Optimizing multimodal diagnostic strategies for periprosthetic joint infection: Current advances and integration

Abstract

Periprosthetic Joint Infection (PJI) represents a significant complication following joint arthroplasty, highlighting the necessity for accurate diagnostic strategies to guide clinical decision-making. This review highlights advancements in PJI diagnostic techniques, including pathogen identification, biomarker profiling, imaging, and molecular biology techniques. Diagnostic accuracy in culture-based pathogen identification is influenced by factors such as sampling method, antibiotic administration, specimen type, incubation period, and type of culture media. Methods such as ultrasonic agitation and chemical dissolution (e.g., dithiothreitol, DTT) have demonstrated potential in improving pathogen identification in biofilms. Moreover, commonly employed biomarkers include C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), α-defensin, D-dimer, and interleukin-6 (IL-6), though each exhibits variable specificity and sensitivity. Imaging techniques such as X-ray, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT) offer diverse diagnostic capabilities, with PET/CT demonstrating high sensitivity and specificity despite higher costs. Furthermore, molecular biology methods such as Polymerase Chain Reaction (PCR) and next-generation sequencing (NGS) provide rapid and sensitive detection, which is especially valuable in culture-negative and polymicrobial infections. However, financial constraints limit their routine clinical use. Future research should focus on further optimizing diagnostic modality, exploring novel diagnostic techniques (such as machine learning, (ML) analysis and point-of-care, (POC) diagnostics), while integrating multimodal strategies to enhance the accuracy and efficiency of PJI identification.

Keywords

periprosthetic joint infection diagnostic test pathogen detection biomarkers imaging techniques molecular biology techniques cost-effectiveness

Introduction

The advancement of medical technology has made hip and knee replacement surgeries standard orthopedic practices designed primarily to improve patients’ quality of life by relieving pain and improving joint function.¹ However, the rising occurrence of these procedures has led to more postoperative complications, including PJI. The PJI, a serious complication after joint replacement, poses significant challenges for the healthcare system and imposes a heavy financial burden on patients and their families. The reported incidence of PJI following primary hip and knee arthroplasty ranges from approximately 0.7% to 2.0%.^2,3 A variety of diagnostic modality have been established for the detection of PJI. Clinical manifestations and associated symptoms greatly affect the early assessment of PJI. The presentation of PJI can differ depending on the timing of infection: acute PJIs typically occur within weeks to months postoperatively and are characterized by localized symptoms such as pain, erythema, elevated skin temperature, swelling, and wound exudate.⁴ However, many chronic infections are clinically difficult to distinguish from aseptic loosening, as they may present with a complete absence of infectious signs.⁵ In severe cases, infection may involve the joint and produce systemic symptoms, including chills, high-grade fever, bacteremia, and other generalized signs.⁶ Further diagnostic techniques include pathogen identification, biomarker testing, imaging, and molecular diagnostics. However, the lack of standardized clinical guidelines complicates the diagnostic process, often necessitating a combination of diagnostic approaches. Therefore, this review aims to consolidate existing diagnostic practices for PJI, evaluates their clinical utility and cost-effectiveness, and proposes integrative frameworks to enhance diagnostic accuracy and practicality.

Pathogen detection

Accurate detection of PJI is largely dependent on culture techniques. However, diagnostic accuracy may be significantly compromised by variables including the method of sample collection, previous antibiotic administration, type of sample, culture duration, sample volume, and the choice of culture medium, all of which may contribute to false-negative results.^7,8 Therefore, optimization of culture protocols is essential to improve detection reliability. The key factors influencing culture success and their recommended optimizations are summarized in Table 1.

Table 1.

Summary of culture optimization strategies.

Factor	Recommendation	Effect on diagnosis
Antibiotics	Discontinue ≥2 weeks before sampling	Reduces false negatives
Sample volume	3–6 tissue samples	Increases culture yield
Sample handling	Use sonication/DTT for biofilm disruption	Improves microbial recovery
Culture duration	Extend to 14–21 days for chronic/slow-growing infections	Captures slow-growing organisms
Culture media	Combine solid medium and pediatric blood culture bottles	Enhances sensitivity and speed

Sampling method

Accurate diagnosis of PJI depends substantially on appropriate sampling techniques. Although peripheral blood cultures provide useful information, definitive diagnosis typically requires synovial fluid or periprosthetic tissue samples. Maintaining strict sterile conditions during sample collection is critical to prevent contamination from skin flora or procedural cross-contamination.⁹ For optimal diagnostic outcomes, ultrasound-guided synovial fluid aspiration is recommended. Recent findings by Treu and Mirzaei et al.^10,11 have shown that ultrasound-guided access to synovial fluid in total hip arthroplasty (THA) patients achieves higher success rates and yields greater fluid volumes compared to fluoroscopy-guided techniques. Complications such as unsuccessful joint cavity aspiration or accidental vascular damage from the puncture needle might affect culture-positivity rates.¹² In failed synovial fluid aspiration cases, a common strategy involves saline lavage followed by resampling. However, studies have demonstrated that lavage may significantly reduce synovial fluid white blood cell counts, potentially complicating both diagnosis and initiation of treatment for PJI.¹³ As a result, the optimization of sampling strategies remains a key focus for advancing the diagnostic accuracy of PJI.

Antibiotics and sample size

Studies by Goh et al.^14,15 have demonstrated that prophylactic antibiotic use before sample collection significantly compromises the reliability of both microbial culture and biomarker testing, potentially resulting in diagnostic uncertainty. Therefore, it is advisable to discontinue antibiotic administration for at least 2 weeks before sampling. Sample volume is another critical factor influencing culture outcomes; insufficient sample sizes may result in false negatives, whereas excessively large volumes may lead to resource waste. Li et al.^16,17 highlighted intraoperative tissue culture as the most commonly employed technique. The Infectious Diseases Society of America (IDSA) recommends collecting no fewer than three, and preferably five to six, periprosthetic intraoperative tissue specimens for both aerobic and anaerobic cultures to obtain the desired results.

Sample type and handling

The type of sample collected, whether synovial fluid, periprosthetic soft tissue, or prosthetic components removed during surgery, significantly impacts culture outcomes. Mozella et al.¹⁸ reported that cultures from periprosthetic soft tissue exhibited higher positivity rates compared to histopathological examination of biofilms on retrieved prosthetic components. Moreover, Gazendam et al.¹⁹ highlighted that in chronic PJI cases, microorganisms often reside within biofilms on prosthetic surfaces, complicating conventional tissue-based microbial isolation of pathogens. Therefore, detection sensitivity is significantly improved by the effective destruction of biofilms and the preservation of microbial viability through the sonication of removed prosthetic components and the subsequent incubation of the shaking fluid. Furthermore, chemical lysis techniques, such as those involving saline or the strong reducing agent DTT, increase culture sensitivity by breaking down biofilm integrity. DTT has a high degree of sensitivity and specificity, and it may reduce the disulfide bond of biofilm proteins, therefore destroying its stability without causing harm to bacteria.²⁰ However, DTT is still primarily used for research purposes and has not yet been widely adopted in clinical practice. Moreover, recent investigations suggest that specific combinations of disinfectants, such as acetic acid, povidone-iodine, and hydrogen peroxide, are highly effective in disrupting biofilm structures and may represent optimal agents for intraoperative chemical debridement in PJI management.^21,22 Further, the introduction of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has transformed culture-based microbial identification by enabling rapid proteomic analysis, reducing reliance on time-consuming and laborious traditional biochemical assays, and significantly shortening diagnostic timelines for PJI.²³ However this technology is relatively costly.

Culture duration and medium

Incubation duration plays a critical role in the accuracy of culture results. Talsma et al.^24–26 observed that extending culture time is necessary to prevent false-negative results, particularly for slow-growing organisms such as non-tuberculous mycobacteria, whereas acute PJI cases typically do not require prolonged incubation. The standard culture period is generally accepted to be 10–14 days, although it may be extended up to 21 days for uncertain pathogens. Furthermore, the selection of culture media significantly impacts diagnostic sensitivity. Birdsall et al.^27,28 compared three culture techniques, solid medium, enrichment broth, and pediatric blood culture bottles, and found that the pediatric bottle method resulted in faster detection times and higher sensitivity when used independently. However, the combined use of solid medium and pediatric culture bottle methods outperformed the combination of solid medium and enrichment broth techniques.

Biomarker detection

The detection of biomarkers, such as CRP, ESR, α-defensin, D-dimer, IL-6, procalcitonin (PCT), and D-lactic acid, is commonly employed in the clinical diagnosis of PJI.^29,30 These tests offer advantages, including rapid turnaround time and relatively low cost. However, when used individually, these biomarkers often exhibit limitations in both specificity and sensitivity. The diagnostic performance characteristics of commonly used biomarkers are compared in Table 2. Future strategies should emphasize combining multiple biomarkers to increase diagnostic accuracy and efficiency.

Table 2.

Diagnostic performance of selected biomarkers.

Biomarker	Sensitivity (%)	Specificity (%)	AUC	Limitations
CRP	85–90	75–80	0.80–0.85	Nonspecific, elevated in inflammation
ESR	80–85	75–80	0.75–0.80	Nonspecific, slow to normalize
α-defensin	85–90	90–95	0.90–0.94	Cost, variable performance in reimplantation
D-dimer	90–95	80–85	0.70–0.75	Nonspecific, elevated in thrombosis
IL-6 (SF)	70–75	85–90	0.91–0.95	Requires synovial fluid aspiration
PCT	60–65	80–85	0.70–0.75	Limited sensitivity

Note. The values presented in this table represent a composite range of results from multiple studies and systematic reviews [29–41] reflecting the typical performance reported in the literature.

AUC: area under the curve.

ESR and CRP

As nonspecific inflammatory markers, ESR and CRP are commonly used in the assessment of inflammation. The ESR indicates the extent of erythrocyte aggregation in response to abnormal proteins during inflammatory states. Further, CRP is synthesized by the liver, peaks within 24–48 h of inflammation onset, and typically returns to baseline levels within approximately 2 weeks. However, both ESR and CRP may be increased in non-infectious conditions such as rheumatoid arthritis, systemic lupus erythematosus, trauma, and various systemic disorders. Therefore, surgeons should not exclude PJI primarily based on ESR and CRP, and if the infection is suspected, further analysis is necessary to confirm the diagnosis.^31,32

Alpha-defensin and D-dimer

Alpha-defensin, a synovial fluid biomarker, is considered a secondary criterion in the diagnostic scoring system for PJI. However, its role in evaluating infection eradication before performing a second-stage revision remains uncertain. Owens et al.³³ suggested that routine testing of α-defensins before the second-stage revision may not be necessary. Furthermore, D-dimer, a fibrin degradation product, primarily reflects fibrinolytic activity. It is associated with inflammation and may be elevated in infected patients. D-dimer has been recognized as a diagnostic marker for infectious conditions such as endocarditis and pneumonia. More recently, it has been applied in PJI diagnostics. However, its levels may also increase in cases of thrombosis, malignancy, autoimmune disorders, pregnancy, and cardiovascular or cerebrovascular diseases.³⁴ Therefore, Lu et al.^35,36 reported that D-dimer demonstrates limited accuracy in differentiating PJI from aseptic failure in THA and total knee arthroplasty (TKA).

IL-6 and D-lactic acid

Recent investigations have demonstrated that IL-6 possesses high diagnostic utility for identifying PJI. At the same time, Li et al.³⁷ reported that synovial fluid (SF) IL-6 levels provided significantly greater diagnostic accuracy for PJI in THA and TKA patients compared to serum IL-6 levels. Qin et al.³⁸ pointed out that the combination of serum IL-6 and SF IL-6 has the potential to further improve the diagnosis of PJI. Further, D-lactic acid has shown high specificity in detecting bacterial infections, particularly septic arthritis. Significantly elevated D-lactic acid levels in synovial fluid support its use as an infection marker. However, further research is required to clarify the relationship between synovial D-lactic acid concentrations and bacterial virulence.³⁹

PCT

Neuroendocrine cells and thyroid parafollicular cells synthesize PCT protein. In healthy individuals, serum PCT levels remain low but are markedly elevated in severe bacterial or fungal infections. Elevated PCT levels may also occur in cases of non-infectious inflammation, such as multiple organ failure and extensive burns. The PCT test demonstrates high diagnostic accuracy in identifying systemic infections.⁴⁰ However, its utility in diagnosing PJI remains controversial. While Ngasoongsong et al. reported that synovial PCT is a reliable, highly specific, and sensitive diagnostic marker for PJI, Busch et al. found that PCT had reduced sensitivity and did not reliably distinguish between aseptic loosening of prostheses and PJI.⁴¹ Therefore, the diagnostic value of PCT in PJI requires further validation through further studies.

Imaging techniques

Imaging techniques assist in the detection and evaluation of orthopedic infection complications, especially implant-associated infections with atypical clinical signs. These methods offer crucial diagnostic support and help direct targeted invasive sampling. A comparative overview of the advantages, limitations, and performance of common imaging modalities is provided in Table 3. Diagnostic approaches include conventional radiological techniques such as X-ray, CT, MRI, and ultrasound (US), as well as nuclear medicine techniques like bone scintigraphy (BS), anti-granulocyte antibody scintigraphy (AGS), leukocyte scintigraphy (LS), and fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT).^42,43 Among them, patients often prefer X-ray, CT, and MRI due to their relatively low cost.

Table 3.

Comparison of imaging modalities in PJI diagnosis.

Modality	Advantages	Limitations	Sensitivity (%)	Specificity (%)	Approximate cost (USD)
X-ray	Low cost, accessible	Low sensitivity/specificity, poor soft tissue detail	50–60	60–70	$50–$150
CT	Detailed bone anatomy	Metal artifacts, radiation exposure	70–75	75–80	$500–$1500
MRI	High soft tissue resolution, no radiation	Metal artifacts, long scan time	80–85	85–90	$1000–$2500
PET/CT	High sensitivity/specificity, functional imaging	High cost, limited availability, radiation	90–95	85–90	$2000–$5000

Note. Performance characteristics (Sensitivity, Specificity) and cost estimates are synthesized from relevant literature reviews and comparative studies [42–48]. Costs are approximate and may vary significantly by region and healthcare facility.

X-ray

Conventional radiographs are frequently employed to evaluate prosthesis implantation and follow-up, and they can identify abnormalities such as periprosthetic fractures, dislocations, wear-related osteolysis, or subsidence. Common radiographic signs indicative of PJI include periosteal reactions, radiolucent zones at the cement-bone or prosthesis-bone interface, patchy osteolysis, prosthesis loosening, periprosthetic bone resorption, and the presence of transcortical sinus tracts. However, due to their low sensitivity and specificity, plain X-rays are limited in reliably differentiating PJI from aseptic loosening.⁴⁴

CT and PET/CT

Studies indicate that PJI on CT is often characterized by aggressive osteolysis with poorly-defined boundaries.⁴⁵ With advancements in nuclear medicine, PET/CT has emerged as a valuable imaging technique for PJI assessment. It offers high sensitivity and specificity, provides both functional and anatomical information in a single examination, and facilitates monitoring of treatment effects⁴⁶ However, its application is limited by relatively high cost.

MRI

The MRI provides excellent imaging contrast for soft tissues and bone, which is advantageous in evaluating orthopedic conditions. However, its diagnostic utility in periprosthetic regions is significantly limited by magnetization artifacts generated by metallic implants. Addressing these artifacts to increase image quality and improve diagnostic precision remains a key focus of research studies.^47,48

Molecular biological techniques

Recent advancements in molecular biology have introduced innovative approaches for the rapid and accurate diagnosis of PJI and the identification of causative pathogens. The benefits of microbial molecular diagnostic modality include high sensitivity, rapid detection, and culture independence.⁴⁹ Gene sequencing technologies are increasingly applied in the diagnosis of PJI and the identification of microbial agents. The performance characteristics, advantages, and limitations of molecular methods are detailed in Table 4.

Table 4.

Molecular methods in PJI diagnosis.

Method	Sensitivity (%)	Specificity (%)	AUC	Approximate cost (USD)	Advantages	Limitations
PCR	75–80	85–90	0.82–0.88	$200–$500	Rapid, targeted	Limited multiplex capability
NGS	85–90	90–95	0.92–0.96	$800–$2000	Broad pathogen detection, culture-free	High cost, complex data interpretation

Note. Performance data are summarized from multiple clinical studies and recent systematic reviews [49–53]. NGS shows particular promise for culture-negative and polymicrobial infections, though standardization and cost-effectiveness remain active areas of investigation.

PCR

PCR is a molecular technique capable of quickly identifying common microorganisms. Despite its speed, studies using the Musculoskeletal Infection Society (MSIS) criteria as a gold standard have found that PCR is markedly less accurate than culture in diagnosing PJI. Although multiplex PCR methods incorporating multiple primers (e.g., 16S rRNA) have been developed to improve detection, their sensitivity remains inadequate, and they fail to demonstrate significant advantages over tissue culture.^50,51

NGS

The rapid advancement of NGS over the past decade has positioned it as a valuable tool for diagnosing PJI. With improvements in high-throughput sequencing, its capability to identify pathogens has become increasingly evident. The NGS has demonstrated significant benefits in diagnosing several infectious diseases and has revolutionized genomic research. Over the past 5 years, growing evidence has underscored its potential role in PJI diagnosis.⁵² Moreover, Tang et al.⁵³ have demonstrated that NGS is especially useful for identifying pathogens in culture-negative patients with a history of antibiotic use and for detecting polymicrobial PJI. Despite these advantages, its high cost remains a major barrier to widespread clinical implementation.

Emerging diagnostic technologies

Novel approaches such as ML and POC testing are increasingly being explored in the diagnosis of PJI, though their maturity and clinical applicability require cautious evaluation.^54,55 ML models, which integrate multimodal data, show considerable promise for improving diagnostic accuracy. For instance, recent studies have reported that ML algorithms combining clinical parameters, biomarkers, and imaging features can achieve AUC values between 0.92 and 0.97 in the context of PJI.⁵⁶ However, these models remain largely in the research phase and must undergo further validation in large, multicenter cohorts to ensure generalizability and clinical utility. Meanwhile, POC tests are designed to provide rapid intraoperative results but have yet to be standardized for widespread clinical implementation. Existing POC platforms targeting biomarkers such as calprotectin, α-defensin and leukocyte esterase demonstrate moderate accuracy, with AUC values in the range of 0.85–0.90.⁵⁷ Nevertheless, these assays require refinement in terms of consistency, standardization, and resistance to interfering factors. Most POC technologies are still in the developmental or early clinical evaluation stages, and are not yet ready for routine use.⁵⁸ In summary, while emerging technologies such as ML and POC testing show strong potential, their integration into mainstream clinical practice will depend on rigorous validation, standardization, and thoughtful consideration of their practicality and cost-effectiveness across diverse healthcare settings.

Integrated diagnostic framework and cost-effectiveness analysis

Given the limitations of individual modalities, a multimodal approach is recommended. The following diagnostic algorithm is proposed based on current evidence and cost-effectiveness considerations:

This integrated framework (Figure 1) proposes a sequential approach, initiating with clinical suspicion and low-cost serum tests (CRP/ESR), progressing to synovial fluid analysis and advanced imaging when indicated, and utilizing molecular techniques for complex or culture-negative cases.

Figure 1.

Proposed diagnostic flowchart for PJI.

Cost-effectiveness analyses suggest that a sequential approach starting with low-cost tests (CRP/ESR) followed by more expensive modalities only when needed provides the best value. The incremental cost-effectiveness ratio (ICER) for adding advanced imaging or molecular testing ranges from $15,000 to $45,000 per quality-adjusted life year (QALY) gained, which is generally considered acceptable in healthcare settings.⁵⁹

Barriers to implementation

The widespread adoption of advanced diagnostic technologies faces several interconnected challenges. Economic constraints and limited resource availability represent a fundamental barrier, particularly as high-cost modalities such as PET/CT and NGS remain financially inaccessible for many healthcare systems, especially in low-resource settings. Beyond financial aspects, operational hurdles further hinder implementation; these include a lack of standardized protocols for biomarker quantification and sample processing, as well as a pronounced shortage of trained personnel capable of interpreting complex imaging or genomic data. Moreover, successful clinical integration is hampered by insufficient validation from large-scale, multi-center studies, which are essential to establish clinical utility, and by stringent, time-consuming regulatory approval processes for novel diagnostic platforms. Together, these challenges create a significant gap between technological innovation and routine clinical application.

Potential limitations

The data presented in the table are a comprehensive range obtained from the literature. Any discrepancies in final measurements are attributable to human factors and variations in technological detection capabilities.

Conclusion

PJI remains a diagnostic challenge due to the inherent limitations of any single diagnostic modality. Therefore, an integrated multimodal strategy—combining clinical assessment, biomarker profiling, medical imaging, and advanced microbiological and molecular techniques—is crucial for achieving accurate diagnosis. Moving forward, efforts should concentrate on refining culture methods and sample handling protocols; discovering and validating novel biomarkers as well as multi-parameter panels, enhancing imaging techniques to minimize artifacts and lower expenses, and advancing molecular diagnostics such as NGS through rigorous validation and cost reduction. Furthermore, there is a need to develop comprehensive, economically viable diagnostic pathways incorporating ML and POC technologies, supported by health economic studies to evaluate the cost-effectiveness of these integrated approaches.

Prospects

Future efforts should prioritize multicenter prospective studies to validate combined diagnostic models, which will inform the development of resource-appropriate algorithms tailored to diverse clinical settings. The integration of artificial intelligence is anticipated to play a key role in synthesizing complex data and supporting diagnostic decisions, while advances in rapid intraoperative tools are essential to real-time surgical guidance. Furthermore, implementing standardized diagnostic pathways across healthcare systems and introducing policy measures to improve reimbursement for advanced diagnostics will be critical. Through continuous technological innovation, interdisciplinary collaboration, and systemic integration, these initiatives hold promise for significantly enhancing the accuracy, efficiency, and cost-effectiveness of PJI diagnosis, thereby improving patient outcomes and alleviating healthcare burdens.

Footnotes

ORCID iDs

Jianhui Zhai

Tao Wang

Author contributions

Jianhui Zhai wrote the article, Yumei Zhang and Jinwang Dong collected the literature, Tao Wang and Rui Liu revised the article. All authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

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