Abstract
Background
Some patients with early periprosthetic joint infection (PJI) can be treated successfully using open débridement with polyethylene exchange rather than two-stage revision; however, the challenge is to diagnose PJI early. In late infection, C-reactive protein (CRP) and interleukin-6 (IL-6) are elevated, but shortly after surgery, CRP is difficult to interpret because it may be elevated even in the absence of infection, and we know little about the normal trajectory of IL-6 immediately after arthroplasty. If a deviation of biomarkers from their normal trajectory is seen, it may help guide the clinician toward early knee aspiration.
Questions/purposes
We studied the normal trajectories of IL-6 and CRP in the immediate hours and days after uncomplicated TKA and examined whether one or the other normalizes more quickly.
Methods
We studied serum IL-6 and CRP levels in 50 patients undergoing primary TKA at five time points: 12 hours preoperatively and postoperatively at 12 hours, 48 hours, 4 days, and 2 weeks. One surgeon operated on all patients using the same approach and postoperative management. The same laboratory methods were used each time. Results are presented as median and range. Repeated-measures analysis was done using Friedman’s (nonparametric) test. No patient showed any clinical sign of infection during our study period. All patients were followed up until 1 year with no evidence of infection and good knee scores.
Results
IL-6 showed a sharp rise from its baseline with a preoperative median value of 6 pg/mL (range, 3-17 pg/mL) to a peak of median value of 133 pg/mL (range, 15-359 pg/mL) at 12 hours postoperatively. At 48 hours, IL-6 had declined to a median value of 82 pg/mL (range, 12-309 pg/mL). At 4 days, it had further declined to a median value of 22 pg/mL (range, 5-67 pg/mL). At 2 weeks, IL-6 reached a median value of 7 pg/mL (range, 3-14 pg/mL), which was not different from the baseline median value with the numbers available (p = 0.455). CRP showed a gradual rise from its baseline preoperative median value of 2 mg/L (range, 1-17 mg/L) to a median value of 15 mg/L (range, 2-111 mg/L) at 12 hours postoperatively, which peaked at 48 hours to a median value of 125 mg/L (range, 22-247 mg/L). At 4 days postoperatively, CRP levels had declined to a median value of 69 mg/L (range, 21-234 mg/L). At 2 weeks, CRP had reached a median value of 12 mg/L (range, 1-72 mg/L), which was still higher than the baseline median value with available numbers (p < 0.001).
Conclusions
We found that after uncomplicated TKA, IL-6 showed a sharp rise to peak at 12 hours, then fell rapidly to near baseline levels by 4 days and returned to the baseline level at 2 weeks. CRP showed a gradual rise to peak at 48 hours, then fell gradually, remaining elevated at 4 days and higher than baseline level at 2 weeks. Future studies can help define more definitive thresholds for IL-6 and CRP; ideally, these should derive from large, multicenter studies. With such data, any deviation from a known normal trajectory can facilitate a quicker decision to perform knee aspiration to diagnose early PJI more promptly.
Level of Evidence
Level III, diagnostic study.
Introduction
Early periprosthetic joint infection (PJI) after TKA is common and serious. However, when it is diagnosed promptly, it can be managed in many patients with a smaller procedure (open débridement and polyethylene exchange) rather than the two-stage revision procedure typically performed for late PJI. Thus, prompt diagnosis of early PJI is imperative, but the clinical presentation of early PJI may be nonspecific and challenging to diagnose. Objective data are needed and knee aspiration is performed to confirm infection. The simple, serologic tests of total and differential count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) constitute the first line of investigation, which can guide the clinician toward early aspiration when indicated.
Although these serologic tests generally have good sensitivity, they have low specificity [1]. CRP has an established role in assessing inflammation after TKA [2, 8, 9, 11] but is hard to interpret for early PJI because it can be elevated for as long as 3 months after surgery even in the absence of infection [10]. Studies have established that interleukin-6 (IL-6), a major endogenous protein mediator of the acute phase response postsurgery, induces CRP synthesis by hepatocytes [5, 7]. Thus, one would expect a rise in serum IL-6 before the CRP level rises and it can be considered as an early biomarker for postsurgery inflammation; studies also show that IL-6 levels are increased in late PJI [3, 4]. Unfortunately, little is known about its normal curve in the hours and days immediately after surgery. It would be useful to know how the two common biomarkers, IL-6 and CRP, rise and return to normal in the days after surgery and whether one or the other normalizes more quickly.
We therefore undertook this prospective study in 50 patients undergoing primary TKA for osteoarthritis to (1) define the normal temporal pattern (trajectory) of IL-6; and (2) define the normal temporal pattern of CRP over a 2-week period. We present our results at five time points, namely 12 hours before surgery and postsurgery at 12 hours, 48 hours, 4 days, and 2 weeks. We have attempted to determine whether IL-6 and CRP levels returned to baseline during this study period.
Patients and Methods
After obtaining approval from our institution’s ethical committee, we prospectively enrolled patients undergoing primary TKA between March and October 2016 for this study. Written informed consent was obtained from the patients before their participation in the study. The expenditure for the entire set of laboratory tests for 50 patients was waived by the institution where the TKAs were performed.
Between March 2016 and October 2016, 55 consecutive patients underwent primary TKA. We excluded patients with comorbid conditions known to affect serum IL-6 concentrations such as inflammatory arthritis or autoimmune disorders, a history of cancer, or long-term steroid intake. This resulted in the exclusion of five patients (three with inflammatory arthritis, one with prostate cancer, and one patient with polymyalgia rheumatica being treated with oral steroids), leaving 50 patients for our study.
Patient age ranged from 48 to 85 years (mean, 69 years); body mass index (BMI) ranged from 20 to 48 kg/m2 (mean, 31 kg/m2). There were 43 women (86%) and seven men (14%). The same surgeon performed all the primary TKAs, and all patients received regional anesthesia. All patients underwent a midvastus approach. Tourniquets were used to create a bloodless surgical field and computer-assisted navigation was used in all patients. Periarticular infiltration, comprising bupivacaine, ketorolac, and epinephrine, and patient-controlled analgesia with morphine were used for pain management along with parenteral/oral paracetamol and diclofenac suppositories. Patients were mobilized on the same day of surgery and drains were removed after 20 to 24 hours. Patients received intravenous antibiotics for 36 hours and deep vein thrombosis prophylaxis in the form of ankle-foot pump exercises, low-molecular-weight heparin, and compression stockings. All patients were discharged 5 days postoperatively.
Along with routine white blood cell count and ESR, the CRP and serum IL-6 were measured 12 (± 1) hours before surgery and after surgery at 12 (± 1) hours, 48 (± 2) hours, 4 days (± 2 hours), and 2 weeks (± 6 hours). All the markers were assessed in the same laboratory at each point. Assessment of serum IL-6 in each patient was done using the electrochemiluminescence immunoassay (Cobas E601 analyser; Roche Diagnostics GmbH, Mannheim, Germany) (normal range, 0–7 pg/mL). Quantitative assay of CRP in each patient was done using an immunoturbidometric assay (Cobas analyser; Roche Diagnostics GmbH) (normal value < 5.0 mg/L). Patients were discharged after their 4-day tests were completed and called for followup at 2 weeks. All patients were followed up for a minimum of 1 year. New Knee Society Score (NKSS) was administered preoperatively and at 3 months and 12 months postoperatively.
All 50 patients had the complete set of tests done, as required for the study, and all patients completed 1-year followup. None of the patients developed infection and the clinical improvement was satisfactory. Normal NKSS ranges from 0 to 255 points; a higher score represents better knee status. In our patients, the preoperative NKSS was at a median value of 96 (interquartile range [IQR], 82-113) postoperatively, at 3 months 169 (IQR, 153-191), and at 1 year, it was a median of 191 (IQR, 167-206), suggesting improved knee status with time.
We analyzed collected data with SPSS for Windows, Version 15.0 (SPSS Inc, Chicago, IL, USA). The values of both IL-6 and CRP at the five points were displayed as box plots to reveal the medians, first and third quartiles, and the Tukey whiskers using software SAS 9.2 (SAS Institute Inc, Cary, NC, USA). The values beyond the whiskers were considered outliers. Normality test (Shapiro-Wilk test) failed; thus, Friedman’s one-way repeat-measures analysis of variance was applied, which gave p < 0.001 for both IL-6 and CRP. Post hoc Dunnett’s test, which is an extension of the Friedman repeated-measures test, compared each pairwise data to find which pair differed from baseline.
Results
Trend of IL-6
Our IL-6 results showed a sharp rise in its value to peak as early as 12 hours postsurgery, which then declined to reach near baseline levels at 4 days. By 2 weeks, IL-6 values returned to baseline levels (Fig. 1). The preoperative baseline median value was 6 pg/mL (range, 3-17 pg/mL) (Table 1). At 12 hours postoperatively, the IL-6 levels had risen to their peak median value of 133 pg/mL (range, 15-359 pg/mL). At 48 hours, the IL-6 levels had decreased to a median value of 82 pg/mL (range, 12-309 pg/mL). At 4 days, there was a further drop to a median level of 22 pg/mL (range, 5-67 pg/mL). At 2 weeks, the IL-6 level reached a median value of 7 pg/mL (range, 3-14 pg/mL), which was not different from the preoperative median value with the numbers available (p = 0.455) (Table 2).
Fig. 1.
Trend of IL-6 from preoperative to 2 weeks postoperatively is shown. “X” represents mean, transverse line represents median, the bars represent the first to the third quartile, whiskers represent range, and dots represent the outliers.
Table 1.
IL-6 and CRP levels over the study period
Table 2.
Trend of IL-6 and CRP: comparison of baseline and postoperative levels
Trend of CRP
Our CRP results showed its value peaking at 48 hours postsurgery, which then declined gradually, remaining higher than baseline levels at 4 days. At 2 weeks, CRP values had still not reached baseline levels (Fig. 2). The preoperative baseline median CRP value was 2 mg/L (range, 1-17 mg/L) (Table 1). At 12 hours postoperatively, the CRP values rose to a median value of 15 mg/L (range, 2-111 mg/L). By 48 hours after TKA, the CRP level had further increased to a peak median value of 125 mg/L (range, 22-247 mg/L). At 4 days postoperatively, their levels had declined to a median value of 69 mg/L (range, 21-234 mg/L). At 2 weeks, CRP levels remained elevated at a median value of 12 mg/L (range, 1-72 mg/L), which was different from the preoperative median value with the numbers available (p < 0.001) (Table 2).
Fig. 2.
Trend of CRP from preoperative to 2 weeks postoperatively is shown. “X” represents mean, transverse line represents median, the bars represent first to the third quartile, whiskers represent range, and dots represent the outliers.
Discussion
Early PJI is common after TKA and if managed quickly, the prognosis is good. Treatment of early PJI is less involved and simpler, in that the surgeon can opt for open débridement and polyethylene exchange, as compared with late PJI, which generally calls for a two-stage revision. Thus, it is crucial to diagnose early PJI as quickly as possible. Whenever clinically suspected, simple serologic tests for inflammatory biomarkers can be helpful and diagnosis is confirmed by knee aspiration and culture. CRP has an established role in assessing inflammation after surgery but is hard to interpret shortly in the days and weeks immediately after arthroplasty, because it can be elevated for as long as 3 months even in the absence of infection [1]. IL-6 induces CRP synthesis [7] and thus is expected to rise before CRP rises. IL-6 levels are known to be elevated in late PJI [3, 4], but little is known about its normal trajectory in the days immediately after surgery [6, 12]. We undertook this prospective study to know how the two common biomarkers, IL-6 and CRP, rise and return to normal in the hours and days immediately after surgery and to see whether one or the other normalizes more quickly.
Our study has several limitations. First, both IL-6 and CRP are reported to be sensitive markers but have low specificity [1]. Their levels are indicators of inflammatory activity and they may be high even in the absence of infection. We think that being simple tests, their usefulness is the first line of investigation when clinical suspicion of early infection arises. If their levels are elevated, it may provide a stronger indication to perform early knee aspiration to confirm or rule out infection so there is no delay in treatment. Second, the study population was not controlled for age, sex, BMI, and comorbidities such as diabetes mellitus, hypertension, or thyroid disorders. However, no studies of which we are aware suggest that these affect IL-6 response. We excluded patients with conditions known to increase baseline interleukin levels such as chronic inflammatory conditions, a history of cancer, and long-term steroid intake [7]. A total of 15 patients in our study received intraoperative steroids, and this should be considered in interpreting our findings. Third, all our study patients were free of complications (including infection) for 1 year, so we cannot comment on the value of these tests in recognition of infection. Infections after TKA are rare, so we think that to determine definitive thresholds for these biomarkers in all patient groups, future large, multicenter studies are needed.
Studies have already established that IL-6 levels are elevated in patients with late PJI after TKA [3, 4]. With its usefulness established for late PJI, IL-6 is likely to be useful in the diagnosis of acute PJI also; but to our knowledge, there is little evidence about the normal trend of IL-6 in the immediate perioperative period after uncomplicated TKA. Honsawek et al. [6], in their study of 49 patients undergoing primary TKA, measured IL-6 levels 24 hours postoperatively and thereafter at 2-, 6-, 14-, and 26-week followup visits. The authors showed that IL-6 values were highest at 24 hours. The drawback was that their study did not show the early peak that occurs as soon as 12 hours after TKA. Also, they measured IL-6 only once, at 24 hours, in the first 2 weeks postoperatively, a period when the levels show a sharp rise and fall between 12 and 96 hours. Wirtz et al. [12] measured IL-6 levels at regular intervals starting from preoperative, immediate postoperative, and thereafter at 6, 12, 24, and 48 hours as well as 3, 4, 5, 6, and 7 days postoperatively in 30 patients. They reported a trend of IL-6 levels rising rapidly in the first 6 hours, then more gradually in the next 6 hours to a peak at 12 hours, and then settling to above baseline levels over the next 4 days. This trend was similar to our study. Although they showed a IL-6 trend in the crucial early period, only 10 of their 30 study patients had TKA; the remainder underwent THA. Additionally, they did not determine the point when IL-6 values returned to baseline levels. Our study established the trend of IL-6 in a larger sample size of 50 patients and at frequent intervals in the crucial immediate postoperative period. We found that IL-6 levels returned to baseline values at 2 weeks.
Several studies have estabished the trend of CRP after TKA [9, 11]. Park et al. [9] in their study of 320, uncomplicated primary TKAs have reported CRP to rise to peak values by 48 hours followed by a fall in the first 2 weeks to reach the normal reference range at 6 weeks and return to preoperative levels at 3 months. White et al. [11], in 13 patients undergoing primary TKA, found CRP levels to peak at 48 to 72 hours postsurgery. These levels returned to normal after discharge from the hospital and at 2 weeks, the levels were still higher than baseline values. Our study shows similar results with peak values at 48 hours, which gradually declined, and at 2 weeks, they were still higher than baseline values.
Our study has demonstrated the normal trajectory of IL-6 and CRP in the immediate hours and days after uncomplicated TKA, but we cannot comment specifically on their value in detecting infection. We have now initiated collecting data of these biomarkers in our patients with the slightest suspicion of early infection. After TKA, infections are rare, so we think that a large, multicenter investigation would be needed to evaluate collective data and establish definitive thresholds for these biomarkers in all patient groups. Future studies could lead to a receiver operating characteristic analysis that might establish a predictive value of IL-6 and CRP in the diagnosis of infection. A deviation of IL-6 values from a known normal trajectory can guide the clinician toward early knee aspiration in patients who may benefit from it.
Acknowledgments
We thank Ketayun Dhanjibhoy MD, Chief of Laboratory Services at Lilavati Hospital and Research Centre, Mumbai, India, for her support with the laboratory tests. We also thank Varsha Patil MSc, Statistics, Independent Consultant, Biostatistics, Navi, Mumbai; Dr P. R. Shreelakshmi, Assistant Professor, SUT Academy of Medical Sciences, Trivandrum; and Dr Dnyaneshwar Gajbhare, Department of Community Medicine, T. N. Medical College, Mumbai, for their valuable statistical analyses.
Footnotes
Each author certifies that neither he, nor any member of his immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.
Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.
Each author certifies that his institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
This work was performed at the Department of Orthopaedics, Lilavati Hospital and Research Centre, Mumbai, India.
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