The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 87, Issue 9

Scientific Articles | September 01, 2005

Serum Interleukin-6 as a Marker of Periprosthetic Infection Following Total Hip and Knee Arthroplasty

Paul E. Di Cesare, MD¹; Eric Chang, BS¹; Charles F. Preston, MD¹; Chuan-ju Liu, PhD¹

¹ Musculoskeletal Research Center, Room 1500, NYU-Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003. E-mail address for P.E. Di Cesare: pedicesare@aol.com

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The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Investigation performed at the Musculoskeletal Research Center, NYU-Hospital for Joint Diseases, New York, NY

The Journal of Bone and Joint Surgery, Incorporated

J Bone Joint Surg Am, 2005 Sep 01;87(9):1921-1927. doi: 10.2106/JBJS.D.01803

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Abstract

Background: The erythrocyte sedimentation rate, the C-reactive protein serum level, and the white blood-cell count are routinely used to diagnose periprosthetic infection. In the present study, the diagnostic accuracy of the interleukin-6 serum level was compared with the accuracy of these standard tests for the evaluation of a group of patients who had had a total hip or total knee arthroplasty and were undergoing a reoperation for the treatment of an infection or another implant-related problem.

Methods: A prospective, case-control study of fifty-eight patients who had had a total hip or knee replacement and were undergoing a reoperation because of an infection (seventeen patients) or another implant-related problem (forty-one patients) was conducted. The serum levels of interleukin-6 and C-reactive protein, the erythrocyte sedimentation rate, and the white blood-cell count were measured. The definitive diagnosis of an infection was determined on the basis of positive histopathological evidence of infection and growth of bacteria on culture of intraoperative specimens. Two-sample Wilcoxon rank-sum (Mann-Whitney) tests were used to determine the presence of a significant difference between patients with and without infection with regard to each laboratory value studied. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of each text were also calculated.

Results: The serum interleukin-6 level, erythrocyte sedimentation rate, and C-reactive protein level were significantly higher in patients who had an infection than in those who did not, both when all patients were considered together and when the total hip arthroplasty and total knee arthroplasty groups were considered separately. With the numbers available, there was no significant difference with regard to the white blood-cell count between patients with and without infection. With a normal serum interleukin-6 level defined as <10 pg/mL, the serum interleukin-6 test had a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1.0, 0.95, 0.89, 1.0, and 97%, respectively.

Conclusions: An elevated serum interleukin-6 level correlated positively with the presence of periprosthetic infection in patients undergoing a reoperation at the site of a total hip or knee arthroplasty. The serum interleukin-6 level is valuable for the diagnosis of periprosthetic infection in patients who have had a total hip or total knee arthroplasty.

Level of Evidence: Diagnostic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Figures in this Article

An assessment for the presence of deep periprosthetic infection is required for the evaluation of a patient who has pain at the site of a joint replacement. Periprosthetic infection should always be suspected as a cause of pain even if there is obvious implant loosening because this diagnosis substantially alters patient management. Chronic periprosthetic infection following total joint arthroplasty is particularly difficult to diagnose if the implant is well fixed and the patient does not present with acute symptoms. While periprosthetic infection following total joint arthroplasty occurs in a small percentage of patients, it has a substantial impact on those who must undergo subsequent procedures, prolonged hospitalization, and a lengthy course of intravenous antibiotics¹; furthermore, it represents a major drain on the resources, including the financial resources, of the health-care system^2,3.

Standard radiographs and the laboratory blood analyses that are used as first-line tests to determine the presence of periprosthetic infection, namely, the erythrocyte sedimentation rate, C-reactive protein serum level, and white blood-cell count, are not consistently reliable⁴. The white blood-cell count is rarely elevated in the presence of a chronic periprosthetic infection^5,6, and both the erythrocyte sedimentation rate and the C-reactive protein level are nonspecific markers of inflammation that may be elevated in association with any of several chronic inflammatory conditions^7,8. The authors of one study concluded that no single laboratory test can accurately detect infection prior to revision arthroplasty⁹.

Accumulating evidence suggests that interleukin-6 (IL-6), a factor produced by monocytes and macrophages that also functions as a hepatocyte-stimulating factor and induces the production of major acute-phase proteins, including C-reactive protein^10-12, may be a valuable marker of infection following major surgery^13-16. Recently, it was established that serum IL-6 levels quickly return to normal after total joint surgery and are not elevated in patients with aseptic loosening¹⁷.

To determine whether assessment of the IL-6 level can be used to detect periprosthetic infection, we studied a series of patients who were undergoing a reoperation at the site of a previous total hip or knee arthroplasty.

Materials and Methods

Materials and Methods | Results | Discussion | References

A prospective case-control study of fifty-eight patients who were undergoing a reoperation at our institution over a twenty-four-month period was performed. The study group included twenty-five men and thirty-three women with a mean age of sixty-three years (range, twenty-five to eighty-seven years). The study was approved by our institutional review board, and the patients gave informed consent. The mean time from the previous procedure until the reoperation was eighty-four months (range, five to 256 months) for all patients, seventy-four months (range, twelve to 168 months) for patients who had an infection, and eighty-seven months (range, five to 256 months) for patients who did not have an infection. All infections were classified as chronic periprosthetic infections. All patients who had an infection were managed with removal of the implant followed by irrigation, débridement, and placement of an antibiotic spacer; all patients who did not have an infection were managed solely with revision of one or more of the total joint components. Patients with chronic inflammatory diseases (for example, rheumatoid arthritis), previous antibiotic treatment prior to surgery, multiple sclerosis, Paget disease of bone, or acquired immune deficiency syndrome were excluded from the study because the IL-6 level has been reported to be elevated in association with these conditions^18-20.

Infection was defined as at least ten polymorphonuclear leukocytes per high-power field on postoperative histologic examination of pathological specimens²¹ and the presence of bacteria on culture of intraoperative specimens obtained before the administration of antibiotics; seventeen patients were classified as having an infection and forty-one were classified as not having an infection. Blood samples were obtained within twenty-four hours before surgery to determine the C-reactive protein level, the IL-6 level, the white blood-cell count, and the erythrocyte sedimentation rate. The erythrocyte sedimentation rate and the white blood-cell count were determined in the hospital clinical laboratory with use of the Westergren technique and the MAXM analyzer (Beckman Coulter, Miami, Florida), respectively. Approximately 3 mL of blood was centrifuged for ten minutes at 4°C; the separated serum was stored at 80°C and was later thawed and used to determine C-reactive protein and IL-6 levels in our laboratory. The C-reactive protein level was determined with use of the High Sensitivity C-Reactive Protein Enzyme Immunoassay Test Kit (BioCheck, Burlingame, California). IL-6 levels were determined with use of an enzyme-linked immunosorbent assay (ELISA) kit (Human IL-6 ELISA Ready-SET-Go; eBioscience, San Diego, California) according to the manufacturer's protocol; these tests can be completed in less than twenty-four hours from the time that the sample is obtained. Briefly, ninety-six-well enzyme-linked immunosorbent assay plates were precoated with monoclonal antibody provided in the kit, and a blocking solution was added to eliminate nonspecific antigen binding. After washing, the wells were incubated with either patient serum or known concentration standards at room temperature. After plate washing, a biotin-labeled detection antibody was added. Following incubation and washing (five times), an avidin-horseradish peroxidase enzyme and color substrate was applied for the detection of binding to the antigen of interest (C-reactive protein or IL-6). The reaction was measured with use of a spectrophotometer at an optical density of 450 nm. A standard curve was developed on the basis of the concentrations of known standards provided. When appropriate, samples were diluted with normal saline solution to ensure results that were within the linear range of the standard curves for the assays; this dilution factor was used to correct for the concentration of those factors from the original sample. Samples were run in triplicate, and the mean was obtained. Two-sample Wilcoxon rank-sum (Mann-Whitney) tests were used to determine significant differences (p < 0.05) between patients with and without infection for each group of test values (white blood-cell count, IL-6, C-reactive protein, erythrocyte sedimentation rate). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of each test were also calculated.

Results

Materials and Methods | Results | Discussion | References

Intraoperative cultures were positive for Staphylococcus aureus for eight patients, Staphylococcus epidermidis for five patients, Pseudomonas aeruginosa for two patients, Streptococcus viridans for one patient, and Corynebacterium species for one patient (Table I). The results of the analysis of preoperative serum samples are presented in Figure 1 (in which the case numbers correspond with those in Table I) and Table II. In all categories, the serum IL-6 and C-reactive protein levels and the erythrocyte sedimentation rate were significantly higher in patients with infection than in those without infection (p < 0.05; Table II). With the numbers available, no significant difference in the white blood-cell count was found between patients with and without infection when all patients undergoing reoperation were considered together or when those undergoing total knee and total hip arthroplasty were considered separately; power analyses for the white blood-cell count, with the level of significance (alpha) set to 0.05, yielded 71% power for all total joint arthroplasties.

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TABLE I Index Procedure, Time from Previous Procedure, and Bacterial Species in Patients with Infection

Case	Previous Procedure^*	Time From Previous Procedure (mo)	Organism
1	TKA	25	Staphylococcus aureus
2	THA	80	Streptococcus viridans
3	TKA	58	Pseudomonas aeruginosa
4	TKA	106	Staphylococcus aureus
5	THA	25	Staphylococcus aureus
6	THA	108	Staphylococcus aureus
7	THA	47	Staphylococcus epidermidis
8	THA	48	Staphylococcus aureus
9	THA	111	Staphylococcus epidermidis
10	TKA	12	Staphylococcus epidermidis
11	TKA	13	Staphylococcus epidermidis
12	TKA	148	Staphylococcus aureus
13	TKA	14	Pseudomonas aeruginosa
14	TKA	120	Staphylococcus aureus
15	TKA	119	Staphylococcus epidermidis
16	THA	168	Corynebacterium species
17	TKA	60	Staphylococcus aureus

TKA = total knee arthroplasty, THA = total hip arthroplasty.

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TABLE I Index Procedure, Time from Previous Procedure, and Bacterial Species in Patients with Infection

Case	Previous Procedure^*	Time From Previous Procedure (mo)	Organism
1	TKA	25	Staphylococcus aureus
2	THA	80	Streptococcus viridans
3	TKA	58	Pseudomonas aeruginosa
4	TKA	106	Staphylococcus aureus
5	THA	25	Staphylococcus aureus
6	THA	108	Staphylococcus aureus
7	THA	47	Staphylococcus epidermidis
8	THA	48	Staphylococcus aureus
9	THA	111	Staphylococcus epidermidis
10	TKA	12	Staphylococcus epidermidis
11	TKA	13	Staphylococcus epidermidis
12	TKA	148	Staphylococcus aureus
13	TKA	14	Pseudomonas aeruginosa
14	TKA	120	Staphylococcus aureus
15	TKA	119	Staphylococcus epidermidis
16	THA	168	Corynebacterium species
17	TKA	60	Staphylococcus aureus

TKA = total knee arthroplasty, THA = total hip arthroplasty.

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TABLE II Results of Analysis of Serum Markers

	All Procedures			Total Knee Arthroplasty			Total Hip Arthroplasty
Test^*	Infection	No Infection	Infection	No Infection	Infection	No infection
ESR (mm/hr)
Mean	82.0†	30.4†	86.1†	26.5†	76.1‡	34.3‡
Standard deviation	33.1	25.9	30.7	16.8	38.0	28.2
WBC (×10⁹/L)
Mean	11.1	7.2	9.7	7.5	13.1	7.1
Standard deviation	6.3	1.6	3.4	1.1	8.9	1.8
CRP (mg/L)
Mean	142.0†	6.4†	179.0†	7.9†	89.1†	5.9†
Standard deviation	145.3	7.4	148.5	9.7	132.8	6.5
IL-6 (pg/mL)
Mean	50.3†	3.2†	59.3†	2.2†	37.6†	3.4†
Standard deviation	40.9	3.6	43.0	1.7	37.0	4.0

^*ESR = erythrocyte sedimentation rate, WBC = white blood-cell count, CRP = C-reactive protein serum level, IL-6 = interleukin-6 serum level. †p < 0.01. ‡p. <0.05.

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TABLE II Results of Analysis of Serum Markers

	All Procedures			Total Knee Arthroplasty			Total Hip Arthroplasty
Test^*	Infection	No Infection	Infection	No Infection	Infection	No infection
ESR (mm/hr)
Mean	82.0†	30.4†	86.1†	26.5†	76.1‡	34.3‡
Standard deviation	33.1	25.9	30.7	16.8	38.0	28.2
WBC (×10⁹/L)
Mean	11.1	7.2	9.7	7.5	13.1	7.1
Standard deviation	6.3	1.6	3.4	1.1	8.9	1.8
CRP (mg/L)
Mean	142.0†	6.4†	179.0†	7.9†	89.1†	5.9†
Standard deviation	145.3	7.4	148.5	9.7	132.8	6.5
IL-6 (pg/mL)
Mean	50.3†	3.2†	59.3†	2.2†	37.6†	3.4†
Standard deviation	40.9	3.6	43.0	1.7	37.0	4.0

^*ESR = erythrocyte sedimentation rate, WBC = white blood-cell count, CRP = C-reactive protein serum level, IL-6 = interleukin-6 serum level. †p < 0.01. ‡p. <0.05.

A threshold laboratory value greater than that presumed to be positive for infection was assigned for the white blood-cell count (11.0 × 10⁹), the erythrocyte sedimentation rate (30 mm/hr), the C-reactive protein level (10 mg/L), and the IL-6 level (10 pg/mL) in order to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of each test. The threshold value for the IL-6 level was based on the fact that, in our distributions of the data on the IL-6 level, the value of 10 pg/mL represented the first percentile for patients with infection and the seventieth percentile for all patients; this value is ten times higher than normal IL-6 levels as reported in the literature^22,23 and approximately three to four times higher than IL-6 levels in our control cohort of patients without infection undergoing revision surgery. As shown in Table III, the IL-6 serum level had the highest accuracy (defined as the sum of true-positive samples and true-negative samples divided by the total number of samples) and, along with the erythrocyte sedimentation rate, the highest sensitivity and negative predictive value of all tests performed.

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TABLE III Sensitivity, Specificity, Positive and Negative Predictive Value, and Accuracy of Serum Markers

Test^*	Sensitivity	Specificity	Positive Predictive Value	Negative Predictive Value	Accuracy
ESR	1.00	0.56	0.49	1.00	69%
WBC	0.47	1.00	1.00	0.82	84%
CRP	0.94	0.78	0.64	0.97	83%
IL-6	1.00	0.95	0.89	1.00	97%

ESR = erythrocyte sedimentation rate, WBC = white blood-cell count, CRP = C-reactive protein serum level, IL-6 = interleukin-6 serum level.

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TABLE III Sensitivity, Specificity, Positive and Negative Predictive Value, and Accuracy of Serum Markers

Test^*	Sensitivity	Specificity	Positive Predictive Value	Negative Predictive Value	Accuracy
ESR	1.00	0.56	0.49	1.00	69%
WBC	0.47	1.00	1.00	0.82	84%
CRP	0.94	0.78	0.64	0.97	83%
IL-6	1.00	0.95	0.89	1.00	97%

ESR = erythrocyte sedimentation rate, WBC = white blood-cell count, CRP = C-reactive protein serum level, IL-6 = interleukin-6 serum level.

Discussion

Materials and Methods | Results | Discussion | References

Interleukin-6 (IL-6) is a 26-kilodalton pleiotropic cytokine that functions as a proinflammatory and anti-inflammatory molecule, a modulator of bone resorption, a promoter of hematopoiesis, and an inducer of plasma-cell development^24-28. IL-6 is produced by stimulated macrophages²⁹ and monocytes when tissue is injured³⁰. The serum IL-6 level in normal individuals is approximately 1 pg/mL^22,23, with slight elevations during the menstrual cycle³¹, modest elevations of up to 10 pg/mL in patients with certain cancers (for example, melanoma)³², and large elevations of 30 to 430 pg/mL for as long as three days after surgery³³.

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Fig. 1: Illustration showing the results of analysis of the erythrocyte sedimentation rate (ESR), white blood-cell count (WBC), serum C-reactive protein level (CRP), and serum IL-6 level (IL-6) for all patients. Open bars pertain to patients with infection, and solid bars pertain to patients without infection.

IL-6 plays an important role in modulating immune function²⁵ as it is a primary stimulator of other acute-phase proteins such as C-reactive protein, serum amyloid A protein³⁰, haptoglobulin, protease inhibitors (for example, a-antitrypsin and a₁-antichymotrypsin), complement factors, and fibrinogen^11,12 and functions to regulate pyrexia by pituitary hormones³⁰. Accumulating evidence indicates that the serum IL-6 level can be a valuable marker of inflammation in association with trauma, sepsis, meningitis, malaria, arthritis, and shock as well as after major cardiac and abdominal surgery^13,16,34-36. Elevated IL-6 levels have been found in association with bacterial meningitis and acute viral infections of the central nervous system^20,37,38. In addition, several investigators have described elevated IL-6 levels in patients with sepsis and documented bacteremia (including neonatal bacterial infection), which in some cases is associated with morbidity and mortality^14-16,39-49. In a study of patients undergoing lung and heart-lung transplantation, elevated IL-6 levels appeared to be indicative of infection, and an abnormally high baseline with several sharp spikes appeared to be indicative of rejection⁵⁰.

The erythrocyte sedimentation rate and the C-reactive protein level are widely used as serum markers for assessing bacterial infection in patients managed with total joint arthroplasty⁵¹. Previous studies have indicated that IL-6 concentrations are associated with inflammatory activity and exhibit more rapid increase and quicker return-to-normal values than either the C-reactive protein level or the erythrocyte sedimentation rate, suggesting that the IL-6 level may be a superior indicator of postoperative inflammatory response^17,51,52. IL-6 levels peak in the first six to twelve hours after surgery and fall back to their baseline range by forty-eight to seventy-two hours postoperatively^10,13,17. After surgery, the erythrocyte sedimentation rate typically increases, with a peak at five to seven days postoperatively, and then slowly decreases to preoperative levels in approximately three months; however, some studies have shown that the erythrocyte sedimentation rate can remain elevated above baseline for as long as one year^4,53-55. C-reactive protein is an acute-phase reactant that is produced by the liver in response to inflammation, infection, and neoplasm^56,57; its serum levels are elevated to their peak values two to three days after surgery and return to normal values approximately three weeks after surgery^51,53,55,58.

One aim of the present study was to determine a threshold serum IL-6 level that, when exceeded, would be consistent with a periprosthetic infection. Kragsbjerg et al.¹³ recommended that an IL-6 level of >50 pg/mL for more than forty-eight hours after an operation should be considered indicative of an acute bacterial infection. While we agree that a level that high is consistent with infection, the infections in the present study were all chronic, without acute signs of infection. On the basis of our data, an IL-6 level of 10 pg/mL has sufficiently high sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of a periprosthetic infection.

Another potential advantage of using the serum IL-6 level is the ability to monitor the infected patient's response to treatment as the IL-6 level typically returns to normal forty-eight to seventy-two hours after the index procedure, whereas the serum C-reactive protein level and the erythrocyte sedimentation rate typically remain elevated over this time-span. It also may be possible to use the serum IL-6 level to diagnose periprosthetic infections in the early postoperative period when the C-reactive protein level and the erythrocyte sedimentation rate are elevated. Since such cases have yet to be studied, threshold serum IL-6 levels need to be determined.

In the present study, serum levels were determined and analyzed preoperatively in patients with and without a suspected infection who were undergoing a reoperation at the site of a previous total joint arthroplasty. IL-6 serum levels were significantly higher (p < 0.01) in patients with an infection than in those without an infection, both among patients who had had a total hip arthroplasty and among those who had had a total knee arthroplasty. Patients who did not undergo a reoperation were not included in this study because definitive data on the presence or absence of infection such as the results of cultures of deep wound specimens and the results of histopathological analysis of tissue specimens were not available; furthermore, previous studies have shown that the serum IL-6 level is not elevated in patients who do not have an infection around the implant¹⁷.

The present study demonstrates that the serum IL-6 level appears to be a more accurate marker than either the erythrocyte sedimentation rate or the C-reactive protein level for the detection of chronic periprosthetic infection. A large multicenter validation study, however, needs to be performed to corroborate these initial findings. On the basis of the results of the present study, we recommend the use of the serum IL-6 level, either alone or in combination with the erythrocyte sedimentation rate and the C-reactive protein level, to test for periprosthetic infection following total hip and total knee arthroplasty. ?

References

Materials and Methods | Results | Discussion | References

Sculco TP. The economic impact of infected total joint arthroplasty. Instr Course Lect.1993;42: 349-51.42349 1993 [PubMed]

Spangehl MJ, Younger AS, Masri BA, Duncan CP. Diagnosis of infection following total hip arthroplasty. Instr Course Lect.1998;47: 285-95.47285 1998 [PubMed]

Hanssen AD, Rand JA. Evaluation and treatment of infection at the site of a total hip or knee arthroplasty. Instr Course Lect.1999;48: 111-22.48111 1999 [PubMed]

Shih LY, Wu JJ, Yang DJ. Erythrocyte sedimentation rate and C-reactive protein values in patients with total hip arthroplasty. Clin Orthop Relat Res.1987;225: 238-46.225238 1987 [PubMed]

Canner GC, Steinberg ME, Heppenstall RB, Balderston R. The infected hip after total hip arthroplasty. J Bone Joint Surg Am.1984;66: 1393-9.661393 1984

Itasaka T, Kawai A, Sato T, Mitani S, Inoue H. Diagnosis of infection after total hip arthroplasty. J Orthop Sci.2001;6: 320-6.6320 2001 [CrossRef]

Du Clos TW, Mold C. C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res.2004;30: 261-77.30261 2004 [PubMed][CrossRef]

Zlonis M. The mystique of the erythrocyte sedimentation rate. A reappraisal of one of the oldest laboratory tests still in use. Clin Lab Med.1993;13: 787-800.13787 1993 [PubMed]

Virolainen P, Lahteenmaki H, Hiltunen A, Sipola E, Meurman O, Nelimarkka O. The reliability of diagnosis of infection during revision arthroplasties. Scand J Surg.2002;91: 178-81.91178 2002 [PubMed]

Baigrie RJ, Lamont PM, Kwiatkowski D, Dallman MJ, Morris PJ. Systemic cytokine response after major surgery. Br J Surg.1992;79: 757-60.79757 1992 [PubMed][CrossRef]

Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J.1990;265: 621-36.265621 1990 [PubMed]

Andus T, Geiger T, Hirano T, Northoff H, Ganter U, Bauer J, Kishimoto T, Heinrich PC. Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-beta 2) regulates beta-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett.1987;221: 18-22.22118 1987 [PubMed][CrossRef]

Kragsbjerg P, Holmberg H, Vikerfors T. Serum concentrations of interleukin-6, tumour necrosis factor-alpha, and C-reactive protein in patients undergoing major operations. Eur J Surg.1995;161: 17-22.16117 1995

Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg.1992;215: 356-62.215356 1992 [PubMed][CrossRef]

van Deuren M, Dofferhoff AS, van der Meer JW. Cytokines and the response to infection. J Pathol.1992;168: 349-56.168349 1992 [PubMed][CrossRef]

Hack CE, De Groot ER, Felt-Bersma RJ, Nuijens JH, Strack van Schijndel RJ, Eerenberg-Belmer AJ, Thijs LG, Aarden LA. Increased plasma levels of interleukin-6 in sepsis. Blood.1989;74: 1704-10.741704 1989 [PubMed]

Wirtz DC, Heller KD, Miltner O, Zilkens KW, Wolff JM. Interleukin-6: a potential inflammatory marker after total joint replacement. Int Orthop.2000;24: 194-6.24194 2000 [PubMed][CrossRef]

Honda M, Kitamura K, Mizutani Y, Oishi M, Arai M, Okura T, Igarahi K, Yasukawa K, Hirano T, Kishimoto T, Mitsuyasu R, Chermann JC, Tokunaga T. Quantitative analysis of serum IL-6 and its correlation with increased levels of serum IL-2R in HIV-induced diseases. J Immunol.1990;145: 4059-64.1454059 1990 [PubMed]

Vreugdenhil G, Lindemans J, van Eijk HG, Swaak AJ. Elevated serum transcobalamin levels in anaemia of rheumatoid arthritis: correlation with disease activity but not with serum tumour necrosis factor alpha and interleukin 6. J Intern Med.1992;231: 547-50.231547 1992 [PubMed][CrossRef]

Frei K, Leist TP, Meager A, Gallo P, Leppert D, Zinkernagel RM, Fontana A. Production of B cell stimulatory factor-2 and interferon gamma in the central nervous system during viral meningitis and encephalitis. Evaluation in a murine model infection and in patients. J Exp Med.1988;168: 449-53.168449 1988 [PubMed][CrossRef]

Lonner JH, Desai P, Dicesare PE, Steiner G, Zuckerman JD. The reliability of analysis of intraoperative frozen sections for identifying active infection during revision hip or knee arthroplasty. J Bone Joint Surg Am.1996;78: 1553-8.781553 1996 [PubMed]

D'Auria L, Bonifati C, Mussi A, D'Agosto G, De Simone C, Giacalone B, Ferraro C, Ameglio F. Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared with healthy subjects and correlate with disease activity. Eur Cytokine Netw.1997;8: 383-7.8383 1997

Yamamura M, Yamada Y, Momita S, Kamihira S, Tomonaga M. Circulating interleukin-6 levels are elevated in adult T-cell leukaemia/lymphoma patients and correlate with adverse clinical features and survival. Br J Haematol.1998;100: 129-34.100129 1998 [PubMed][CrossRef]

Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A, Tsunasawa S, Sakiyania F, Matsui H, Takahura Y, Tamiguchi T, Kishimoto T. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature.1986;324: 73-6.32473 1986 [PubMed][CrossRef]

Goodman SB, Huie P, Song Y, Schurman D, Maloney W, Woolson S, Sibley R. Cellular profile and cytokine production at prosthetic interfaces. Study of tissues retrieved from revised hip and knee replacements. J Bone Joint Surg Br.1998;80: 531-9.80531 1998 [PubMed][CrossRef]

Cerutti A, Zan H, Schaffer A, Bergsagel L, Harindranath N, Max EE, Casali P. CD40 ligand and appropriate cytokines induce switching to IgG, IgA, and IgE and coordinated germinal center and plasmacytoid phenotypic differentiation in a human monoclonal IgM+IgD+ B cell line. J Immunol.1998;160: 2145-57.1602145 1998 [PubMed]

Barton BE. IL-6: insights into novel biological activities. Clin Immunol Immunopathol.1997;85: 16-20.8516 1997 [PubMed][CrossRef]

Van Snick J. Interleukin-6: an overview. Annu Rev Immunol.1990;8: 253-78.8253 1990 [PubMed][CrossRef]

Baigrie RJ, Lamont PM, Dallman M, Morris PJ. The release of interleukin-1 beta (IL-1) precedes that of interleukin 6 (IL-6) in patients undergoing major surgery. Lymphokine Cytokine Res.1991;10: 253-6.10253 1991

Kishimoto T. The biology of interleukin-6. Blood.1989;74: 1-10.741 1989 [PubMed]

Angstwurm MW, Gartner R, Ziegler-Heitbrock HW. Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine.1997;9: 370-4.9370 1997 [PubMed][CrossRef]

Mouawad R, Benhammouda A, Rixe O, Antoine EC, Borel C, Weil M, Khayat D, Soubrane C. Endogenous interleukin 6 levels in patients with metastatic malignant melanoma: correlation with tumor burden. Clin Cancer Res.1996;2: 1405-9.21405 1996 [PubMed]

Sakamoto K, Arakawa H, Mita S, Ishiko T, Ikei S, Egami H, Hisano S, Ogawa M. Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine.1994;6: 181-6.6181 1994 [PubMed][CrossRef]

Cruickshank AM, Fraser WD, Burns HJ, Van Damme J, Shenkin A. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci (Lond).1990;79: 161-5.79161 1990 [PubMed]

Pape HC, Remmers D, Grotz M, Kotzerke J, von Glinski S, van Griensven M, Dahlweid M, Sznidar S, Tscherne H. Reticuloendothelial system activity and organ failure in patients with multiple injuries. Arch Surg.1999;134: 421-7.134421 1999 [PubMed][CrossRef]

Pape HC, Schmidt RE, Rice J, van Griensven M, das Gupta R, Krettek C, Tscherne H. Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden. Crit Care Med.2000;28: 3441-8.283441 2000 [PubMed][CrossRef]

Houssiau FA, Bukasa K, Sindic CJ, Van Damme J, Van Snick J. Elevated levels of the 26K human hybridoma growth factor (interleukin 6) in cerebrospinal fluid of patients with acute infection of the central nervous system. Clin Exp Immunol.1988;71: 320-3.71320 1988 [PubMed]

Helfgott DC, Tatter SB, Santhanam U, Clarick RH, Bhardwaj N, May LT, Sehgal PB. Multiple forms of IFN-beta 2/IL-6 in serum and body fluids during acute bacterial infection. J Immunol.1989;142: 948-53.142948 1989

Calandra T, Gerain J, Heumann D, Baumgartner JD, Glauser MP. High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group. Am J Med.1991;91: 23-9.9123 1991 [PubMed][CrossRef]

Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med.1989;169: 333-8.169333 1989 [PubMed][CrossRef]

Waage A, Halstensen A, Shalaby R, Brandtzaeg P, Kierulf P, Espevik T. Local production of tumor necrosis factor alpha, interleukin 1, and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response. J Exp Med.1989;170: 1859-67.1701859 1989 [PubMed][CrossRef]

Dofferhoff AS, Bom VJ, de Vries-Hospers HG, van Ingen J, vd Meer J, Hazenberg BP, Mulder PO, Weits J. Patterns of cytokines, plasma endotoxin, plasminogen activator inhibitor, and acute-phase proteins during the treatment of severe sepsis in humans. Crit Care Med.1992;20: 185-92.20185 1992 [CrossRef]

Buck C, Bundschu J, Gallati H, Bartmann P, Pohlandt F. Interleukin-6: a sensitive parameter for the early diagnosis of neonatal bacterial infection. Pediatrics.1994;93: 54-8.9354 1994 [PubMed]

Doellner H, Arntzen KJ, Haereid PE, Aag S, Austgulen R. Interleukin-6 concentrations in neonates evaluated for sepsis. J Pediatr.1998;132: 295-9.132295 1998 [PubMed][CrossRef]

Krueger M, Nauk MS, Sang S, Hentschel R, Wieland H, Berner R. Cord blood levels of interleukin-6 and interleukin-8 for the immediate diagnosis of early-onset infection in premature infants. Biol Neonate.2001;80: 118-23.80118 2001 [PubMed][CrossRef]

Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med.1993;119: 771-8.119771 1993 [PubMed]

Goldie AS, Fearon KC, Ross JA, Barclay GR, Jackson RE, Grant IS, Ramsay G, Blyth AS, Howie JC. Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. The Sepsis Intervention Group. JAMA.1995;274: 172-7.274172 1995 [PubMed][CrossRef]

Messer J, Eyer D, Donato L, Gallati H, Matis J, Simeoni U. Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection. J Pediatr.1996;129: 574-80.129574 1996 [CrossRef]

Moscovitz H, Shofer F, Mignott H, Behrman A, Kilpatrick L. Plasma cytokine determinations in emergency department patients as a predictor of bacteremia and infectious disease severity. Crit Care Med.1994;22: 1102-7.221102 1994 [PubMed][CrossRef]

Yoshida Y, Iwaki Y, Pham S, Dauber JH, Yousem SA, Zeevi A, Morita S, Griffith BP. Benefits of posttransplantation monitoring of interleukin 6 in lung transplantation. Ann Thorac Surg.1993;55: 89-93.5589 1993 [CrossRef]

White J, Kelly M, Dunsmuir R. C-reactive protein level after total hip and total knee replacement. J Bone Joint Surg Br.1998;80: 909-11.80909 1998 [CrossRef]

Niskanen RO, Korkala O, Pammo H. Serum C-reactive protein levels after total hip and knee arthroplasty. J Bone Joint Surg Br.1996;78: 431-3.78431 1996

Bilgen O, Atici T, Durak K, Karaeminogullari, Bilgen MS. C-reactive protein values and erythrocyte sedimentation rates after total hip and total knee arthroplasty. J Int Med Res.2001;29: 7-12.297 2001

Aalto K, Osterman K, Peltola H, Rasanen J. Changes in erythrocyte sedimentation rate and C-reactive protein after total hip arthroplasty. Clin Orthop Relat Res.1984;184: 118-20.184118 1984 [PubMed]

Moreschini O, Greggi G, Giordano MC, Nocente M, Margheritini F. Postoperative physiopathological analysis of inflammatory parameters in patients undergoing hip or knee arthroplasty. Int J Tissue React.2001;23: 151-4.23151 2001 [PubMed]

Kushner I, Gewurz H, Benson MD. C-reactive protein and the acute-phase response. J Lab Clin Med.1981;97: 739-49.97739 1981

Pepys MB. C-reactive protein fifty years on. Lancet.1981;1: 653-7.1653 1981 [PubMed][CrossRef]

Larsson S, Thelander U, Friberg S. C-reactive protein (CRP) levels after elective orthopedic surgery. Clin Orthop Relat Res.1992;275: 237-42.275237 1992

Topics

erythrocyte sedimentation rate ; hip region ; hip joint ; infection ; c-reactive protein measurement ; interleukin-6 ; knee replacement arthroplasty

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Paul E. Di Cesare, Eric Chang, Charles F. Preston, Chuan-ju Liu; Serum Interleukin-6 as a Marker of Periprosthetic Infection Following Total Hip and Knee Arthroplasty. The Journal of Bone & Joint Surgery. 2005 Sep;87(9):1921-1927.

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