
==== Front
J Orthop Translat
J Orthop Translat
Journal of Orthopaedic Translation
2214-031X
2214-0328
Chinese Speaking Orthopaedic Society

S2214-031X(24)00089-5
10.1016/j.jot.2024.08.002
Review Article
Prevalence, risk factors, microbiological results and clinical outcome in unexpected positive intraoperative cultures in unclear and presumed aseptic hip and knee revision arthroplasties – A ten-year retrospective analysis with a minimum follow up of 2 years
Simon Sebastian ab
Martalanz Luca a
Frank Bernhard J.H. a
Hartmann Susana Gardete a
Mitterer Jennyfer A. a
Sebastian Sujeesh a
Huber Stephanie ab
Hofstaetter Jochen G. researchlab@oss.at
ab⁎
a Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, 1130, Vienna, Austria
b II. Department of Orthopaedic Surgery, Orthopaedic Hospital Vienna-Speising, 1130, Vienna, Austria
⁎ Corresponding author. Michael Ogon Laboratory for Orthopaedic Research Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, Vienna, 1130, Austria. researchlab@oss.at
17 8 2024
9 2024
17 8 2024
48 156162
22 12 2023
17 7 2024
3 8 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

The aim of this study was to assess the prevalence, microbiological spectrum, risk factors, and clinical outcomes of unexpected-positive-intraoperative-cultures (UPIC) in presumed aseptic and unclear revision-total-hip-/knee-arthroplasties (rTHA and rTKA) compared to culture-negative (CN) revisions.

Methods

This study reviewed all International-consensus-meeting-2018 (ICM 2018) negative or inconclusive rTHA (n = 751) and rTKA (n = 679) performed at our institution from 2011 to 2020 with a minimum follow-up of two years. A Kaplan-Meier-analysis was performed to determine the septic and aseptic-free implant survival in cases with UPIC's and matched culture-negative cases. Patient demographics, risk factors, microbiological spectrum and clinical outcomes were evaluated.

Results

There were significantly more UPIC cases in rTHA 196/751 (26.1 %) compared to rTKA 113/679 (16.6 %); (p < 0.001). UPICs in rTKA and rTHA have a lower septic and aseptic implant-free-survival compared to CN revisions. Patients with a history of nickel allergy have a higher risk of an UPIC in rTHA and rTKA (p < 0.001). Septic re-revisions after UPIC had a significantly (H: p = 0.004; K: p = 0.030) shorter time period to the primary/previous surgery (H: 84 (IQR:41–797); K: 115 (IQR:55–446)) compared to patients with aseptic re-revisions after UPIC (H:1248 (IQR:178-3534); K: 827 (IQR:361-1183)).

Conclusion

UPICs have a higher rate of septic and aseptic failure than CN outcomes. UPICs are twice as common in rTHA compared to rTKA. Preoperative PJI workup reduces the UPIC rate. Nickel allergy is a risk factor for UPIC. Early revisions with UPICs after primary THA or TKA have a higher risk of septic failure.

The translational potential of this article

This article provides new information on revision rates for UPIC and potential risk factors for UPIC and its treatment failure.

Graphical abstract

Image 1

Keywords

Aseptic implant-free survival
Revision-total-hip-arthroplasty
Revision-total-knee-arthroplasty
Risk factors
Septic and unexpected-positive-intraoperative-cultures
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pmc1 Introduction

Besides infection, the most common causes for revision total hip (rTHA) and knee (rTKA) are loosening, wear, instability, or dislocation [[1], [2], [3]]. In aseptic loosening, there is a concern that low-grade PJI may have been the underlying cause of failure [4]. In presumed aseptic rTHA and rTKA unexpected positive intraoperative culture/s (UPIC) are commonly encountered [5,6]. UPICs are often associated with low-virulent pathogen, however there are conflicting data regarding the clinical relevance and management of UPIC [5,[7], [8], [9], [10], [11], [12]]. While some studies have shown that pathogen-detection in presumed aseptic revisions does not affect implant survival [5,[12], [13], [14], [15]], others have shown higher revision rates [9,[16], [17], [18]]. Moreover, a contamination is also a possible cause for a UPIC and cannot be excluded [4,19].

Preoperative joint aspiration and microbiological analysis of periprosthetic synovial fluid has known limitations in detecting pathogens, especially in low-grade infections. Moreover, in some cases, the preoperative PJI workup is inconclusive [20]. These patients do not have clear signs of infection but also cannot be classified as clearly aseptic. In these unclear cases, the treatment algorithm is difficult because over- and undertreatment should be avoided [21]. PJI cannot be excluded in patients who do not meet the ICM (International-consensus-meeting) definition [9]. However, the prevalence and clinical outcomes of aseptic and septic re-revision after UPICs or culture-negative (CN) cases in rTHA and rTKA differ between studies, and no clear risk factors have been identified in the literature.

The aim of this study was to evaluate preoperatively presumed aseptic or unclear rTHA and rTKA with ICM-2018 negative or inconclusive criteria. Moreover, we are looking for some results that have an impact on the decision-making process of rTHA and rTKA. We described the septic and aseptic free implant survival in rTHA and rTKA with UPICs and CN results. We also identified certain risk factors for UPICs and their failure, and evaluated the microbiological spectrum in UPICs and septic failures.

2 Material and methods

This retrospective cohort study was approved by the institutional review board (EK11/2020). We analysed our institutional arthroplasty registry and prospectively maintained PJI infection database of our tertiary care academic centre between January 1st 2011 and December 31st 2020. All presumed aseptic and inconclusive revisions were included in this study. Revisions included single-stage exchange, mobile or one- or two-component replacements, hemi-to total arthroplasty, patellar resurfacing, open reduction and internal fixation (ORIF), rTHA or rTKA with intraoperative culture sample(s) (Fig. 1).Figure 1 Aseptic free implant survival after 1a, 2a, 5a and 10a (95%-Confidence-interval); a (years), CN (culture negative), UPIC (unexpected positive intraoperative cultures.

Figure 1

Revisions were excluded if (1) PJI was known or suspected preoperatively, (2) the revision was part of the management of an ongoing PJI (second stage of a two-stage revision), or (3) intraoperative cultures were not obtained or results were not available.

The minimum follow-up was 24 months after the UPIC revision. Follow-up was performed by patient recall, review of our clinical databases for clinical visits, review of the Austrian electronic health record (ELGA) launched in 2015, and review of our death registry. From 2011 to 2015, only re-revisions from our institution were included.

We analysed the outcome between UPICs (Revisions with at least one positive microbiological result) and CNs (Revisions with a negative microbiological result) revisions by evaluating the septic (Procedures due to PJI) and aseptic (Procedures for any aseptic reason) re-revision rates, and the microbiological spectrum. Patient demographics, patient-specific risk factors and reason for revision and re-revision were assessed. Moreover, the causative pathogen(s) of PJI, knee or hip joint, and revision after primary or revision surgery were analysed.

Preoperative evaluation was performed by using serum C-reactive protein (CRP), leukocyte count, synovial fluid CRP, cell-count, and polymorphonuclear leukocyte (PMN) count. The number of preoperative joint aspirations increased over the study period, but was relatively low at the beginning of our retrospective analysis. Patients were preoperatively categorized according to the ICM-2018 criteria. The ICM 2018 PJI score was used to classify all included revisions as inconclusive (3–5) or as non-infected (<3) [22].

All patients received routine intravenous second-generation cephalosporin or vancomycin for those with a history of allergy to penicillin or cephalosporins. Tissue samples or swabs were taken intraoperatively and explanted devices were subjected to sonication as previously described [23]. Microbial identification and antimicrobial susceptibility testing were performed by LABCON GmbH (Austria).

Descriptive statistics were used with means, standard deviations and medians for continuous study parameters and frequencies and percentages for categorical variables. When data were skewed, the interquartile range (IQR) was used. Continuous data were compared using Mann–Whitney U tests or 2-sample t-tests for non-parametric and parametric data, respectively. Categorical data were compared using Pearson's chi-squared test or Fisher's exact test, as appropriate. The Kaplan–Meier method with 95 % confidence intervals (CI) was used to determine septic- and aseptic-free implant survival at 1, 2, 5 and 10 years for the UPIC and CN study cohorts, with subsequent septic or aseptic revision as the end point. Patients who died or were lost to follow-up after 2 years were censored. The 95 % CIs were calculated using the Greenwood's asymmetric exponential formula. Statistical significance was 2-tailed and set at a P-value ≤0.05. All analyses were performed using IBM® SPSS® version 25 and GraphPad PRISM® version 8.

3 Results

3.1 Septic and aseptic implant free survival

A total of 751 rTHA and 679 rTKA patients were evaluated. There were significantly more UPIC cases in rTHA 196/751 (26.1 %) compared to rTKA 113/679 (16.6 %); (p < 0.001). We observed a lower preoperative aspiration rate in rTHA 18/196 (9.2 %) compared to rTKA 46/113 (40.7 %); p < 0.001. UPICs in rTKA and rTHA have lower 1-, 2-, 5- and 10-year septic and aseptic implant-free survival compared to CN revisions (Figure 1, Figure 2).Figure 2 Septic free implant survival after 1a, 2a, 5a and 10a (95%-Confidence-interval); a (years), CN (culture negative), UPIC (unexpected positive intraoperative cultures.

Figure 2

Aseptic failures were significantly higher in UPIC rTHA 15/59 (25.4 %) with previous revisions compared to UPIC rTHA 14/137 (10.2 %) after primary (p = 0.006). There was no significant distribution of aseptic failure in rTKA between UPIC after primary and UPIC after previous revisions (p = 0.392). There was no significant distribution of septic failure for rTHA and rTKA between UPIC after primary and UPIC after previous revisions (H: p= > 0.99; K: p = 0.370). Furthermore, there was no significantly higher septic (H: p = 1.00; K: p = 0.618) or aseptic (H: p = 0.186; K: p = 0.680) failure rate in ICM-2018 non-infected or inconclusive patients (Table 1).Table 1 Baseline demographics, and operative data for revision total hip and knee arthroplasty with UPIC (unexpected positive intraoperative results). ICM-2018 (International Consensus Meeting-2018), SSI (Surgical Site Infections), CCI (Charlson Comorbidity Index), CRP (C-reactive protein), AB (antibiotic) treatment for at least 2 weeks; *<0.05; **<0.001.

Table 1Baseline, demographic, and operation data for revision total hip and knee arthroplasties with UPICs	
Variables	Hip	Knee	p-value	
n = 196/751 (26.1 %)	n = 113/679 (16.6 %)	
BMI	28.5 (±6.1)	30.4 (±6.1)	0.021*	
Age	71 (25; 90)	71 (41; 88)	0.239	
Gender male	72 (36.7 %)	32 (28.3 %)	0.136	
 female	124 (63.3 %)	81 (71.7 %)	
SSI (0–35)	5.5 (±2.9)	4.4 (±2.6)	0.015*	
CCI (0->5)	3.4 (±2.3)	3.5 (±1.6)	0.956	
Preoperative aspiration	18 (9.2 %)	46 (40.7 %)	<0.001**	
 Synovial cell-count (109)	1.5 (±2.1)	1.0 (+0.9)	0.632	
 Synovial PMN (%)	45.4 % (±22.2)	35.3 % (±12.3)	0.150	
 Synovial CRP (mg/l)	1.8 (±2.5)	1.3 (±1.3)	0.919	
Serum Cell-count 109/l	8.5 (±5.1)	7.6 (±3.1)	0.577	
Serum CRP (mg/l)	6.6 (±6,1)	5.0 (±4.7)	0.517	
Time to primary/previous revision	2191 (±3899)	2212 (±3923)	0.890	
AB treatment postoperatively	136/196 (69.4 %)	67/113 (59.3 %)	0.072	
After primary	137 (68.9 %)	84 (74.3 %)	0.405	
 Septic failure	9/137 (6.6 %)	4/84 (4.8 %)	0.579	
 Aseptic failure	14/137 (10.2 %)	7/84 (8.3 %)	0.523	
After a previous revision	59 (31.1 %)	29 (25.7 %)	0.405	
 Septic revision	4/59 (6.8 %)	3/29 (10.3 %)	0.680	
 Septic failure	0/4	2/3 (66.7 %)	0.143	
 Aseptic failure	2/4 (50.0 %)	0/3	0.429	
 Aseptic revision	55/59 (93.2 %)	26/29 (89.7 %)	0.680	
 Septic failure	4/55 (7.3 %)	1/26 (3.8 %)	>0.99	
 Aseptic failure	13/55 (23.6 %)	4/26 (15.4 %)	0.395	
ICM-2018 Not-infected	155 (79.1 %)	97 (85.8 %)	0.140	
 AB treatment postoperatively	100/155 (65.8 %)	53/97 (54.6 %)	0.118	
 Septic failure	11/155 (7.1 %)	5/57 (8.7 %)	0.682	
 Aseptic failure	26/155 (16.8 %)	10/57 (17.5 %)	0.895	
ICM-2018 Inconclusive	41 (20.3 %)	16 (14.2 %)	0.140	
 AB treatment postoperatively	36/41 (90.2 %)	14/16 (87.5 %)	>0.99	
 Septic failure	2/37 (5.4 %)	2/14 (14.3 %)	0.300	
 Aseptic failure	3/37 (8.1 %)	1/14 (7.1 %)	>0.99	
Single/multiple culture positive	157 (80.1 %)	98 (86.7 %)	0.140	
 AB treatment postoperatively	105/157 (66.9 %)	54/98 (55.1 %)	0.059	
 Septic failure	10/157 (6.4 %)	4/98 (4.1 %)	0.435	
 Aseptic failure	26/157 (16.6 %)	10/98 (10.2 %)	0.156	
≥2 Culture positive	39 (19.9 %)	15 (13.3 %)	0.140	
 AB treatment postoperatively	31/39 (79.5 %)	13/15 (86.7 %)	0.708	
 Septic failure	3/39 (7.7 %)	3/15 (20.0 %)	0.331	
 Aseptic failure	3/39 (7.7 %)	1/15 (6.7 %))	>0.99	
High-virulent microorganisms	25 (12.8 %)	20 (17.7 %)	0.235	
 AB treatment postoperatively	20/25 (80.0 %)	13/20 (65.0 %)	0.258	
 Septic failure	3/25 (12.0 %)	0/20	0.242	
 Aseptic failure	5/25 (20.0 %)	1/20 (5.0 %)	0.205	
Low-virulent microorganisms	171 (87.2 %)	93 (82.3 %)	0.235	
 AB treatment postoperatively	116/171 (67.4 %)	55/93 (59.1 %)	0.158	
 Septic failure	10/171 (5.9 %)	7/93 (7.5 %)	0.564	
 Aseptic failure	24/171 (14 %)	10/93 (10.8 %)	0.447	
Reason for revision	196	113		
Single-stage exchange	21 (10.7 %)	73 (64.6 %)	<0.001**	
 Aseptic loosening	16	38		
 Dislocation/Instability	3	24		
 Pain	—	4		
 Malpositioning/Malaligment	1	4		
 Wear	—	2		
 Other	1	1		
Mobile part exchange	33 (16.8 %)	15 (13.3 %)	0.405	
 Wear	15	3		
 Dislocation/Instability	13	8		
 Other	5	4		
Cup/Femoral component exchange	83 (42.3 %)	2 (1.8 %)	<0.001**	
 Aseptic loosening	61	2		
 Disclocation	15	—		
 Cup Protrusio	4	—		
 Implant failure	2	—		
 Wear	1	—		
Stem/Tibial component exchange	47 (24 %)	5 (4.4 %)	<0.001**	
 Aseptic loosening	42	5		
 Dislocation	3	—		
 Fracture	2	—		
Single stage + ORIF	9 (4.6 %)	2 (1.8 %)	0.197	
Hemi- to Total-arthropalsty	3 (1.5 %)	7 (6.2 %)	0.041*	
Patella resurfacing	-	9 (8 %)	—	

3.2 Risk factors for UPIC

There is a significantly (<0.001) higher rate of single-stage exchange and a significantly (<0.001) lower rate of single-component exchange in UPIC rTKA compared to rTHA. Patients with a history of nickel allergy have a higher risk of UPIC outcomes in rTHA and rTKA (p < 0.001) (Table 2, Table 3).Table 2 Microbiological spectrum for unexpected positive intraoperative cultures in revision total hip and knee arthroplasties. Strep (Streptococcus), Staph. (Staphylococcus), MSSE (Methicillin-susceptible Staph. epidermidis); MRSE (Methicillin-resistant Staph. epidermidis), MRSA (Methicillin-resistant Staph. Aureus), VRE (Vancomycin-resistant Enterococci), MRGN (Multiresistant-gram negative).

Table 2Microbiological spectrum for unexpected positive intraoperative cultures in revision total hip and knee arthroplasties	

Total unexpected positive results	Total	Hip	Knee	
n = 309	n = 196 (63.4 %)	n = 113 (36.6 %)	
Total number of analyzed cultures	1.039	649	390	
 Positive rate	438 (42.2 %)	292 (45 %)	146 (37.4 %	
Monomicrobial	264 (85.4 %)	165 (84.2 %)	99 (87.6 %)	
Polymicrobial	45 (14.6 %)	31 (15.8 %)	14 (12.4 %)	
UPIC from swab sample	188 (60.8 %)	115 (58.7 %)	73 (64.6 %)	
UPIC from sonication sample	43 (13.9 %)	30 (15.3 %)	13 (11.5 %)	
UPIC from tissue sample	48 (15.5 %)	26 (13.3 %)	22 (19.5 %)	
UPIC from combined samples	30 (9.7 %)	25 (12.8 %)	5 (4.4 %)	
Number of detected microorganisms	337	210	127	
Gram positive Bacteria	308 (91.4 %)	194 (92.4 %)	114 (89.8 %)	
Staphylococcus Epidermidis	97	74	23	
 MSSE	47	28	19	
 MRSE	52	48	4	
Cutibacterium acnes	66	36	30	
Cutibacterium avidum	3	3	—	
Staphylococcus Hominis	22	15	7	
Staphylococcus Capitis	18	11	7	
Staphylococcus Haemolyticus	9	5	4	
Staphylococcus Lugdunensis	6	3	3	
Staphylococcus aureus	3	2	1	
 MRSA	1	1	—	
Staphylococcus Warneri	3	—	3	
Other CoNS	9	6	3	
Bacillus spp.	22	9	13	
Micrococcus spp.	5	4	1	
Micrococcus luteus	5	3	2	
Enterococcus faecalis	8	6	2	
Enterococcus faecium	4	2	2	
 VRE	2	1	1	
alpha-hemolytic streptococci	8	4	4	
Corynebacterium spp.	5	4	1	
Other Gram positive bacteria	16	7	9	
Gram negative bacteria	21 (6.2 %)	11 (5.2 %)	10 (7.9 %)	
Neisseria spp.	5	3	2	
Escherichia coli	3	2	1	
 3 MRGN	2	2	—	
Pseudomonas aeruginosa	2	2	—	
Enterobacter cloacae	2	—	2	
 3 MRGN	1	—	1	
Other Gram negative bacteria	9	4	5	
Fungi	8 (2.4 %)	5 (2.4 %)	3 (2.4 %)	
Candida parapsilosis	7	4	3	
Aspergillus spp.	1	1	—	

Table 3 Baseline demographic, and operative data for revision total hip arthroplasty. Mean with SD (standard deviation), median with IQR (Interquartile-range); UPIC (unexpected positive intraoperative cultures) included presumed aseptic and inconclusive revisions; BMI (Body-Mass-Index); ASA (American Society of Anesthesiologists Classification); CRP (C-reactive protein); PMN (Polymorphonuclear neutrophils); ORIF (open reduction and internal fixation) The number of septic re-revisions after a specific operation is compared with the total number of this procedure; *<0.05; **<0.001.

Table 3Baseline demographic, and operative data for revision total hip arthroplasty	
Revision total hip arthroplasties	UPIC n = 196 (26.1 %)	CN n = 555 (73.9 %)	P-value	
BMI	28.5 (±6.1)	28.1 (±4.9)	0.865	
Age	70 (61; 77)	71 (61; 77)	0.606	
Gender male	72 (36.7 %)	180 (32.4 %)	0.859	
 female	124 (63.3 %)	375 (67.6 %)	
ASA-score 1	27/196 (13.8 %)	51/555 (9.2 %	0.399	
 2	142/196 (72.4 %)	419/555 (75.5 %)	
 3	27/196 (13.8 %)	77/555 (13.9 %)	
 4	0 %	8/555 (1.4 %)	
Smoking	27/196 (13.8 %)	71/555 (12.8 %)	0.725	
Nickel allergy	14/196 (7.1 %)	7/555 (1.3 %)	<0.001**	
Deceased/lost to follow-up	4	25	0.124	
 Death after revision (days)	472 (±233)	344 (±206)	0.312	
Operation Time (min)	102 (80,137)	99 (78; 127)	0.134	
Serum Cell-count 10^9/l	8.5 (±5.1)	8.1 (±4.6)	0.917	
Serum CRP (mg/l)	14.6 (±23.8)	9.7 (±14.4)	0.687	
Hemoglobin (g/dl)	13.1 (±1.4)	13.4 (±1.5)	0.221	
Preoperative aspiration	18 (9.2 %)	21 (3.8 %)	0.003*	
 Synovial cell-count (x10^9)	1.5 (±2.1)	1.2 (±1.1)	0.318	
 Synovial PMN (%)	45.4 % (±22.2)	30.4 (±15.5)	0.137	
 Synovial CRP (mg/l)	1.8 (±2.5)	0.45 (±0.35)	0.518	
Re-revision	41/196 (20.9 %)	67/555 (12.1 %)	0.002*	
Septic revisions after	12/196 (6.1 %)	10/555 (1.8 %)	0.002*	
 Single stage exchange	3/24 (12.5 %)	0/76 (0.0 %)	0.013*	
 Cup exchange	4/84 (4.8 %)	7/243 (2.9 %)	0.482	
 Stem exchange	4/41 (9.8 %)	0/102 (0.8 %)	0.006*	
 Modular exchange	0/32 (0.0 %)	1/93 (1.1 %)	>0.99	
 ORIF	1/12 (8.3 %)	1/32 (3.1 %)	0.476	
 Ossification	0/2 (0.0 %)	1/9 (11.1 %)	>0.99	
Early septic revision ≤90 days	7/13 (53.8 %)	4/10 (40 %)	0.670	
Late septic revision >90 days	5/13 (46.2 %)	6/10 (60 %)	0.670	
Reason for aseptic re-revision	29 (14.8 %)	57 (10.1 %)	0.091	
 Aseptic loosening	3/29 (10.3 %)	29/57 (50.0 %)	<0.001**	
 Dislocation	16/29 (55.2 %)	16/57 (28.6 %)	0.020*	
 Wear	3/29 (10.3 %)	3/57 (5.4 %)	0.406	
 Fracture	4/29 (13.8 %)	6/57(10.8 %)	0.729	
 Other	3/29 (10.3 %)	3/57 (5.4 %)	0.406	

3.3 Reasons for failure after UPIC revision

Patients with septic re-revision after UPIC had a significantly (H: p = 0.004; K: p = 0.030) shorter time period to the primary/previous surgery (H: 84 (IQR: 41–797); K: 115 (IQR: 55–446)) compared to patients with aseptic re-revision after UPIC (H: 1248 (IQR: 178-3534); K: 827 (IQR: 361-1183)) in both rTHA and rTKA.

There were significantly (p < 0.001) more consecutive revisions in rTHA 45/196 (22.9 %) compared to rTKA 4/113 (3.5 %). Overall, 7/45 (15.6 %) conversion rTHA and 6/151 (3.9 %) planned rTHA had a septic re-revision (p = 0.012). In addition, 1/4 (25 %) of conversion rTKA and 7/109 (6.4 %) of planned rTKA had septic re-revisions (p = 0.258) (Table 1).

3.4 Number of culture positive results

UPICs with ≥2 positive intraoperative cultures with the same microorganism had a significantly higher risk of septic re-revision in rTKA (≥2 culture positive: 3/15 (20 %) compared to single culture positive rTKA 4/98 (4.1 %); p = 0.048). This was not the case in rTHA (≥2 culture positive: 3/38 (7.9 %) compared to single culture positive rTKA 10/157 (6.4 %); p = 0.720). In these cases, all patients received postoperative antibiotic treatment (Table 1).

3.5 Antibiotic treatment

In total, 44/196 (22.4 %) rTHA and 23/113 (20.4 %) rTKA with UPIC results received postoperative antibiotic treatment for at least two weeks. All other patients started treatment after the third postoperative day for a duration of less than two weeks (H: 92/196 (46.9 %); K: 44/113 (38.9 %)) or received no antibiotic treatment (H: 60/196 (30.6 %); K: 45/113 (53.1 %)). There was no significant distribution for septic or aseptic revision in patients with or without or inadequate antibiotic treatment in rTHA and rTKA. Patients with ICM-2018 for non-infected (H: 100/155 (65.8 %); 53/97 (54.6 %)) compared to ICM-2018 for inconclusive (H: 36/41 (90.2 %); K: 14/16 (87.5 %)) received significantly less antibiotic treatment postoperatively (H: p = 0.004; K: p = 0.013) (Table 1).

3.6 Virulence of causative pathogen

There were more septic re-revisions in rTHA in patients with high-virulent 3/25 (12 %) compared to low-virulent 10/171 (5.9 %) microorganisms, but this was not significantly higher (p = 0.100). However, patients with high-virulent microorganisms (H:20/25 (80 %); K:15/20 (75 %)) received antibiotics more often than patients with low-virulent microorganisms (H:110/172 (63.9 %), K:55/93 (59.1 %)) (Table 1).

3.7 Microbiological result

A total of 309 UPICs were evaluated in revision total knee and hip arthroplasties (Table 2). All intraoperative microbiological results are shown in Table 2. There was no significant distribution in the type of previous revision. Furthermore, septic revision prior to UPIC revision did not have significantly higher septic re-revisions rate in our cohort (p = 0.053). The mean number of intraoperative cultures was 3.4 (±2.4) for rTHA and 3.5 (±2.4) for rTKA. All microbiological results were analysed, including swabs, sonication and tissue samples. Almost 98 % of the swabs were collected between 2011 and 2017, while 64.6 % of the tissue samples were collected between 2017 and 2020. We compared the microbiological spectrum of patients with UPIC revisions with the spectrum of the septic re-revisions after UPIC in the same patients. In 10/13 (76.9 %) septic rTHA after UPIC revision and 5/7 (71.4 %) septic rTKA after UPIC revision we found a positive intraoperative result. Interestingly, when we found the same microorganisms (rTHA 4/10 (40 %); rTKA 4/5 (80 %)), they showed a different antibiogram and gained resistance to antibiotics. Three additional microorganisms and six other microorganisms were found in culture-positive re-revisions compared to the previous UPIC results.

4 UPICs in revision total hip arthroplasty

In this study, a total of 751 presumed aseptic/unclear rTHA were evaluated. There were 196/751 (26.1 %) UPIC and 555/751 (73.9 %) CN results. UPIC revisions had a significant higher rate of successful ultrasound guided taps preoperatively compared to CN revisions (p = 0.003). Preoperative visible effusion on ultrasound may correlate with UPIC. Moreover, re-revisions were higher in UPICs compared to CN cases (p = 0.002). Single stage exchange and stem exchange have a higher rate of septic-re-revision after UPIC rTHA compared to other revision reasons. All results between UPIC and CN in rTHA are shown in Table 4.Table 4 Baseline demographic, and operative data for revision total knee arthroplasty. Mean with SD (standard deviation), median with IQR (Interquartile-range); UPIC (unexpected positive intraoperative cultures) included presumed aseptic and inconclusive revisions; BMI (Body-Mass-Index); ASA (American Society of Anesthesiologists Classification); CRP (C-reactive protein); PMN (Polymorphonuclear neutrophils); ORIF (open reduction and internal fixation) The number of septic re-revisions after a specific operation is compared with the total number of this procedure; *<0.05; **<0.001.

Table 4Baseline demographic, and operative data for revision total knee arthroplasty	
Revision total knee arthroplasty	UPIC n = 113 (16.6 %)	CN n = 566 (72.6 %)	P-value	
BMI	30.4 (±6.1)	30.4 (±5.8)	0.095	
Age	70 (61; 77))	71 (64; 76)	0.607	
Gender male	32 (28.3 %)	165 (27.6 %)	0.273	
 female	81 (71.7 %)	401 (72.4 %)	
ASA-score 1	12/113 (10.6 %)	58/566 (10.2 %)	0.892	
 2	89/113 (78.8 %)	449/566 (79.3)	
 3	9/113 (7.9 %)	59/566 (10.4 %)	
 4	3/113 (2.7 %)	0 %	
Smoking	18/113 (15.9 %)	61/566 (10.8 %)	0.119	
Nickel allergy	8/113 (7.1 %)	10/566 (1.8 %)	0.005*	
Deceased/lost to follow-up	3	14	>0.99	
 Death after revision (days)	506 (±191)	428 (±242)	0.614	
Operation time (min)	125 (102; 146)	119 (93; 142)	0.106	
Serum Cell-count 109/l	7.6 (±3.1)	7.5 (±2.3)	0.251	
Serum CRP (mg/l)	5.0 (±4.7)	5.8 (±7.4)	0.561	
Hemoglobin (g/dl)	13.9 (±1.3)	13.7 (±1.4)	0.431	
Preoperative aspiration	46 (40.7 %)	62 (11.0 %)	<0.001**	
 Synovial cell-count (109)	1.0 (+0.9)	1.0 (±1.4)	0.618	
 Synovial PMN (%)	35.3 % (±12.3)	39.9 (±15.5)	0.190	
 Synovial CRP (mg/l)	1.3 (±1.3)	1.5 (±1.2)	0.430	
Re-revision	18/113 (15.9 %)	57/566 (10.1 %)	0.098	
Septic revision after	7/113 (6.2 %)	10/566 (1.8 %)	0.013*	
 Single stage exchange	4/87 (4.6 %)	6/389 (1.5 %)	0.024*	
 Inlay exchange	2/13 (15.4 %)	3/65 (4.6 %)	0.192	
 Patella resurfacing	0/9 (0.0 %)	1/94 (1.1 %)	>0.99	
 ORIF	1/2 (50.0 %)	0/7 (0.0 %)	0.222	
 Extensor tendon rupture	0/2 (0.0 %)	0/10 (0.0 %)	—	
Early septic revision ≤90 days	1/7 (14.3 %)	2/10 (20 %)	>0.99	
Late septic revision >90 days	6/7 (85.7 %)	8/10 (80 %)	
Reason for aseptic re-revision	11/113 (9.7 %)	47/566 (8.3 %)	0.619	
 Instability	1/11 (9.1 %)	23/47 (48.9 %)	0.013*	
 Aseptic loosening	3/11(27.3 %)	10/47 (21.3 %)	0.696	
 Wear	2/11(18.2 %)	2/47 (4.3 %)	0.159	
 Patella resurfacing	—	9/47 (19.1 %)	—	
 Quadriceps tendon rupture	2/11 (18.2 %)	—	—	
 Other	3/11 (27.3 %)	3/47 (6.4 %)	0.075	

The area under the curve (AUC) for the time between primary/previous revision and UPIC rTHA with septic revision as the state variable was 0.707 (CI-95 % 0.548-0.865). The cut-off value based on Youdon-index was 682 days. Revisions within 682 days after index surgery have a higher risk of septic re-revision than aseptic re-revision in THA.

5 UPICs in revision total knee arthroplasty

A total of 679 presumed aseptic rTHA were evaluated. There were 113/679 (16.6 %) UPICs and 566/679 (7383.4 %) CN results. UPIC revisions showed a significant higher rate of successful taps preoperatively compared to CN revisions (p < 0.001). The septic re-revision rate is higher in UPIC compared to CN results (p = 0.013). There is no significant higher aseptic re-revision rate between UPICs compared to CN results (p = 0.619). Nevertheless, the risk of a re-revision is threefold higher in UPICs compared to CN result. System exchange has a higher rate of septic-re-revision after UPIC rTHA compared to other reasons for revision. All results between UPIC and CN results in rTHA can be found in Table 3.

The area under the curve (AUC) for the time between primary/previous surgery and UPIC rTKA with septic revision as state variable was 0.792 (CI-95 % 0.555-1.00). Cut-off values based on Youdon-index were 539 days. Indicating revisions within 539 days after index surgery have a higher risk for septic re-revision than aseptic re-revisions in TKA. All patella resurfacing procedures were excluded from the calculation of operative time, as there was a significantly higher number in the CN group compared to the UPIC group, all other procedures were included in the calculation.

6 Discussion

In this currently largest study on UPIC's in presumed aseptic or ICM-inconclusive hip and knee revision arthroplasties, we found that the rate of UPIC was generally higher in the hip than in the knee. UPIC results had a higher septic and aseptic re-revision rate compared to CN results. Risk factors for septic failure in this study were, conversion revisions, single-stage-exchange revisions and early revision after index surgery. In addition, nickel allergy was a risk factor for having an UPIC.

The UPIC rate in this study was higher than in other studies, especially in rTHA [5,6,24,25]. However, other studies included only unexpected positive cases. Our study, included both clear UPICs and inconclusive patients according to the ICM-2018 criteria. The higher rate of UPICs in rTHA compared to rTKA may be explained by the higher rate of single-stage exchanges and the lower rate of single-component exchanges in rTKA compared to rTHA. Another reason could be the significantly lower preoperative diagnostic workup for PJI and the presence of inconclusive revisions according to ICM-2018 criteria. In the study by Jacobs et al. rTHA also had a higher rate of UPIC compared to rTKA [12]. Therefore, all patients with presumed aseptic revision arthroplasty should undergo a thorough diagnostic workup and if infection is still suspected, intraoperative cultures should be obtained during surgery in order to select the appropriate treatment [5,9,13].

Overall, the infection-free implant survival in this study is comparable to that reported by Neufeld et al. who reported infection-free implant survival in UPIC rTHA and rTKA of 86 % and 95 %, respectively, at 5 years [8,25]. Interestingly, not only are septic re-revisions higher, but also aseptic re-revisions are significantly higher in UPIC revisions compared to CN revisions. In addition, if the same microorganism was found in the UPIC revision and the septic re-revision, then all microorganisms have gained resistance to antibiotics. In the study by Frank et al. and Mitterer et al. changes in the microbiological spectrum and resistance pattern are common between different septic revisions [23,26]. The question remains whether these aseptic re-revisions are truly aseptic or undiagnosed chronic PJI. Therefore, septic failure due to CN PJI may be higher than expected. These patients are known to have poor outcomes and a high rate of salvage procedures [27].

The risk of re-revision in THAs with two or more cultures of the same bacteria was not increased in the paper by Milandt et al [16]. In this study, high virulent microorganisms, a previous septic revision, UPICs with ≥2 culture-positive specimens and inconclusive revisions according to ICM-2018 criteria, did not show a higher septic or aseptic failure rate. One explanation may be that these patients were significantly more likely to be treated with appropriate antibiotics for several weeks, depending on resistance.

The time period for septic failure after UPIC is shorter than the time period for aseptic failure. The time period in this study is a common time period for PJI revision [28]. Early revisions with UPIC should probably be treated as infected due to a higher septic re-revision rate.

In addition, patients with nickel allergy showed a higher risk for UPICs in both rTHA and rTKA. The study by Neufeld et al. reported adverse metal reaction as a risk factor for subsequent PJI in patients with UPC [8]. The study by Prieto et al. reported high rates of infection after aseptic revision due to adverse metal reaction because of a change in the local environment that predisposing to infection [29]. The higher rate of UPIC in nickel allergy patients in this study may be partially explained by adverse tissue reactions as described by Kirchen et al [30]. However, in the Australian registry study by Vertullo et al. an allergy friendly TKA did not reduce revision rates for PJI or loosening [31]. Nickel allergy patients in this study also did not show a higher rate of septic re-revision, which can probably be interpreted as contamination, especially with low virulence microorganisms.

The present study has several limitations. First, the retrospective nature of the study design, with all its disadvantages. Second, due to the incomplete preoperative workup, occult infection could not always be ruled out. Third, the preoperative evaluation and clinical routine for the treatment of UPIC in rTKA and rTHA have changed over time. Moreover, different surgeons with different experience preformed surgical procedures. Nevertheless, these are real-world data.

In conclusion, UPICs have a higher rate of septic and aseptic failure than CN outcomes. UPICs are twice as common in rTHA compared to rTKA. Preoperative PJI workup reduces the UPIC rate. Nickel allergy is a risk factor for UPIC, but did not show a higher rate of septic re-revision. Early revisions with UPICs after primary THA or TKA have a higher risk septic failure. UPICs with high virulent microorganisms, a previous septic revision, UPICs with ≥2 culture-positive specimens and inconclusive ICM-2018 criteria should be treated with ABs.

Funding/support statement

The author(s) received no financial or material support for the research, authorship, and/or publication of this article.

Declaration of Competing Interest

None.

Acknowledgement

Philip Manolopoulos is greatly acknowledged for his contribution in data collection.
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References

1 Heckmann N.D. Yang J. Ong K.L. Lau E.C. Fuller B.C. Bohl D.D. Revision surgery for instability after total hip arthroplasty: does timing matter? J Arthroplasty 36 2021 1779 1783.e2 10.1016/j.arth.2020.12.035 33504458
2 Lewis P.L. Robertsson O. Graves S.E. Paxton E.W. Prentice H.A. W-Dahl A. Variation and trends in reasons for knee replacement revision: a multi-registry study of revision burden Acta Orthop 92 2021 182 188 10.1080/17453674.2020.1853340 33263453
3 Kingsbury S.R. Smith L.K. Shuweihdi F. West R. Czoski Murray C. Conaghan P.G. A comparative study of patients presenting for planned and unplanned revision hip or knee arthroplasty Bone Joint Lett J 104-B 2022 59 67 10.1302/0301-620X.104B1.BJJ-2021-0032.R2
4 Hipfl C. Mooij W. Perka C. Hardt S. Wassilew G.I. Unexpected low-grade infections in revision hip arthroplasty for aseptic loosening Bone Joint Lett J 103-B 2021 1070 1077 10.1302/0301-620X.103B6.BJJ-2020-2002.R1
5 Purudappa P.P. Sharma O.P. Priyavadana S. Sambandam S. Villafuerte J.A. Unexpected positive intraoperative cultures (UPIC) in revision Hip and knee arthroplasty- A review of the literature J Orthop 17 2020 1 6 10.1016/j.jor.2019.06.028 31879464
6 Ribera A. Morata L. Moranas J. Agulló J.L. Martínez J.C. López Y. Clinical and microbiological findings in prosthetic joint replacement due to aseptic loosening J Infect 69 2014 235 243 10.1016/j.jinf.2014.05.003 24861245
7 Barrack R.L. Aggarwal A. Burnett R.S.J. Clohisy J.C. Ghanem E. Sharkey P. The fate of the unexpected positive intraoperative cultures after revision total knee arthroplasty J Arthroplasty 22 2007 94 99 10.1016/j.arth.2007.03.029 17823025
8 Neufeld M.E. Lanting B.A. Shehata M. Howard J.L. MacDonald S.J. Teeter M.G. Prevalence and outcomes of unexpected positive intraoperative cultures in presumed aseptic revision hip arthroplasty J bone jt surg 2021 Publish Ah 10.2106/JBJS.20.01559
9 Saleh A. Guirguis A. Klika A.K. Johnson L. Higuera C.A. Barsoum W.K. Unexpected positive intraoperative cultures in aseptic revision arthroplasty J Arthroplasty 29 2014 2181 2186 10.1016/j.arth.2014.07.010 25124809
10 Bereza P.L. Ekiel A. Auguściak-Duma A. Aptekorz M. Wilk I. Wojciechowski P. Identification of asymptomatic prosthetic joint infection: microbiologic and operative treatment outcomes Surg Infect 18 2017 582 587 10.1089/sur.2016.253
11 Simon S. Frank B.J.H. Aichmair A. Dominkus M. Mitterer J.A. Hartmann S.G. Alpha-defensin as a diagnostic tool in revision total knee arthroplasties with unexpected positive intraoperative cultures and unexpected culture negative intraoperative cultures Knee Surgery, Sport Traumatol Arthrosc 31 2023 1462 1469 10.1007/s00167-022-07268-w
12 Jacobs A.M.E. Bénard M. Meis J.F. van Hellemondt G. Goosen J.H.M. The unsuspected prosthetic joint infection Bone Joint Lett J 99-B 2017 1482 1489 10.1302/0301-620X.99B11.BJJ-2016-0655.R2
13 Kloos J. Vander Linden K. Vermote S. Berger P. Vandenneucker H. Prevalence, interpretation, and management of unexpected positive cultures in revision TKA: a systematic review Knee Surgery 2022 10.1007/s00167-021-06856-6 Sport Traumatol Arthrosc
14 Portillo M.E. Salvadó M. Alier A. Sorli L. Martínez S. Horcajada J.P. Prosthesis failure within 2 Years of implantation is highly predictive of infection Clin Orthop Relat Res 471 2013 3672 3678 10.1007/s11999-013-3200-7 23904245
15 Boot W. Moojen D.J.F. Visser E. Lehr A.M. De Windt T.S. Van Hellemondt G. Missed low-grade infection in suspected aseptic loosening has no consequences for the survival of total hip arthroplasty Acta Orthop 86 2015 678 683 10.3109/17453674.2015.1086942 26364842
16 Milandt N.R. Gundtoft P.H. Overgaard S. A single positive tissue culture increases the risk of rerevision of clinically aseptic THA: a national register study Clin Orthop Relat Res 477 2019 1372 1381 10.1097/CORR.0000000000000609 31136437
17 Vargas-Reverón C. Soriano A. Fernández-Valencia J.A. Martínez-Pastor J.C. Morata L. Muñoz-Mahamud E. Prevalence and impact of positive intraoperative cultures in partial hip or knee revision J Arthroplasty 35 2020 1912 1916 10.1016/j.arth.2020.02.025 32147341
18 Staats K. Kolbitsch P. Sigmund I.K. Hobusch G.M. Holinka J. Windhager R. Outcome of total hip and total knee revision arthroplasty with minor infection criteria: a retrospective matched-pair analysis J Arthroplasty 32 2017 1266 1271 10.1016/j.arth.2016.11.016 28027814
19 Pérez-Prieto D. Hinarejos P. Alier A. Sorlí L. Martínez S. Puig L. Adherence to a reliable PJI diagnostic protocol minimizes unsuspected positive cultures rate BMC Musculoskelet Disord 22 2021 653 10.1186/s12891-021-04431-1 34340666
20 Antonios J.K. Lim E.S. Chang Y.-H.H. Bingham J.S. Clarke H.D. Spangehl M.J. The fate of the inconclusive periprosthetic joint infection workup and reliability of data points Orthopedics 46 2023 10.3928/01477447-20230310-08
21 van Sloten M. Gómez-Junyent J. Ferry T. Rossi N. Petersdorf S. Lange J. Should all patients with a culture-negative periprosthetic joint infection be treated with antibiotics? Bone Joint Lett J 104-B 2022 183 188 10.1302/0301-620X.104B1.BJJ-2021-0693.R2
22 Parvizi J. Tan T.L. Goswami K. Higuera C. Della Valle C. Chen A.F. The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria J Arthroplasty 33 2018 1309 1314.e2 10.1016/j.arth.2018.02.078 29551303
23 Frank B.J.H. Aichmair A. Simon S. Schwarz G.M. Dominkus M. Hofstaetter J.G. Analysis of culture positive first and second stage procedures in periprosthetic knee and hip joint infections J Arthroplasty 2021 10.1016/j.arth.2021.01.074
24 Neufeld M.E. Lanting B.A. Shehata M. Howard J.L. MacDonald S.J. Teeter M.G. Prevalence and outcomes of unexpected positive intraoperative cultures in presumed aseptic revision hip arthroplasty J Bone Jt Surg 103 2021 1392 1401 10.2106/JBJS.20.01559
25 Neufeld M.E. Lanting B.A. Shehata M. Naudie D.D.R. McCalden R.W. Teeter M.G. The prevalence and outcomes of unexpected positive intraoperative cultures in presumed aseptic revision knee arthroplasty J Arthroplasty 37 2022 2262 2271 10.1016/j.arth.2022.05.036 35598759
26 Mitterer J.A. Frank B.J.H. Gardete-Hartmann S. Panzenboeck L.F. Simon S. Krepler P. Changes of the microbiological spectrum and antibiotic resistance pattern in postoperative spinal implant infections with multiple culture-positive revision surgeries Spine J 22 2022 1934 1943 10.1016/j.spinee.2022.07.086 35853535
27 Tan T.L. Kheir M.M. Shohat N. Tan D.D. Kheir M. Chen C. Culture-negative periprosthetic joint infection JBJS Open Access 3 2018 e0060 10.2106/JBJS.OA.17.00060
28 Gundtoft P.H. Overgaard S. Schønheyder H.C. Møller J.K. Kjærsgaard-Andersen P. Pedersen A.B. The “true” incidence of surgically treated deep prosthetic joint infection after 32,896 primary total hip arthroplasties Acta Orthop 86 2015 326 334 10.3109/17453674.2015.1011983 25637247
29 Prieto H.A. Berbari E.F. Sierra R.J. Acute delayed infection: increased risk in failed metal on metal total hip arthroplasty J Arthroplasty 29 2014 1808 1812 10.1016/j.arth.2014.04.008 24851788
30 Kirchen N. Reich L. Waldstein W. Hopf T. Heller K.-D. Wienert S. ARMD-Reaktionsmuster bei Kniegelenkendoprothesen Orthopä 49 2020 183 189 10.1007/s00132-019-03776-9
31 Vertullo Christopher J. Lewis Peter L. Graves Stephen Kelly Lan Michelle Lorimer PM. Twelve-year outcomes of an oxinium total knee replacement compared with the same cobalt-chromium design: an analysis of 17,577 prostheses from the Australian orthopaedic association national joint replacement registry J Bone Jt Surg 99 2017 e37 10.2106/JBJS.ER.16.00092
