered aseptic, based on white blood cell (WBC) count, ESR, and CRP level. Rasouli and colleagues19 used an Ibis biosensor to perform polymerase chain reaction (PCR) on synovial fluid from 44 patients who underwent aseptic revision of TKA failures. The authors detected a pathogen in 17 (38%) of the 44 presumed aseptic patients and concluded some aseptic loosening cases are actually chronic low-grade organism PJIs not diagnosed according to current PJI criteria.
In this article, we present the case of a patient with a stiff, painful knee after TKA and with ESR, CRP level, and synovial fluid analysis within normal limits. Open biopsy for cultures showed P acnes PJI, which was successfully treated with 2-stage revision. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 69-year-old man with a past medical history of hypertension underwent left primary TKA in 2012. In 2014, he presented to our office complaining of chronic left knee pain and stiffness that had developed insidiously over the first 3 months after surgery and never improved, despite rigorous physical therapy (Table).
Despite not meeting MSIS diagnostic criteria, the patient elected to undergo open biopsy for synovial culture as a last resort. During surgery, there was no purulence in the joint, and frozen section showed <5 neutrophils per high-power field. All cultures from 5 separate synovial tissue samples grew P acnes, confirming the PJI diagnosis. Cultures turned positive after being incubated an average of 12.2 days (range, 10-14 days). Sensitivities showed the organism was responsive to oxacillin. The risks and benefits of 2-stage revision surgery were discussed with the patient at the next office visit, and he decided on 2-stage revision. On November 4, 2014, he underwent open synovectomy, irrigation and débridement with iodine and Dakin solution, hardware removal, and cement antibiotic spacer placement without complication (Figures 3A, 3B).
Just before stage 2 revision on January 6, 2015, preoperative inflammatory markers were within normal limits. During surgery, additional cultures were taken from synovial tissue. At 15 days, these cultures showed no growth, confirming eradication of the infection. The patient underwent reimplantation without complication and had an uneventful postoperative course with no wound-healing issues (Figures 4A, 4B).
Discussion
Because PJIs with low-virulence organisms can present with normal levels of inflammatory markers and negative fluid analysis and culture from joint aspirations, they pose a diagnostic challenge for arthroplasty surgeons. In this case report, there was a low index of suspicion for PJI based on radiographic, physical examination, and laboratory findings. Our patient did not meet MSIS diagnostic criteria for PJI before undergoing open biopsy. Initial cultures from joint aspiration of synovial fluid were negative, and inflammatory markers were within normal limits. However, all 5 synovial tissue biopsy specimens that were cultured confirmed a low-grade periprosthetic infection with P acnes—likely the reason for the poor outcome. This case supports Zappe and colleagues13 and Millett and colleagues,14 who found that a subset of patients with a low-grade organism PJI had normal to mildly elevated inflammatory markers and negative fluid analysis and cultures from joint aspirations.
Hardware-involved orthopedic infections are often caused by bacteria that form a biofilm, which can be difficult to culture. Biofilm matrix binds cells into aggregates, which grow only a single colony on culture media, decreasing positive yield. Therefore, synovial fluid cultures are often negative, because of the low number of planktonic cells removed by aspirate. Using FISH and PCR, Stoodley and colleagues16 found biofilm on hardware removed for “culture-negative aseptic loosening.” This is especially important for low-grade organism infections that lack a strong inflammatory response in the joint and that may be missed with traditional screening. This may be one reason our patient’s synovial fluid cultures and inflammatory markers were negative.
Another reason these low-grade infections can be missed is that P acnes is notoriously difficult to culture—it may take up to 15 days to grow in a special medium.20 Intraoperative cultures may be read as false-negative if not incubated the right amount of time. In many hospitals, aerobic and anaerobic cultures are discarded if there is no growth after 3 to 5 days. In our patient’s case, the earliest that cultures turned positive was on day 10—which is consistent with other reports, including one by Butler-Wu and colleagues,15 who suggested a minimum incubation of 13 days for optimal recovery of organisms. Our case highlights the importance of lengthening incubation to allow for growth of low-virulent organisms. Given the different types of management used for PJI and aseptic loosening, it is imperative that surgeons take cultures during revision TJA and that cultures are held up to 14 days to allow enough time for low-virulence organisms to grow.
Fortunately, PJI with low-virulence organisms can be treated successfully. Treating P acnes PJI with exchange arthroplasty and IV antibiotics has documented success rates as high as 92%.21 Again, we emphasize the importance of obtaining intraoperative cultures to determine antibiotic sensitivities, which can guide treatment. Our patient’s infection was eradicated with 2-stage revision and IV antibiotics, and his symptoms, ROM, and function improved significantly.
Diagnosing PJI after TJA can be challenging, as there is no definitive test that is sensitive, specific, rapid, and minimally invasive. Researchers have looked for novel serum or synovial fluid biomarkers that may be elevated in PJI. Synovial interleukin 6 (IL-6) and synovial α-defensin show great promise. In 2 separate studies, elevated IL-6 levels strongly correlated with infection.22,23 Jacovides and colleagues23 found that a synovial IL-6 level higher than 4270 pg/mL had a 100% positive predictive value and a 91% negative predictive value for diagnosing PJI. In some trials, synovial α-defensin has shown up to 100% sensitivity and specificity for PJI diagnosis. Most notably, in a trial by Frangiamore and colleagues,24 α-defensin levels were elevated to statistically significant levels in P acnes PJI, indicating this test may help in diagnosing PJI with low-virulence organisms. Finally, PCR has also shown promise in detecting low-grade joint infections. PCR uses 16 primers that allow not only for the identification of pan-genomic bacterial markers, specific bacterial organisms, and Candida, but also for the presence of antibiotic resistance markers. Use of pan-genomic PCR also allows for detection of a wider variety of pathogens, including organisms commonly missed by conventional culture methods.25Early intervention can significantly improve outcomes in PJI. Therefore, we recommend maintaining a high index of suspicion for low-virulence PJI in patients with chronic pain and decreased functionality after TJA with well-placed implants, despite their not meeting current MSIS diagnostic criteria for PJI. As new microbiological tools for detecting PJI with low-grade organisms are developed, use of these technologies can be incorporated into the diagnosis algorithm. Screening tools more sensitive in detecting low-grade organisms can help avoid the morbidity associated with interoperative synovial biopsies for culture and can allow for more efficient surgical planning. These tools, along with increased clinical awareness of potential PJIs, ultimately will lead to earlier detection, accurate diagnosis, and optimal treatment.
Am J Orthop. 2017;46(3):E148-E153. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
Take-Home Points
- Despite standardization of diagnostic criteria by the MSIS for the diagnosis of PJI, some low-grade inflections create a diagnostic challenge for clinicians.
- P acnes infection following TJA can be present despite patients having normal serum inflammatory marker levels and synovial fluid aspirations.
- Patients with a PJI with low virulence organisms can present with painful, arthrofibrotic joints that do not appear to be clinically infected.
- Biopsy for pathology and culture can aid in the diagnosis of suspected PJI in patients who fail to meet MSIS criteria.
- If detected and accurately diagnosed, PJI with P acnes can be successfully eradicated with IV antibiotics and 2-stage revision arthroplasty with a good functional outcome.
Total joint arthroplasty (TJA) is a routinely performed, highly efficacious procedure for patients with degenerative osteoarthritis.1,2 In the United States in 2003, more than 450,000 total knee arthroplasties (TKAs) were performed, and this number is projected to increase by more than 673% by 2030, as America’s population continues to age.3 With the increase in primary TJAs has come an increase in revision TJAs. The most common cause of revision TJA is infection (25.2%), which has a rate of 1% to 4% after primary TJA.1,4 Despite advancements in implant technology, preoperative preventive strategies, perioperative techniques, and postoperative management, a recent meta-analysis of patient follow-up data revealed that 15% to 20% of patients remained dissatisfied after TJA, despite having technically well-placed implants.5,6
Recent studies have suggested that prosthetic joint infection (PJI) may be underreported because of the difficulty in diagnosis, which may be one of the reasons why patients remain dissatisfied after TJA.7 As a result, new efforts have been made to develop uniform criteria for PJI diagnosis.8 In 2011, the Musculoskeletal Infection Society (MSIS) developed a new definition for the PJI diagnosis, based on clinical and laboratory criteria, in order to increase diagnostic accuracy. However, MSIS acknowledged that PJI may be present even if these criteria are not met, particularly in the case of low-grade infections, as patients may not present with clinical signs of infection and may have normal inflammatory markers and joint aspirates. The biofilm-forming bacteria Propionibacterium acnes and Staphylococcus epidermidis are 2 such low-virulence organisms—once commonly considered contaminants but now recognized as potential pathogens for postoperative joint infections.9 In a review performed at a major orthopedic hospital, Bjerke-Kroll and colleagues10 found that the rate of PJI with P acnes has been increasing linearly over the past 14 years. According to reports in the literature,11-13P acnes has been isolated in 2% to 4% of all cases of PJI, and Zappe and colleagues13 found a P acnes PJI rate of 6% in a retrospective analysis performed at their institution. Given the high rate of P acnes colonization of the axilla, this organism is now increasingly recognized as a cause of infection after shoulder surgery, as found in a case series of 10 patients with P acnes PJI after total shoulder arthroplasty (TSA).14 However, there is still limited data on the role of P acnes in lower extremity PJI.
Although patients with P acnes PJI can present with overt signs of infection, more often they lack systemic or local signs of infection, making the diagnosis difficult.15 Surgeons may not consider PJI as a cause of TJA failure in patients who do not meet diagnostic criteria.7 In a case series of patients with P acnes PJI after TSA, Millett and colleagues14 concluded that erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are not always reliable indicators of infection with low-virulence organisms. Eighty percent of patients in their study had normal ESR and CRP level before surgery. Zappe and colleagues13 reported on P acnes PJI diagnoses in 4 total hip arthroplasties (THAs), 3 TKAs, and 1 TSA. Of the 8 patients, 6 (75%) had borderline elevated CRP levels, and 4 (50%) had normal synovial fluid analysis and cultures from joint aspirations. In a study using electron microscopy and fluorescence in situ hybridization (FISH) labeling, Stoodley and colleagues16 found, in 8 polyethylene liners removed from culture-negative THA patients for aseptic loosening, extensive biofilm colonization with S epidermidis.
Reports of PJI cases misdiagnosed as aseptic loosening also suggest that screening and diagnostic tools are not sensitive enough to detect all infections and that PJI likely is underdiagnosed. In a prospective cohort study, Portillo and colleagues17 categorized patients who were undergoing revision surgery after TJA by cause of failure: aseptic loosening, mechanical failure, or PJI based on current MSIS guidelines. Intraoperative cultures were taken during the revisions. P acnes was isolated in 2 (3%) of the 63 cases classified as PJI and in 12 (19%) of the 63 classified as aseptic loosening. Tsukayama and colleagues18 reported an 11% rate of positive intraoperative cultures for P acnes during revision surgery in cases that the operating surgeon considered aseptic, based on white blood cell (WBC) count, ESR, and CRP level. Rasouli and colleagues19 used an Ibis biosensor to perform polymerase chain reaction (PCR) on synovial fluid from 44 patients who underwent aseptic revision of TKA failures. The authors detected a pathogen in 17 (38%) of the 44 presumed aseptic patients and concluded some aseptic loosening cases are actually chronic low-grade organism PJIs not diagnosed according to current PJI criteria.
In this article, we present the case of a patient with a stiff, painful knee after TKA and with ESR, CRP level, and synovial fluid analysis within normal limits. Open biopsy for cultures showed P acnes PJI, which was successfully treated with 2-stage revision. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 69-year-old man with a past medical history of hypertension underwent left primary TKA in 2012. In 2014, he presented to our office complaining of chronic left knee pain and stiffness that had developed insidiously over the first 3 months after surgery and never improved, despite rigorous physical therapy (Table).
Despite not meeting MSIS diagnostic criteria, the patient elected to undergo open biopsy for synovial culture as a last resort. During surgery, there was no purulence in the joint, and frozen section showed <5 neutrophils per high-power field. All cultures from 5 separate synovial tissue samples grew P acnes, confirming the PJI diagnosis. Cultures turned positive after being incubated an average of 12.2 days (range, 10-14 days). Sensitivities showed the organism was responsive to oxacillin. The risks and benefits of 2-stage revision surgery were discussed with the patient at the next office visit, and he decided on 2-stage revision. On November 4, 2014, he underwent open synovectomy, irrigation and débridement with iodine and Dakin solution, hardware removal, and cement antibiotic spacer placement without complication (Figures 3A, 3B).
Just before stage 2 revision on January 6, 2015, preoperative inflammatory markers were within normal limits. During surgery, additional cultures were taken from synovial tissue. At 15 days, these cultures showed no growth, confirming eradication of the infection. The patient underwent reimplantation without complication and had an uneventful postoperative course with no wound-healing issues (Figures 4A, 4B).
Discussion
Because PJIs with low-virulence organisms can present with normal levels of inflammatory markers and negative fluid analysis and culture from joint aspirations, they pose a diagnostic challenge for arthroplasty surgeons. In this case report, there was a low index of suspicion for PJI based on radiographic, physical examination, and laboratory findings. Our patient did not meet MSIS diagnostic criteria for PJI before undergoing open biopsy. Initial cultures from joint aspiration of synovial fluid were negative, and inflammatory markers were within normal limits. However, all 5 synovial tissue biopsy specimens that were cultured confirmed a low-grade periprosthetic infection with P acnes—likely the reason for the poor outcome. This case supports Zappe and colleagues13 and Millett and colleagues,14 who found that a subset of patients with a low-grade organism PJI had normal to mildly elevated inflammatory markers and negative fluid analysis and cultures from joint aspirations.
Hardware-involved orthopedic infections are often caused by bacteria that form a biofilm, which can be difficult to culture. Biofilm matrix binds cells into aggregates, which grow only a single colony on culture media, decreasing positive yield. Therefore, synovial fluid cultures are often negative, because of the low number of planktonic cells removed by aspirate. Using FISH and PCR, Stoodley and colleagues16 found biofilm on hardware removed for “culture-negative aseptic loosening.” This is especially important for low-grade organism infections that lack a strong inflammatory response in the joint and that may be missed with traditional screening. This may be one reason our patient’s synovial fluid cultures and inflammatory markers were negative.
Another reason these low-grade infections can be missed is that P acnes is notoriously difficult to culture—it may take up to 15 days to grow in a special medium.20 Intraoperative cultures may be read as false-negative if not incubated the right amount of time. In many hospitals, aerobic and anaerobic cultures are discarded if there is no growth after 3 to 5 days. In our patient’s case, the earliest that cultures turned positive was on day 10—which is consistent with other reports, including one by Butler-Wu and colleagues,15 who suggested a minimum incubation of 13 days for optimal recovery of organisms. Our case highlights the importance of lengthening incubation to allow for growth of low-virulent organisms. Given the different types of management used for PJI and aseptic loosening, it is imperative that surgeons take cultures during revision TJA and that cultures are held up to 14 days to allow enough time for low-virulence organisms to grow.
Fortunately, PJI with low-virulence organisms can be treated successfully. Treating P acnes PJI with exchange arthroplasty and IV antibiotics has documented success rates as high as 92%.21 Again, we emphasize the importance of obtaining intraoperative cultures to determine antibiotic sensitivities, which can guide treatment. Our patient’s infection was eradicated with 2-stage revision and IV antibiotics, and his symptoms, ROM, and function improved significantly.
Diagnosing PJI after TJA can be challenging, as there is no definitive test that is sensitive, specific, rapid, and minimally invasive. Researchers have looked for novel serum or synovial fluid biomarkers that may be elevated in PJI. Synovial interleukin 6 (IL-6) and synovial α-defensin show great promise. In 2 separate studies, elevated IL-6 levels strongly correlated with infection.22,23 Jacovides and colleagues23 found that a synovial IL-6 level higher than 4270 pg/mL had a 100% positive predictive value and a 91% negative predictive value for diagnosing PJI. In some trials, synovial α-defensin has shown up to 100% sensitivity and specificity for PJI diagnosis. Most notably, in a trial by Frangiamore and colleagues,24 α-defensin levels were elevated to statistically significant levels in P acnes PJI, indicating this test may help in diagnosing PJI with low-virulence organisms. Finally, PCR has also shown promise in detecting low-grade joint infections. PCR uses 16 primers that allow not only for the identification of pan-genomic bacterial markers, specific bacterial organisms, and Candida, but also for the presence of antibiotic resistance markers. Use of pan-genomic PCR also allows for detection of a wider variety of pathogens, including organisms commonly missed by conventional culture methods.25Early intervention can significantly improve outcomes in PJI. Therefore, we recommend maintaining a high index of suspicion for low-virulence PJI in patients with chronic pain and decreased functionality after TJA with well-placed implants, despite their not meeting current MSIS diagnostic criteria for PJI. As new microbiological tools for detecting PJI with low-grade organisms are developed, use of these technologies can be incorporated into the diagnosis algorithm. Screening tools more sensitive in detecting low-grade organisms can help avoid the morbidity associated with interoperative synovial biopsies for culture and can allow for more efficient surgical planning. These tools, along with increased clinical awareness of potential PJIs, ultimately will lead to earlier detection, accurate diagnosis, and optimal treatment.
Am J Orthop. 2017;46(3):E148-E153. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
1. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
2. Kamath AF, Ong KL, Lau E, et al. Quantifying the burden of revision total joint arthroplasty for periprosthetic infection. J Arthroplasty. 2015;30(9):1492-1497.
3. Kurtz SM, Ong KL, Schmier J, et al. Future clinical and economic impact of revision total hip and knee arthroplasty. J Bone Joint Surg Am. 2007;89(suppl 3):144-151.
4. Zmistowski B, Restrepo C, Huang R, Hozack WJ, Parvizi J. Periprosthetic joint infection diagnosis: a complete understanding of white blood cell count and differential. J Arthroplasty. 2012;27(9):1589-1593.
5. Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
6. Djahani O, Rainer S, Pietsch M, Hofmann S. Systematic analysis of painful total knee prosthesis, a diagnostic algorithm. Arch Bone Jt Surg. 2013;1(2):48-52.
7. Parvizi J, Suh DH, Jafari SM, Mullan A, Purtill JJ. Aseptic loosening of total hip arthroplasty: infection always should be ruled out. Clin Orthop Relat Res. 2011;469(5):1401-1405.
8. Della Valle C, Parvizi J, Bauer TW, et al. Diagnosis of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg. 2010;18(12):760-770.
9. Dramis A, Aldlyami E, Grimer RJ, Dunlop DJ, O’Connell N, Elliott T. What is the significance of a positive Propionibacterium acnes culture around a joint replacement? Int Orthop. 2009;33(3):829-833.
10. Bjerke-Kroll BT, Christ AB, Mclawhorn AS, Sculco PK, Jules-Elysée KM, Sculco TP. Periprosthetic joint infections treated with two-stage revision over 14 years: an evolving microbiology profile. J Arthroplasty. 2014;29(5):877-882.
11. Pandey R, Berendt AR, Athanasou NA. Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service. Arch Orthop Trauma Surg. 2000;120(10):570-574.
12. Segawa H, Tsukayama DT, Kyle RF, Becker DA, Gustilo RB. Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. J Bone Joint Surg Am. 1999;81(10):1434-1445.
13. Zappe B, Graf S, Ochsner PE, Zimmerli W, Sendi P. Propionibacterium spp. in prosthetic joint infections: a diagnostic challenge. Arch Orthop Trauma Surg. 2008;128(10):1039-1046.
14. Millett PJ, Yen YM, Price CS, Horan MP, van der Meijden OA, Elser F. Propionibacterium acnes infection as an occult cause of postoperative shoulder pain: a case series. Clin Orthop Relat Res. 2011;469(10):2824-2830.
15. Butler-Wu SM, Burns EM, Pottinger PS, et al. Optimization of periprosthetic culture for diagnosis of Propionibacterium acnes prosthetic joint infection. J Clin Microbiol. 2011;49(7):2490-2495.
16. Stoodley P, Ehrlich GD, Sedghizadeh PP, et al. Orthopaedic biofilm infections. Curr Orthop Pract. 2011;22(6):558-563.
17. Portillo ME, Salvadó M, Alier A, et al. Prosthesis failure within 2 years of implantation is highly predictive of infection. Clin Orthop Relat Res. 2013;471(11):3672-3678.
18. Tsukayama DT, Strada R, Gustilo RB. Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections. J Bone Joint Surg Am. 1996;78(4):512-523.
19. Rasouli MR, Harandi AA, Adeli B, Purtill JJ, Parvizi J. Revision total knee arthroplasty: infection should be ruled out in all cases. J Arthroplasty. 2012;27(6):1239-1243.e1-e2.
20. Schäfer P, Fink B, Sandow D, Margull A, Berger I, Frommelt L. Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy. Clin Infect Dis. 2008;47(11):1403-1409.
21. Zeller V, Ghorbani A, Strady C, Leonard P, Mamoudy P, Desplaces N. Propionibacterium acnes: an agent of prosthetic joint infection and colonization. J Infect. 2007;55(2):119-124.
22. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
23. Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J Arthroplasty. 2011;26(6 suppl):99-103.e1.
24. Frangiamore SJ, Gajewski ND, Saleh A, Farias-Kovac M, Barsoum WK, Higuera CA. α-Defensin accuracy to diagnose periprosthetic joint infection—best available test? J Arthroplasty. 2016;31(2):456-460.
25. Hartley JC, Harris KA. Molecular techniques for diagnosing prosthetic joint infections. J Antimicrob Chemother. 2014;69(suppl 1):i21-i24.
1. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
2. Kamath AF, Ong KL, Lau E, et al. Quantifying the burden of revision total joint arthroplasty for periprosthetic infection. J Arthroplasty. 2015;30(9):1492-1497.
3. Kurtz SM, Ong KL, Schmier J, et al. Future clinical and economic impact of revision total hip and knee arthroplasty. J Bone Joint Surg Am. 2007;89(suppl 3):144-151.
4. Zmistowski B, Restrepo C, Huang R, Hozack WJ, Parvizi J. Periprosthetic joint infection diagnosis: a complete understanding of white blood cell count and differential. J Arthroplasty. 2012;27(9):1589-1593.
5. Parvizi J, Adeli B, Zmistowski B, Restrepo C, Greenwald AS. Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(14):e104.
6. Djahani O, Rainer S, Pietsch M, Hofmann S. Systematic analysis of painful total knee prosthesis, a diagnostic algorithm. Arch Bone Jt Surg. 2013;1(2):48-52.
7. Parvizi J, Suh DH, Jafari SM, Mullan A, Purtill JJ. Aseptic loosening of total hip arthroplasty: infection always should be ruled out. Clin Orthop Relat Res. 2011;469(5):1401-1405.
8. Della Valle C, Parvizi J, Bauer TW, et al. Diagnosis of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg. 2010;18(12):760-770.
9. Dramis A, Aldlyami E, Grimer RJ, Dunlop DJ, O’Connell N, Elliott T. What is the significance of a positive Propionibacterium acnes culture around a joint replacement? Int Orthop. 2009;33(3):829-833.
10. Bjerke-Kroll BT, Christ AB, Mclawhorn AS, Sculco PK, Jules-Elysée KM, Sculco TP. Periprosthetic joint infections treated with two-stage revision over 14 years: an evolving microbiology profile. J Arthroplasty. 2014;29(5):877-882.
11. Pandey R, Berendt AR, Athanasou NA. Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service. Arch Orthop Trauma Surg. 2000;120(10):570-574.
12. Segawa H, Tsukayama DT, Kyle RF, Becker DA, Gustilo RB. Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. J Bone Joint Surg Am. 1999;81(10):1434-1445.
13. Zappe B, Graf S, Ochsner PE, Zimmerli W, Sendi P. Propionibacterium spp. in prosthetic joint infections: a diagnostic challenge. Arch Orthop Trauma Surg. 2008;128(10):1039-1046.
14. Millett PJ, Yen YM, Price CS, Horan MP, van der Meijden OA, Elser F. Propionibacterium acnes infection as an occult cause of postoperative shoulder pain: a case series. Clin Orthop Relat Res. 2011;469(10):2824-2830.
15. Butler-Wu SM, Burns EM, Pottinger PS, et al. Optimization of periprosthetic culture for diagnosis of Propionibacterium acnes prosthetic joint infection. J Clin Microbiol. 2011;49(7):2490-2495.
16. Stoodley P, Ehrlich GD, Sedghizadeh PP, et al. Orthopaedic biofilm infections. Curr Orthop Pract. 2011;22(6):558-563.
17. Portillo ME, Salvadó M, Alier A, et al. Prosthesis failure within 2 years of implantation is highly predictive of infection. Clin Orthop Relat Res. 2013;471(11):3672-3678.
18. Tsukayama DT, Strada R, Gustilo RB. Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections. J Bone Joint Surg Am. 1996;78(4):512-523.
19. Rasouli MR, Harandi AA, Adeli B, Purtill JJ, Parvizi J. Revision total knee arthroplasty: infection should be ruled out in all cases. J Arthroplasty. 2012;27(6):1239-1243.e1-e2.
20. Schäfer P, Fink B, Sandow D, Margull A, Berger I, Frommelt L. Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy. Clin Infect Dis. 2008;47(11):1403-1409.
21. Zeller V, Ghorbani A, Strady C, Leonard P, Mamoudy P, Desplaces N. Propionibacterium acnes: an agent of prosthetic joint infection and colonization. J Infect. 2007;55(2):119-124.
22. Deirmengian C, Kardos K, Kilmartin P, Cameron A, Schiller K, Parvizi J. Diagnosing periprosthetic joint infection: has the era of the biomarker arrived? Clin Orthop Relat Res. 2014;472(11):3254-3262.
23. Jacovides CL, Parvizi J, Adeli B, Jung KA. Molecular markers for diagnosis of periprosthetic joint infection. J Arthroplasty. 2011;26(6 suppl):99-103.e1.
24. Frangiamore SJ, Gajewski ND, Saleh A, Farias-Kovac M, Barsoum WK, Higuera CA. α-Defensin accuracy to diagnose periprosthetic joint infection—best available test? J Arthroplasty. 2016;31(2):456-460.
25. Hartley JC, Harris KA. Molecular techniques for diagnosing prosthetic joint infections. J Antimicrob Chemother. 2014;69(suppl 1):i21-i24.
