Total hip arthroplasty is one of the most reliable and cost-effective surgical procedures for the treatment of patients with a painful and diseased hip1. A severe complication is infection, which may lead to revision surgery2. Periprosthetic infection is considered one of the most devastating of prosthesis-related complications3 and can result in substantial morbidity and a decline in functional outcome4.
The timely identification and precise localization of a periprosthetic hip infection, including a differentiation from mechanical loosening, is essential to allow the initiation of appropriate medical and surgical therapy5. Unfortunately, assessment of suspected periprosthetic hip infection has thus far not been standardized in a universally accepted diagnostic protocol6. Despite clinical suspicion, physical examination, multiple diagnostic tests, and complex algorithms, an accurate diagnosis remains challenging7-10. A delay in the diagnosis and treatment of a periprosthetic hip infection can have a critical impact on maintaining the prosthesis and joint function.
A variety of imaging techniques such as radiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, leukocyte scintigraphy, or fluorodeoxyglucose positron emission tomography (FDG PET) are used for the evaluation of a patient with a suspected periprosthetic hip infection6,11-15. However, the choice of the most accurate imaging technique and optimal radiopharmaceutical remains controversial12,16. Several authors have reported different diagnostic accuracies using the same imaging technique11,15-21. A literature search revealed no previous systematic review or meta-analysis that provides a total overview of the imaging accuracy for diagnosing periprosthetic hip infection exclusively. The aim of this systematic review and meta-analysis was to obtain an estimate of the diagnostic accuracy of different imaging modalities used for diagnosing periprosthetic hip infection.
Materials and Methods
The imaging modalities that were reviewed for the assessment of periprosthetic hip infection were radiography, ultrasonography, CT, MRI, scintigraphy, and PET.
A computer-aided search of the PubMed and Embase databases was conducted in June 2014 and was updated in April 2015. The search was restricted to primary studies that were written in English. For each database, a specific search strategy was developed (Fig. 1) with an information specialist. Reference lists of the identified studies and relevant reviews were hand-searched for supplementary eligible studies. The search was performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) Statement22.
The following inclusion criteria were used to identify eligible studies: (1) Radiography, ultrasonography, CT, MRI, scintigraphy, or PET had been used to identify suspected periprosthetic hip infections. (2) The study had a valid reference standard of at least 1 positive intraoperative culture, regardless of whether it had been combined with histopathological evidence of acute inflammation of the periprosthetic tissue obtained from surgical debridement or prosthesis removal (highly suggestive evidence) and/or a sinus tract that communicated with the prosthesis (definitive evidence)13,23,24 and/or a clinical follow-up interval of at least 6 months. (3) Adequate details to reconstruct a 2 × 2 contingency table in order to determine that the results of the index tests were provided. Exclusion criteria were (1) nonhuman studies and (2) non-English-language studies. Potential overlap of patient populations when >1 study was by the same author and/or institution was assessed by comparing the patient demographics. The study with the largest number of patients was selected when an overlap of patient populations between studies was observed.
The titles were screened for eligibility by 1 reviewer (S.J.V.) and then were processed for abstract assessment. The titles and abstracts were independently screened and assessed for eligibility in an unblinded standardized manner by 2 reviewers (S.J.V. and O.P.P.T.). Studies considered to be of dubious eligibility were rejected. The final decision on inclusion was made on the basis of the full text of the article.
Methodological Quality Assessment
The criteria list of QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) for evaluating the internal and external validity of diagnostic studies recommended by the Cochrane Screening and Diagnostic Tests Methods Group (srdta.cochrane.org/handbook-dta-reviews) was used for grading the methodological quality of the selected studies25. Evaluation was performed by the 2 reviewers (S.J.V. and O.P.P.T) independently. Internal and external criteria were used for the determination of the methodological limitations and for descriptive purposes.
The 2 reviewers (S.J.V. and O.P.P.T) independently extracted relevant data that included demographic, implant, and index test characteristics. Imaging procedures, image interpretation, and the effects of time after surgery as determined by the publication data (to form subgroups when possible), such as data regarding diagnostic performance indexes (e.g., sensitivity and specificity), were analyzed in detail.
The quality of diagnostic accuracy studies, defined with both the internal and external validity, was assessed with use of the framework provided by QUADAS-2. Studies, however, were not excluded from the systematic review on the basis of quality.
Quantitative Analysis (Meta-Analysis)
For the diagnostic modalities, true-positive, false-positive, true-negative, and false-negative results were derived from a 2 × 2 contingency table. The interpretation criteria with the highest diagnostic accuracy were selected when multiple interpretation sets for the same index test were used. When studies noted results of >1 observer, the first reader’s findings were included. The statistical heterogeneity of the diagnostic odds ratio (DOR) of each imaging index test across studies was tested by the chi-square test (QDOR) for independence with k – 1 degree of freedom (with k indicating the number of studies)26. The Spearman rank correlation coefficient ρ value of the DOR was used in case of heterogeneity in order to measure the correlation between sensitivity and specificity. A ρ value of less than –0.40 suggests that the variation between studies may be explained by different cutoff points, or diagnostic thresholds, on a summary receiver-operating characteristic curve26,27.
Sensitivity and specificity were pooled independently and were weighted by the inverse of the variance, with use of Meta-DiSc software28. The logit-transformed sensitivity, specificity, and corresponding 95% confidence interval (CI) of the index tests were compared with use of z-test statistics. A p value of <0.05 was considered significant.
The search strategy identified 3,451 studies from MEDLINE and 3,344 studies from Embase. The source population was formed by the total of 6,795 studies (including duplicates). In 1,523 studies, overlap was found between the retrieved studies from Embase and MEDLINE. Of the initial 6,795 studies, 6,537 were excluded after analyzing the information provided in the title and abstract.
The full-text articles of the remaining 258 studies were reviewed for eligibility. No other studies were extracted from the reference lists of these studies. There was no disagreement between the reviewers regarding the definitive inclusion of the studies. The reasons for exclusion were that the study was not a clinical diagnostic study (25%), did not describe periprosthetic hip infection (19%), was not written in English (17%), or contained no specified definition of positivity regarding the index test for periprosthetic hip infection (13%); diagnostic imaging was not the main topic (10%); no differentiation was made regarding different prosthetic joint replacements (8%); a 2 × 2 contingency table could not be generated (7%); and there was potential overlap of the patient population (1%). Eventually, 36 studies were included in this review. In general, no differentiation a priori was made for the type of hip implant, the interpretation criteria used for the index test, or the time period between surgery and imaging.
Description of Study Characteristics
A total of 31 of the 36 studies, published between 1988 and 2014, were included for meta-analysis. Of those studies, 12 used FDG PET17,21,29-38, 8 used bone scintigraphy33,35,36,39-43, 6 used leukocyte scintigraphy19,44-48, and 5 used antigranulocyte scintigraphy20,39,49-51. Of these, 7 used combined leukocyte and bone-marrow scintigraphy17,29,34,44,46,52,53, 3 used combined bone-gallium scintigraphy43,45,54, and 3 used combined bone and leukocyte scintigraphy37,42,55. Altogether, a total of 2,434 diagnostic images, 680 (28%) with and 1,754 (72%) without periprosthetic hip infection, were evaluated for 1,753 hip prostheses, 475 (27%) of which were associated with infection. The characteristics of the studies are detailed in the Appendix. Of the 5 studies not included for meta-analysis, 3 studies used radiography, 1 study used ultrasonography, and 1 study used CT (Table I).
Critical Appraisal and Methodological Quality
The Appendix contains data on the internal and external validity and the reproducibility of the included studies.
The external validity showed low concerns with regard to applicability to clinical practice in >85% of the included studies. The internal validity of the included studies showed more concerns with regard to the risk of bias. More than 50% of the included studies did not provide sufficient information on patient selection, reference standard, and flow and timing. The details of the internal and external validity are shown in the Appendix.
Quantitative Analysis (Meta-Analysis)
Pooled estimated results with regard to diagnostic accuracy could not be calculated for radiography, ultrasonography, CT, and MRI because of insufficient available clinical data.
Meta-analysis was performed for bone scintigraphy, leukocyte scintigraphy, and FDG PET. The sensitivity and specificity of the included studies according to the index test and the pooled estimates by random effects analysis are described in the Appendix.
Bone scintigraphy: For the 8 studies (492 hip prostheses) that evaluated bone scintigraphy, the test of homogeneity for the DOR indicated no statistical heterogeneity (QDOR = 6.66, 7 degrees of freedom). The pooled sensitivity and specificity were 80% (95% CI, 72% to 86%) and 69% (95% CI, 64% to 73%), respectively, and the accuracy was 0.71.
Combined bone and gallium scintigraphy: The DOR of the 3 studies (121 hip prostheses) that evaluated bone-gallium scintigraphy was homogeneous (QDOR = 1.23, 2 degrees of freedom). The pooled sensitivity was 59% (95% CI, 42% to 74%), the specificity was 97% (95% CI, 91% to 99%), and the accuracy was 0.86.
Combined bone and leukocyte scintigraphy: For the 3 studies (172 hip prostheses) that evaluated bone-leukocyte scintigraphy, the DOR was homogeneous (QDOR = 3.62, 2 degrees of freedom). The pooled sensitivity and specificity were 77% (95% CI, 55% to 91%) and 95% (95% CI, 90% to 98%), respectively, with diagnostic accuracy of 0.93.
Leukocyte scintigraphy: The DOR of the included 6 studies (404 hip prostheses) that evaluated leukocyte scintigraphy was significantly heterogeneous (QDOR = 11.57, 5 degrees of freedom; p = 0.041). The pooled sensitivity and specificity were 88% and 85%, respectively, with an accuracy of 0.86. Evaluation of potential sources of heterogeneity showed a significant effect of the image review procedure (see Appendix), more specifically, the use of different cutoff points (regression coefficient ρ = –0.543, p = 0.266). One study used a sensitive criterion for a positive leukocyte scan, where any periprosthetic uptake was considered a positive index test44. The exclusion of this study (leaving 5 studies in the analysis) resulted in a homogeneous DOR (QDOR = 3.68, 4 degrees of freedom), and the pooled sensitivity and specificity (334 hip prostheses) were 88% (95% CI, 81% to 94%) and 92% (95% CI, 88% to 96%), with an accuracy of 0.91.
Combined leukocyte and bone marrow scintigraphy: The test of homogeneity for the DOR of the included 7 studies (351 hip prostheses) that evaluated leukocyte-bone marrow scintigraphy indicated no statistical heterogeneity (QDOR = 9.54, 6 degrees of freedom). The pooled sensitivity was 69% (95% CI, 58% to 79%), the specificity was 96% (95% CI, 93% to 98%), and the accuracy was 0.91.
Antigranulocyte scintigraphy: Five studies (169 hip prostheses) evaluated periprosthetic hip infection with antigranulocyte scintigraphy, the QDOR of 5.24 (4 degrees of freedom) was homogeneous. The pooled sensitivity was 84% (95% CI, 70% to 93%) and the specificity was 75% (95% CI, 66% to 82%), with an accuracy of 0.81.
FDG PET: Twelve studies (725 hip prostheses) evaluating FDG PET were included, with a heterogeneous QDOR of 36.28 (11 degrees of freedom, p < 0.0001). The pooled sensitivity and specificity were 83% and 91%, with an accuracy of 0.88. Evaluation of potential sources of heterogeneity showed a significant effect of the image review procedure, more specifically, the use of various diagnostic thresholds (regression coefficient ρ = –0.406, p = 0.191). Most authors used increased uptake in the bone-prosthesis interface, with or without limitation of localization in the neck, head, fistulous tract, or synovial tissue, as the criterion for infection of the index test. Different criteria for positivity were used by 2 studies: 1 study compared uptake in the bone-prosthesis interface with bladder activity36, and 1 study used the stringent criterion that uptake in the bone-prosthesis interface should be more than uptake in the periprosthetic soft tissue, fistulous tract, or synovial tract32. Excluding these 2 studies with exceptional criteria compared with other studies (10 studies), the DOR was homogeneous (QDOR = 10.64, 9 degrees of freedom; p = 0.301). The pooled sensitivity and specificity (n = 666 hip prostheses) were 86% (95% CI, 80% to 90%) and 93% (95% CI, 90% to 95%), respectively, with diagnostic accuracy of 0.90.
Comparison of Techniques
The pooled estimates of the sensitivity and specificity are shown in Figure 2, and a detailed comparison is available in the Appendix.
Bone scintigraphy: Bone scintigraphy combined with gallium or leukocyte scintigraphy significantly improves specificity (p < 0.0001 for both), while bone-gallium scintigraphy significantly decreases sensitivity (p = 0.013).
Leukocyte scintigraphy: Leukocyte scintigraphy, whether combined with bone marrow scintigraphy or not, improves specificity compared with bone scintigraphy alone (p < 0.0001 for both). When leukocyte scintigraphy is combined with bone marrow scintigraphy, no significantly increased specificity was found, but sensitivity decreases significantly (p < 0.0001) compared with leukocyte scintigraphy alone. Leukocyte scintigraphy showed no significant difference compared with bone-leukocyte scintigraphy. Antigranulocyte scintigraphy was significantly less specific compared with leukocyte scintigraphy and leukocyte-bone marrow scintigraphy (p < 0.0001 for both).
FDG PET: Compared with leukocyte scintigraphy alone, FDG PET was not significantly different with regard to sensitivity (p = 0.650) and specificity (p = 0.640). Leukocyte scintigraphy combined with bone-marrow scintigraphy was significantly less sensitive compared with FDG PET (p = 0.002). FDG PET was significantly more specific compared with bone scintigraphy and with antigranulocyte scintigraphy (p < 0.0001 for both).
Imaging techniques have become important modalities for diagnosing periprosthetic joint infection. The results of this meta-analysis revealed that the most accurate, currently used imaging modalities with high specificity in diagnosing periprosthetic hip infection are leukocyte scintigraphy and FDG PET.
Leukocyte scintigraphy has a long history of use for the detection of infections, and the present analysis showed a relatively high accuracy for diagnosing periprosthetic hip infection. However, significant heterogeneity was found among the results of the included studies. The heterogeneity was related to interstudy differences of interpretation criteria. Excluding 1 study that used a sensitive reading procedure resulted in a homogeneous study set. The results of this meta-analysis showed that, when appropriate interpretation criteria are used, leukocyte scintigraphy may be a specific and accurate imaging technique for diagnosing periprosthetic hip infection. Our results suggest that standardized interpretation criteria may be useful for improving the diagnostic performance of leukocyte scintigraphy. Therefore, the results of individual studies should be interpreted with caution.
Interpretation of leukocyte scintigraphy is potentially hampered by the fact that labeled leukocytes not only accumulate in infections but also accumulate physiologically in the bone marrow56. In order to reduce the number of false-positive results, leukocyte scintigraphy is often combined with bone marrow scintigraphy, which has been proposed as an imaging modality of choice for diagnosing periprosthetic joint infection11,12,16,57. The current results for periprosthetic hip infection showed increased specificity for combined leukocyte and bone marrow scintigraphy, as previously proposed18. Another potential drawback is the relatively time-consuming procedure of in vitro labeling of the leukocytes. More recently, antigranulocyte scintigraphy was introduced as an alternative for leukocyte scintigraphy, with the advantage of in vivo labeling of leukocytes, and was proposed as a promising diagnostic tool for the detection of infection. However, regarding the detection of periprosthetic hip infection, we found a relatively modest pooled specificity of 75%, which is significantly lower than that for FDG PET and for leukocyte scintigraphy. Our results suggest that antigranulocyte scintigraphy may not be the preferred imaging58,59.
FDG PET is increasingly used and investigated in suspected periprosthetic joint infection11,60,61, and current results showed that this modality has considerable potential for diagnosing periprosthetic hip infection17,32-34,36,37. Compared with leukocyte scintigraphy, FDG PET offers advantages such as time efficiency, increased resolution, and the use of low-dose CT. However, the exact role in diagnosing periprosthetic hip infection remains uncertain because of the limited availability, relatively high costs, and heterogeneity of the results in several studies16,30,36-38,62,63. The present study showed that varying diagnostic thresholds influenced the homogeneity of study results18. Although more investigation is needed, uptake along the bone-prosthesis interface of the femoral component is considered the most reliable indicator for periprosthetic hip infection, while accumulation around the head, neck, and distal tip of the prosthesis can remain for up to 2 years after implantation32,34,63. Altogether the results suggest that more studies on clinical accuracy using reliable and consistent diagnostic criteria are needed.
The results of this meta-analysis confirmed a high sensitivity and low specificity for the use of bone scintigraphy in the diagnosis of periprosthetic hip infection48,64-66. Unfortunately, especially in the first years after implantation, bone scintigraphy lacks the specificity needed to differentiate between infection and mechanical loosening. Nevertheless, bone scintigraphy is widely available and can exclude any form of loosening in patients with a low suspicion for periprosthetic hip infection. However, a positive bone scintigraphy result frequently leads to a second, more specific investigation and can therefore be used in combination with gallium or leukocyte scintigraphy. Although it is a more specific diagnostic modality, the combination of bone and gallium scintigraphy is infrequently used in daily practice because of important drawbacks11,67-70, including a relatively high radiation dose and uptake related to inflammation rather than infection43,45,54,57. As for the combination of bone and leukocyte scintigraphy, our results showed that this technique is highly specific, in contrast to the conclusions of several authors that no added value was achieved with this technique68,71. However, the limited number of available studies regarding both combined bone scintigraphy techniques means that these conclusions should be interpreted with caution.
Throughout the literature, evidence of heterogeneity in data concerning diagnostic accuracy in studies assessing periprosthetic joint infections was found. A possible explanation may lie in the lack of a gold standard, although a valid reference test (at least 1 positive culture) was an inclusion criterion in this meta-analysis. In addition, the diversity of interpretation criteria used for the index tests and the insufficient details regarding implants and imaging procedures reduced the statistical power. Furthermore, only a few of the primary studies described the reproducibility (interobserver and intraobserver variability of the investigated imaging technique, which is a major limitation because diagnostic results may be hampered by large interobserver variability.
This meta-analysis demonstrated that leukocyte scintigraphy and FDG PET have appropriate accuracy in confirming or excluding the diagnosis of periprosthetic hip infection. Although not significantly different, combined leukocyte and bone marrow scintigraphy was the most specific imaging technique. Hence, on the basis of the current evidence, these 3 imaging modalities could be used with satisfactory accuracy in a patient with suspected periprosthetic hip infection. However, FDG PET may not yet be the preferred imaging technique because of relatively high costs and limited availability. Furthermore, FDG PET will only receive full acceptance in the assessment of periprosthetic hip infection when consistent diagnostic criteria can be successfully developed.
Tables listing the characteristics of the included studies; characteristics of the reference tests and implants; data on the diagnostic accuracy of bone scintigraphy, combined bone and gallium scintigraphy, combined bone and leukocyte scintigraphy, leukocyte scintigraphy, combined leukocyte and bone marrow scintigraphy, antigranulocyte scintigraphy, and FDG PET for the detection of periprosthetic hip infection; the search string used for identifying studies on diagnostic imaging of periprosthetic hip infection; the results of the search for studies on diagnostic imaging of periprosthetic hip infection; analysis of the interpretation criteria used in the included studies of FDG PET for diagnosing periprosthetic hip infection using the z-test; comparison of imaging techniques in diagnosing periprosthetic hip infection with the z-test; and data on the QUADAS-2 evaluation; as well as figures showing the methodological quality of the included studies with QUADAS-2; charts showing the diagnostic accuracy of bone scintigraphy, combined bone and gallium scintigraphy, combined bone and leukocyte scintigraphy, leukocyte scintigraphy, combined leukocyte and bone marrow scintigraphy, antigranulocyte scintigraphy, and FDG PET for the detection of periprosthetic hip infection; and the PRISMA 2009 flow diagram are available with the online version of this article at jbjs.org.
NOTE: The authors thank information specialist Chantal den Haan at Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, for her contribution in constructing a search strategy for this systematic review and meta-analysis.
Investigation performed at the Centre for Orthopaedic Research Alkmaar (CORAL), Medical Centre Alkmaar, Alkmaar, the Netherlands
Disclosure: This study was conducted without external funding. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article.
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