Comparison of Procalcitonin and C-Reactive Protein for the Diagnosis of Periprosthetic Joint Infection before Revision Total Hip Arthroplasty

Abstract

Objective:

To compare the clinical informative value of procalcitonin (PCT) and C-reactive protein (CRP) serum concentrations in the diagnosis of periprosthetic joint infection (PJI) before revision total hip arthroplasty (THA).

Design and Methods:

We conducted a prospective observational study of 71 consecutive patients (74 hips) undergoing revision THA. Procalcitonin and CRP serum concentrations and white blood cell (WBC) count were measured pre-operatively. Diagnostic accuracy was analyzed by the receiver-operating characteristic (ROC) curve and the area under the curve (AUC).

Results:

The PJI incidence was 35.2% in patients with revision THA. Procalcitonin and CRP serum concentrations and WBC count were statistically higher in the PJI cohort compared with the no PJI cohort (p<0.05). The AUCs for PCT, CRP, and WBC count were 0.851 (95% confidence interval [CI] 0.773–0.929), 0.830 (95% CI 0.751–0.910), and 0.633 (95% CI 0.518–0.747), respectively. Serum PCT and CRP showed a significantly higher diagnostic ability than WBC count (p<0.05). No significant difference was found between serum PCT and CRP (p=0.367).

Conclusion:

Procalcitonin does not offer an advantage over CRP in diagnosing PJI. However, PCT and CRP proved to be more reliable than WBC count.

Total hip arthroplasty (THA) is used most commonly to treat joint failure caused by osteoarthritis, rheumatoid arthritis, avascular necrosis, and traumatic arthritis. In the last 50 y, both the number and the rate of THA increased steadily. Epidemiologic surveys showed that in the United States, the rate of primary THA per 100,000 persons increased by approximately 50% between 1990 and 2002 [1]. Periprosthetic joint infection (PJI) remains one of the most severe complications after THA. The overall incidence of PJI after joint arthroplasty is estimated to be 0.7% [2]. For THA, the incidence of infection was 1.63% within 2 y and 0.59% between 2 y and 10 y [3]. The consequences of PJI can result in decreased knee or hip function and diminished patient quality of life, and lead to implant failure that necessitates revision arthroplasty.

C-reactive protein (CRP) is the first-found acute phase protein, which develops in a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignant disease; and tissue injury or necrosis [4]. Serum CRP concentration is a sensitive marker of inflammation. In normal subjects concentrations are usually below 3 mcg/mL, but may increase to 10 mcg/mL in association with bacterial infections [4]. The CRP concentration also had excellent diagnostic test performance for infection before revision total knee arthroplasty, with a sensitivity of 0.91, specificity of 0.86, positive likelihood ratio of 6.89, and accuracy of 0.88) [5]. The American Academy of Orthopedic Surgeons Clinical Practice Guideline identified serum CRP value greater than 10 mg/L as one of the four thresholds for PJI diagnosis, along with abnormal erythrocyte sedimentation rate, synovial white blood cell (WBC) count, or synovial neutrophil differential percentage [6].

Procalcitonin (PCT), composed of 116 amino acids, is produced by parafollicular cells of the thyroid and by the neuroendocrine cells of the lung and the intestine. The concentrations of PCT in the blood stream of healthy individuals is below the limit of detection (10 pg/mL) of clinical assays [7]. The concentations of PCT increases in response to a pro-inflammatory stimulus, especially of bacterial origin. Numerous studies have shown PCT to be a sensitive marker of bacterial infection [8 –10]. Many studies evaluate PCT as a diagnostic tool and compare it with CRP. A systematic review and meta-analysis showed that PCT concentration was more sensitive (88% [95% confidence interval {CI}, 80%–93%] versus 75% [95% CI, 62%–84%]) and more specific (81% [95% CI, 67%–90%] versus 67% [95% CI, 56%–77%]) than CRP concentration for differentiating bacterial from non-infective causes of inflammation [11]. Therefore, we assumed that serum PCT had better diagnostic ability for PJI than serum CRP. The purpose of the present study was to assess the diagnostic value of serum PCT concentration compared with CRP concentration in the identification of PJI before revision THA.

Patients and Methods

Study design and inclusion criteria

This prospective observational study was conducted from January 2010 to June 2013. All patients with a THA needing re-operation for failure were eligible. Patients were excluded with chronic inflammatory diseases, any autoimmune disorder, coronary heart disease, and active cancer. The study protocol was approved by the human research ethics committee of our hospital, and the included patients provided written informed consent.

Patients

Our study recruited 71 patients (74 hips), which included 22 males (23 hips) and 49 females (51 hips) with a mean age of 65 y (range, 36–83 y).

Definitions of PJI

The final diagnosis of PJI required two of the following three criteria to be met: At least one positive culture on solid medium grown from intra-operative specimens; purulence surrounding the prosthesis observed at the time of debridement or removal of the prosthesis; acute inflammation consistent with infection present during histopathologic examination [12].

Laboratory tests

Approximately 5 mL of blood was obtained on the day of revision at 7:00 am. White blood cell count was quantified immediately by the hospital laboratory using an automated cell analyzer (XE 20100, Sysmex, Japan). The remaining 3 mL of blood was centrifuged for 10 min at 4°C; the separated serum was stored at −20°C and was used later to determine PCT and CRP concentrations. Procalcitonin was measured by immunochromatography (Brahms Diagnostika, Berlin, Germany). C-reactive protein was measured by an immunoturbidimetric assay (Vitros 950 analyzer, Rochester, NY).

Statistical analysis

Continuous variables were compared using the Mann-Whitney U non-parametric test. Categorical variables were compared with χ² test. Receiver–operating characteristic (ROC) curves and the areas under the curve (AUC) were determined for PCT, CRP, and WBC. The areas under the ROC curves were compared using the z statistic. The best cutoff value was defined as the test result with the highest sensitivity and specificity and that lay closest to the left upper corner of the curve. All p values were two-tailed. Statistical significance was defined as p<0.05. Statistical analyses were performed using SPSS version 17 (IBM Inc., Armonk, NY).

Results

General characteristics

Among the 71 included patients (74 hips), 25 patients (26 hips) were diagnosed with PJI. The PJI incidence was 35.2% in patients (35.1% for hips) with revision THA. The PJI and non-PJI cohorts did not differ statistically in terms of demographics with no difference in age (p=0.205), gender (p=0.688), and body mass index (p=0.246; Table 1). However, there was a statistically significant difference in the median serum PCT concentrations between the two cohorts (p=0.021). There was also a statistically significant difference for serum CRP (p=0.005) and WBC count (p=0.031) between the two cohorts (Table 1 and Fig. 1).

FIG. 1.

Serum procalcitonin (PCT) and C-reactive protein (CRP) concentrations, and white blood cell (WBC) counts in patients with and without periprosthetic joint infection (PJI). (A) Serum PCT. (B) Serum CRP. (C) WBC count.

Table 1.

Demographic Data and Serum Markers for the Study Population

	PJI (n=25)	No PJI (n=46)	p
Age (y)	67 (48–83)	62 (36–79)	0.205
Gender (male/female)	7/18	15/31	0.688
BMI (kg/m²)	29.2 (23.1–35.7)	28.4 (22.4–35.2)	0.246
PCT (ng/mL)	5.6 (0.3–19.8)	0.3 (0–5.1)	0.021
CRP (mg/L)	81.2 (10.5–187.2)	8.1 (2.6–51.1)	0.005
WBC (×10⁹/L)	13.5 (9.4–15.4)	7.1 (4.2–11.6)	0.031

BMI=body mass index; PJI=periprosthetic joint infection; PCT=procalcitonin; CRP=C-reactive protein; WBC=white blood cell count.

Diagnostic ability

The AUCs for serum PCT, CRP, and WBC count for diagnosis of PJI before revision THA were 0.851 (95% CI 0.773–0.929, p<0.001), 0.830 (95% CI 0.751–0.910, p<0.001), and 0.633 (95% CI 0.518–0.747, p=0.030), respectively. No significant difference of diagnostic ability was found between serum PCT and CRP concentrations (p=0.367, z=0.714). However, serum PCT and CRP showed significantly higher diagnosis ability than WBC count, the p values were 0.002 (z=3.094) and 0.006 (z=2.773), respectively. The diagnostic ability for these serum markers are shown in Table 2, and the ROC curves are shown in Figure 2.

FIG. 2.

Receiver-operating characteristic (ROC) curves comparing markers' ability to detect periprosthetic joint infection (PJI) before revision total hip arthroplasty (THA).

Table 2.

Diagnosis Ability of Serum Procalcitonin, C-Reactive Protein, and White Blood Cell Count for Detecting Periprosthetic Joint Infection Before Total Hip Arthroplasty

	ROC				Cutoff
Markers	AUC	SE	95% CI	p	Cutoff	TP	FP	FN	TN	Sen	Spe	+LR	−LR
PCT	0.851	0.040	0.773–0.929	<0.001	0.5 ng/mL	20	12	5	34	0.800	0.739	3.04	0.27
CRP	0.830	0.041	0.751–0.910	<0.001	15 mg/L	19	13	6	33	0.760	0.717	2.69	0.33
WBC	0.633	0.058	0.518–0.747	0.003	10.5×10⁹/L	16	21	9	25	0.640	0.543	1.40	0.66

PCT=procalcitonin; CRP=C-reactive protein; WBC=white blood cell count; ROC=receiver–operating characteristic curves; AUC=areas under the curve; SE=standard error; TP=true-positive; FP=false-positive; FN=false-negative; TN=true-negative; Sens=sensitivity; Spec=specificity; +LR=positive likelihood ratio; −LR=negative likelihood ratio.

For serum PCT, the optimum cutoff was >0.5 ng/mL, resulting in a sensitivity of 0.800 and a specificity of 0.739. For serum CRP, the optimum cutoff was >15 mg/L, resulting in a sensitivity of 0.760 and a specificity of 0.717. For WBC count, the optimum cutoff was >10.5×10⁹/L, resulting in a sensitivity of 0.640 and a specificity of 0.543 (Table 2).

Discussion

Our results demonstrate that serum PCT concentrations can diagnosis PJI before revision THA. Furthermore, comparison of serum PCT concentration serum CRP demonstrates no significant difference of diagnostic ability for PJI (p=0.367, z=0.714). These results show PCT measurements do not offer an advantage over CRP, but PCT measurements provide another sensitive marker for diagnosis of PJI. Our study also found serum PCT and CRP concentrations showed significantly better diagnostic ability than WBC count (p<0.05). These results support the view of some authors that the serum WBC count has a minimal role in identifying patients with PJI [13,14].

Serum PCT and CRP concentration can be affected by many factors. In our study, we excluded patients with chronic inflammatory diseases, any autoimmune disorder, coronary heart disease, and active cancer. Procalcitonin and CRP concentrations also can be affected by operations. Pulido et al. [2] reported that PJI can be classified as 31% acute or early infection, 56% chronic late infection, and 13% acute hematogenous infection. It seems that our observation may not be applicable in acute PJI after arthroplasty.

Test combination is a good way to improve diagnostic ability. In the study of Schinsky et al., [12], the diagnostic accuracy of a single elevated erythrocyte sedimentation rate (ESR) >30 mm/h, elevated CPR >10 mg/dL, and synovial fluid WBC count >4200 WBC/mL were 57% (50%–64%), 78% (72%–84%), and 90% (86%–94%), respectively; when combined, elevated ESR or CRP, >9,000 WBC/mcL, the diagnostic accuracy increased to 98% (92%–100%) [12]. In our study, we did not combine serum PCT with CRP for PJI diagnosis. In Figure 2, the ROCs of PCT and CRP can be seen to have similar characteristics. Procalcitonin and CRP have similar responses to inflammation. Thus, combined serum PCT and CRP concentrations will not improve the diagnostic ability for PJI. Further study is needed to find the marker combined with PCT to improve diagnostic ability.

There are some limitations to our study. First, there is still no gold standard for comparison in diagnosing PJI. We used the standard based on intra-operative culture, gross purulence, or a final histopathologic result. However, intra-operative cultures have also been fraught with sampling errors and substantial false-positive rates [15]. This may result in bias for assessing the diagnostic accuracy. Second, many studies have shown biomarkers in synovial fluid have high diagnostic ability for PJI [16 –18]. Our study was only designed to compare serum PCT and CRP. Third, we only recruited 71 patients to the study, which was a small sample size.

In conclusion, PCT measurements do not offer an advantage over CRP measurements for prediction PJI before revision THA. However, PCT and CRP proved to be more reliable than WBC count.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Kurtz

, Mowat

, Ong

, et al. Prevalence of primary and revision total hip and knee arthroplasty in the United States from 1990 through 2002. J Bone Joint Surg Am, 2005; 87:1487–1497.

Pulido

, Ghanem

, Joshi

, et al. Periprosthetic joint infection: The incidence, timing, and predisposing factors. Clin Orthop Relat Res, 2008; 466:1710–1715.

Ong

, Kurtz

, Lau

, et al. Prosthetic joint infection risk after total hip arthroplasty in the Medicare population. J Arthroplasty, 2009; 24:105–109.

Black

, Kushner

, Samols

. C-reactive Protein. J Biol Chem, 2004; 279:48487–48490.

Greidanus

, Masri

, Garbuz

, et al. Use of erythrocyte sedimentation rate and C-reactive protein level to diagnose infection before revision total knee arthroplasty. A prospective evaluation. J Bone Joint Surg Am, 2007; 89:1409–1416.

Parvizi

, Della Valle

. AAOS Clinical Practice Guideline: Diagnosis and treatment of periprosthetic joint infections of the hip and knee. J Am Acad Orthop Surg, 2010; 18:771–772.

Dandona

, Nix

, Wilson

, et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab, 1994; 79:1605–1608.

Reinhart

, Karzai

, Meisner

. Procalcitonin as a marker of the systemic inflammatory response to infection. Intensive Care Med, 2000; 26:1193–1200.

Gendrel

, Bohuon

. Procalcitonin as a marker of bacterial infection. Pediatr Infect Dis J, 2000; 19:679–687.

10.

Ugarte

, Silva

, Mercan

, et al. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med, 1999; 27:498–504.

11.

Simon

, Gauvin

, Amre

, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: A systematic review and meta-analysis. Clin Infect Dis, 2004; 39:206–217.

12.

Schinsky

, Della Valle

, Sporer

, et al. Perioperative testing for joint infection in patients undergoing revision total hip arthroplasty. J Bone Joint Surg Am, 2008; 90:1869–1875.

13.

Zmistowski

, Restrepo

, Huang

, et al. Periprosthetic joint infection diagnosis: A complete understanding of white blood cell count and differential. J Arthroplasty, 2012; 27:1589–1593.

14.

Toossi

, Adeli

, Rasouli

, et al. Serum white blood cell count and differential do not have a role in the diagnosis of periprosthetic joint infection. J Arthroplasty, 2012; 27:51–54.e1.

15.

Padgett

, Silverman

, Sachjowicz

, et al. Efficacy of intraoperative cultures obtained during revision total hip arthroplasty. J Arthroplasty, 1995; 10:420–426.

16.

Fink

, Makowiak

, Fuerst

, et al. The value of synovial biopsy, joint aspiration and C-reactive protein in the diagnosis of late peri-prosthetic infection of total knee replacements. J Bone Joint Surg Br, 2008; 90:874–878.

17.

Dinneen

, Guyot

, Clements

, et al. Synovial fluid white cell and differential count in the diagnosis or exclusion of prosthetic joint infection. Bone Joint J, 2013; 95-B:554–557.

18.

Fink

, Gebhard

, Fuerst

, et al. High diagnostic value of synovial biopsy in periprosthetic joint infection of the hip. Clin Orthop Relat Res, 2013; 471:956–964.