Orthopaedic implants have transformed the management of fractures and degenerative joint disease by improving stability, restoring mobility, and reducing disability. However, infection involving internal fixation devices or joint prostheses remains one of the most serious complications of orthopaedic surgery. Implant-associated infection may lead to persistent pain, delayed union or nonunion, implant loosening, repeated surgical procedures, prolonged antimicrobial therapy, increased healthcare expenditure, loss of function, and occasionally limb-threatening complications. Diagnosis is particularly difficult when infection is indolent. Classical signs such as fever, erythema, wound discharge, sinus formation, and purulence may be absent, especially in chronic or low-grade infections. Microbiological culture remains essential for etiological diagnosis but may require several days and may be negative after prior antimicrobial exposure or in infections caused by slow-growing organisms. International definitions have therefore adopted combinations of clinical, microbiological, histopathological, synovial, and biochemical criteria. The 2018 International Consensus Meeting definition for periprosthetic hip and knee infection recognizes a sinus tract or two concordant positive cultures as major diagnostic criteria and incorporates several additional minor parameters.[1] The European Bone and Joint Infection Society has similarly proposed a structured three-level diagnostic approach.[2] For fracture-related infection, an international consensus group defined confirmatory findings such as fistula or sinus communicating with the fracture or implant, purulent drainage or intraoperative pus, phenotypically indistinguishable microorganisms from at least two deep samples, and histopathological evidence of microorganisms.[3,4] Serum inflammatory biomarkers remain attractive because they are inexpensive, minimally invasive, rapidly available, and widely accessible. C-reactive protein is an acute-phase reactant synthesized predominantly by hepatocytes in response to inflammatory cytokines. It rises relatively rapidly after bacterial infection but may also increase after trauma, surgery, autoimmune disease, and other inflammatory states. Erythrocyte sedimentation rate reflects changes in plasma proteins and erythrocyte aggregation. It is inexpensive but responds more slowly and is influenced by age, anemia, renal disease, inflammatory disorders, and other non-infectious conditions. Procalcitonin is a precursor of calcitonin that may increase substantially during systemic bacterial infection. Because PCT is less strongly stimulated by many non-bacterial inflammatory states, it has attracted interest as a potentially more specific marker of bacterial infection. However, localized orthopaedic implant infection may not generate a sufficiently strong systemic response to substantially elevate serum PCT. A 2024 diagnostic meta-analysis reported pooled PCT sensitivity of only 44.1% for periprosthetic joint infection, despite specificity of 85.2% and an AUC of approximately 0.76.[5] In contrast, CRP has repeatedly demonstrated moderate-to-good diagnostic performance. Recent pooled evidence has reported CRP sensitivity around 79% and specificity around 78% in periprosthetic joint infection, although no serum biomarker is sufficiently accurate to independently establish or exclude infection.[6] Direct comparison of CRP, ESR, and PCT in a mixed orthopaedic implant population may therefore help clarify their roles in routine clinical practice. The present study compared the diagnostic performance of CRP, ESR, and serum procalcitonin for early detection of orthopaedic implant-associated infection among patients treated at a tertiary-care teaching hospital in North India. Objectives Primary Objective To compare the diagnostic accuracy of CRP, ESR, and serum procalcitonin for detecting orthopaedic implant-associated infection. Secondary Objectives 1. To compare serum concentrations of CRP, ESR, and PCT between infected and non-infected implant cases. 2. To determine the sensitivity and specificity of each biomarker. 3. To calculate PPV, NPV, positive and negative likelihood ratios, and overall diagnostic accuracy. 4. To compare the areas under the ROC curves of CRP, ESR, and PCT. 5. To examine whether PCT provides additional rule-in value when interpreted alongside CRP.

Study Design This was a prospective hospital-based diagnostic-accuracy study. Study Setting The study was conducted in the Department of Orthopaedics, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India. Study Duration Patients were recruited from April 1, 2025 to March 31, 2026. Study Population Adult patients with an orthopaedic implant in situ who were being evaluated for possible implant-related infection or undergoing revision or implant-removal surgery were consecutively assessed for eligibility. The study population included patients with fracture fixation implants and patients with hip or knee joint prostheses. Inclusion Criteria a) Age ≥18 years. b) Internal orthopaedic fixation device or joint prosthesis in situ. c) Clinical or radiological suspicion of implant infection, painful implant, aseptic loosening, delayed union/nonunion, or planned revision/removal surgery. d) CRP, ESR, and PCT testing during the index diagnostic evaluation. e) Sufficient clinical, microbiological, operative, and/or histopathological evaluation to establish final infection status. f) Written informed consent. Exclusion Criteria a. Established acute infection at a non-orthopaedic site. b. Active systemic inflammatory or autoimmune disease likely to markedly alter CRP or ESR. c. Major surgery or new major trauma within the preceding 14 days likely to interfere with interpretation of serum inflammatory markers. d. Severe systemic sepsis clearly unrelated to the implant. e. Incomplete biomarker data. f. Insufficient microbiological or clinical information to establish final infection status. Sample Size The planned sample size was 120 patients. Assuming an anticipated diagnostic sensitivity of approximately 85%, an infection prevalence of approximately 35%, a 95% confidence level, and an absolute precision of approximately 11%, the minimum estimated sample size was approximately 116 patients. The final target was rounded to 120 patients to allow for incomplete or non-evaluable observations. Clinical Evaluation At enrollment, information was recorded regarding: • age; • sex; • type of implant; • indication for original implantation; • duration since implantation; • pain; • swelling; • wound discharge; • sinus formation; • implant loosening; • delayed union or nonunion; • history of previous infection; • recent antimicrobial exposure; • diabetes mellitus and other relevant comorbidities. Index Tests Blood samples were obtained during the initial diagnostic work-up. C-Reactive Protein Serum CRP was measured using a quantitative laboratory assay. For clinical diagnostic comparison, CRP ≥10 mg/L was considered positive. Erythrocyte Sedimentation Rate ESR was measured using the standardized Westergren method or the equivalent laboratory-standard method. ESR ≥30 mm in the first hour was considered positive. Procalcitonin Serum procalcitonin was measured using a quantitative immunoassay. PCT ≥0.25 ng/mL was considered positive for the principal diagnostic analysis. ROC analysis was additionally used to examine discrimination across the full range of values. Reference Standard for Implant Infection Because CRP and ESR themselves are incorporated into some formal periprosthetic joint infection scoring systems, a biomarker-independent reference standard was used for diagnostic-performance analysis to minimize incorporation bias. Final infection status was determined from the complete clinical episode, including: • sinus or fistula communicating with the implant; • intraoperative purulence; • multiple deep-tissue specimens for microbiological culture; • concordant growth of an organism from ≥2 independent deep samples where available; • histopathological evidence of acute inflammation or microorganisms; • operative findings; • relevant radiological and clinical information. • For fracture-fixation cases, classification followed the principles of the international fracture-related infection consensus definition.[3,4] For arthroplasty cases, clinical, microbiological and histopathological findings were interpreted in accordance with accepted ICM/EBJIS principles.[1,2] An adjudicated final diagnosis of infected or non-infected was assigned. Where possible, clinicians adjudicating final infection status were blinded to the PCT result, and biomarker values were not used as confirmatory reference criteria. Microbiological Evaluation • For patients undergoing surgery, multiple deep tissue samples were collected using separate sterile instruments. • Superficial wound swabs were not considered definitive evidence of implant infection. • Specimens were transported promptly to the microbiology laboratory and processed using standard aerobic and anaerobic culture methods. • Where available, identification and antimicrobial susceptibility testing were performed according to institutional laboratory protocols. Outcomes Primary Outcome Diagnostic accuracy of CRP, ESR, and PCT for orthopaedic implant-associated infection. Secondary Outcomes • sensitivity; • specificity; • PPV; • NPV; • positive likelihood ratio; • negative likelihood ratio; • overall diagnostic accuracy; • ROC-AUC; • comparison of biomarker concentrations between infected and non-infected patients. Statistical Analysis • Continuous variables were tested for distributional characteristics. • Normally distributed variables were summarized as mean ± standard deviation, while skewed biomarker concentrations were summarized using median and interquartile range. • Categorical variables were presented as number and percentage. • Comparisons between infected and non-infected groups were performed using independent-samples t test for normally distributed continuous variables, Mann-Whitney U test for skewed continuous variables, and chi-square or Fisher's exact test for categorical variables. • For each biomarker, 2 × 2 contingency tables were constructed against the final infection reference standard. • Sensitivity, specificity, PPV, NPV, positive likelihood ratio, negative likelihood ratio, and overall diagnostic accuracy were calculated. • Ninety-five percent confidence intervals were estimated for sensitivity and specificity. • ROC curves were generated and AUC values were calculated. • A two-sided p-value <0.05 was considered statistically significant. Ethical Considerations • The study was conducted in accordance with the Declaration of Helsinki. • Approval was obtained from the Institutional Ethics Committee of Pt. B.D. Sharma PGIMS before initiation of the study. • Written informed consent was obtained from all participants.

Study Population A total of 120 patients were included in the final analysis. The mean age of the cohort was 47.2 ± 15.8 years, and 82 patients (68.3%) were male. Seventy-two patients (60.0%) had fracture-fixation implants and 48 (40.0%) had hip or knee arthroplasty implants. Based on the final reference standard, 42 patients (35.0%) had orthopaedic implant-associated infection and 78 patients (65.0%) were classified as non-infected. The estimated infection prevalence in the study population was therefore 35.0% (95% CI approximately 27.1%–43.9%). Table 1. Baseline characteristics of the study population Characteristic Infection, n=42 No infection, n=78 Total, n=120 Age, years 47.8 ± 15.9 46.9 ± 15.8 47.2 ± 15.8 Male sex 31 (73.8%) 51 (65.4%) 82 (68.3%) Female sex 11 (26.2%) 27 (34.6%) 38 (31.7%) Fracture-fixation implant 25 (59.5%) 47 (60.3%) 72 (60.0%) Hip/knee arthroplasty 17 (40.5%) 31 (39.7%) 48 (40.0%) Diabetes mellitus 12 (28.6%) 11 (14.1%) 23 (19.2%) Previous antibiotic exposure 15 (35.7%) 18 (23.1%) 33 (27.5%) Values are mean ± SD or n (%). Comparison of Serum Biomarker Levels All three inflammatory biomarkers were higher among patients with confirmed implant infection. Median CRP concentration was 31.6 mg/L among infected patients compared with 5.8 mg/L among non-infected patients. Median ESR was 48 mm/hour compared with 22 mm/hour, respectively. PCT was also higher in infected patients, although substantial overlap existed between the groups. Table 2. CRP, ESR and PCT according to final infection status Biomarker Infection, n=42 No infection, n=78 p-value CRP, mg/L 31.6 (15.4–72.8) 5.8 (2.6–9.8) <0.001 ESR, mm/hour 48 (35–71) 22 (13–34) <0.001 Procalcitonin, ng/mL 0.18 (0.08–0.46) 0.06 (0.03–0.11) <0.001 Values are median (interquartile range). Diagnostic Performance of CRP At a threshold of CRP ≥10 mg/L, 36 of the 42 infected patients tested positive. Among the 78 non-infected patients, 60 tested negative. This corresponded to sensitivity 85.7%, specificity 76.9%, PPV 66.7%, NPV 90.9%, positive likelihood ratio 3.71, negative likelihood ratio 0.19, and overall accuracy 80.0%. The high NPV suggested that a low CRP substantially reduced, although did not eliminate, the probability of implant infection. Diagnostic Performance of ESR At ESR ≥30 mm/hour, sensitivity was 78.6% and specificity was 69.2%. The corresponding NPV was 85.7%, while PPV was 57.9%. ESR therefore demonstrated useful but inferior discrimination compared with CRP. Diagnostic Performance of Procalcitonin At PCT ≥0.25 ng/mL, only 19 of the 42 infected patients tested positive. Sensitivity was consequently relatively low at 45.2%. However, only four of the 78 non-infected patients had a positive PCT result, producing a specificity of 94.9%. PCT therefore showed the highest specificity and highest positive likelihood ratio among the three biomarkers. Table 3. Diagnostic accuracy of CRP, ESR and procalcitonin Parameter CRP ≥10 mg/L ESR ≥30 mm/h PCT ≥0.25 ng/mL True positive 36 33 19 False negative 6 9 23 True negative 60 54 74 False positive 18 24 4 Sensitivity 85.7% 78.6% 45.2% 95% CI for sensitivity 72.2–93.3% 64.1–88.3% 31.2–60.1% Specificity 76.9% 69.2% 94.9% 95% CI for specificity 66.4–84.9% 58.3–78.4% 87.5–98.0% PPV 66.7% 57.9% 82.6% NPV 90.9% 85.7% 76.3% Positive likelihood ratio 3.71 2.55 8.82 Negative likelihood ratio 0.19 0.31 0.58 Overall accuracy 80.0% 72.5% 77.5% Receiver Operating Characteristic Analysis CRP demonstrated the largest area under the ROC curve. The AUC values were CRP 0.86 (95% CI 0.79–0.92), ESR 0.79 (95% CI 0.70–0.87), and PCT 0.74 (95% CI 0.65–0.83). Thus, CRP demonstrated good discrimination, whereas ESR and PCT demonstrated moderate discrimination. Table 4. ROC analysis of serum biomarkers Biomarker AUC 95% CI Interpretation CRP 0.86 0.79–0.92 Good ESR 0.79 0.70–0.87 Moderate Procalcitonin 0.74 0.65–0.83 Moderate Exploratory Combined Interpretation When either CRP or PCT positivity was considered supportive of infection, sensitivity increased modestly but specificity decreased. Conversely, simultaneous positivity of both CRP and PCT produced very high specificity, suggesting that PCT may be most useful as a confirmatory adjunct in a patient who already has clinical suspicion and elevated CRP rather than as an independent screening test. Summary of Principal Findings 1. All three biomarkers were significantly higher among patients with confirmed implant infection. 2. CRP demonstrated the highest overall discriminatory performance. 3. ESR had lower specificity and overall accuracy than CRP. 4. PCT had poor sensitivity but excellent specificity. 5. A normal PCT could not exclude implant infection. 6. Markedly elevated PCT increased the probability of bacterial implant infection. 7. None of the biomarkers was sufficiently accurate to replace microbiological and clinical diagnostic criteria

The present study compared three readily available serum inflammatory biomarkers in patients undergoing evaluation for orthopaedic implant-associated infection. The principal finding was that CRP provided the best overall balance between sensitivity and specificity, while PCT provided the greatest specificity but insufficient sensitivity for screening. The observed CRP sensitivity of 85.7%, specificity of 76.9%, and AUC of 0.86 are consistent with contemporary evidence. A large systematic review of serum biomarkers for PJI reported pooled CRP sensitivity of approximately 79.4%, specificity of 77.7%, and a summary ROC area of approximately 0.87, closely paralleling the diagnostic pattern observed in the present cohort.[6]. A prospective study of patients undergoing revision arthroplasty likewise reported a CRP AUC of 0.862 with sensitivity of 90.4%, supporting CRP as a useful but imperfect screening marker.[7]. These findings suggest that CRP remains clinically useful because of its relative sensitivity, accessibility, rapid turnaround, and high negative predictive value. However, CRP lacks infection specificity. Tissue injury, inflammatory disease, postoperative inflammation, and other infections may result in elevated concentrations. For this reason, an elevated CRP cannot independently confirm an orthopaedic implant infection. Diagnostic Value of ESR ESR demonstrated moderate sensitivity and specificity in the present study. Although ESR remains inexpensive and widely available, its slower kinetics and susceptibility to multiple physiological and pathological influences reduce its diagnostic precision. Piper et al. studied CRP and ESR across knee, hip, shoulder, and spinal implant infections and demonstrated that performance and optimum cutoffs varied according to implant location.[8] Similarly, a systematic review of late fracture-related infection concluded that serum inflammatory markers were insufficiently accurate for independent diagnosis. Pooled CRP sensitivity and specificity were approximately 77.0% and 67.9%, while pooled ESR sensitivity was substantially lower in the studies available for meta-analysis.[9] The present results therefore support the view that ESR is best interpreted as a supportive or suggestive marker, particularly when combined with clinical findings and CRP. Diagnostic Value of Procalcitonin PCT demonstrated a different diagnostic profile. Its specificity of 94.9% was the highest among the three markers, but sensitivity was only 45.2%. This finding is biologically plausible. Procalcitonin is strongly associated with systemic bacterial inflammatory responses, while many implant infections—particularly chronic biofilm-associated infections—remain localized and may produce little systemic PCT elevation. Sun et al. performed a 2024 diagnostic meta-analysis involving 621 patients from nine studies. The pooled sensitivity of serum PCT for PJI was only 44.1%, while specificity was 85.2% and the summary AUC was 0.76.[5] These figures closely resemble the diagnostic pattern in the present study. Therefore, a normal PCT result should not be interpreted as evidence against implant infection. However, the high specificity suggests that PCT may contribute useful rule-in information when elevated. Comparison With Previous Procalcitonin Studies Published studies of PCT have been inconsistent. Yuan et al. prospectively evaluated patients undergoing revision total hip arthroplasty and reported an AUC of 0.851 for PCT and 0.830 for CRP, with no statistically significant difference between them.[10] In contrast, Busch et al. prospectively investigated low-grade periprosthetic joint infection and reported poor diagnostic sensitivity for serum PCT, particularly at conventional higher thresholds.[11] The variable results probably reflect differences in infection acuity, causative organisms, biomarker thresholds, prevalence of systemic manifestations, reference standards, prior antibiotic exposure, and patient selection. The findings of the current study favor the interpretation that serum PCT is a specific adjunct rather than a sensitive screening test. CRP and PCT in Fracture-Related Infection • A recent retrospective investigation by Liu et al. examined combined CRP and PCT testing in fracture-related infection and reported sensitivity of 90.48%, specificity of 96.83%, PPV of 96.61%, and NPV of 91.04% for the combined approach.[12] • Those estimates were considerably higher than those observed for individual serum biomarkers in the present cohort. • Several factors may explain the difference, including patient spectrum, timing of biomarker measurement, infection severity, reference definition, and statistical approach. • Nevertheless, the study supports the broader concept that PCT may add value when interpreted alongside CRP rather than replacing it. Importance of the Reference Standard One methodological concern in biomarker studies is incorporation bias. CRP and ESR form part of some PJI diagnostic scoring systems. If the same markers are simultaneously assessed as index tests and included in the reference diagnosis, their apparent accuracy may be artificially increased. The present study therefore used microbiological, histopathological, operative, and confirmatory clinical findings to determine final infection status without relying on CRP, ESR, or PCT as definitive reference criteria. This strategy provided a more independent comparison of the three biomarkers. Clinical Implications CRP CRP may be regarded as the most useful first-line serum screening marker among the three tested biomarkers. Its relatively high sensitivity and NPV make a normal result useful for reducing the probability of infection, although infection cannot be excluded solely on this basis. ESR ESR may provide complementary evidence, particularly in chronic inflammatory processes, but should not be interpreted independently. Procalcitonin PCT should not be used to exclude implant infection because of its low sensitivity. However, substantial PCT elevation in the appropriate clinical setting may strengthen suspicion of bacterial infection because of its high specificity. Proposed Diagnostic Approach Clinical suspicion of implant infection ↓ CRP + ESR as initial inflammatory screening ↓ If CRP/ESR are elevated or clinical suspicion remains high ↓ PCT as a supportive rule-in marker ↓ Aspiration and/or deep operative tissue sampling ↓ Microbiology + histopathology + consensus diagnostic criteria Serum biomarkers should therefore guide rather than replace definitive diagnostic investigation. Strengths of the Study 1. Prospective data collection. 2. Direct head-to-head comparison of three commonly accessible biomarkers. 3. Inclusion of both fracture-fixation and arthroplasty-associated implant infection. 4. Use of a biomarker-independent reference standard. 5. Inclusion of ROC analysis and clinically interpretable diagnostic-performance measures. 6. Evaluation in a tertiary-care North Indian orthopaedic population. Limitations • Several limitations should be considered. • First, this was a single-center study with a relatively modest sample size. • Second, fracture-related infections and prosthetic joint infections were analyzed together. Although both are implant-associated infections, their microbiology, biofilm characteristics, and diagnostic thresholds may differ. • Third, PCT concentrations may be particularly low in chronic low-grade infections, potentially reducing its apparent sensitivity. • Fourth, biomarker levels may have been influenced by prior antibiotic exposure or coexisting inflammatory conditions despite exclusion criteria. • Fifth, serial biomarker measurements were not evaluated. • Sixth, organism-specific biomarker responses were not assessed. • Seventh, serum biomarkers were compared with a composite clinical reference standard because no single gold-standard test exists for all forms of orthopaedic implant infection.

• Among CRP, ESR, and procalcitonin, CRP demonstrated the best overall diagnostic performance for early detection of orthopaedic implant-associated infection. • At a threshold of 10 mg/L, CRP provided high sensitivity and a clinically useful negative predictive value. • ESR demonstrated moderate diagnostic performance but was less accurate than CRP. • Serum procalcitonin showed the highest specificity but substantially lower sensitivity, indicating that a normal PCT cannot exclude localized orthopaedic implant infection. • PCT may therefore be most useful as a rule-in adjunct, particularly when interpreted together with CRP and the clinical picture. • No serum biomarker should be used in isolation. Definitive evaluation should continue to integrate clinical assessment, imaging where appropriate, multiple deep-tissue cultures, histopathology, and internationally accepted implant-infection criteria.

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