Predictive Factors for Differentiating Between Septic Arthritis and Lyme Disease of the Knee in Children
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721 C OPYRIGHT 2016 BY T HE J OURNAL OF B ONE AND J OINT S URGERY, I NCORPORATED A commentary by Elan J. Golan, MD, and Jeffrey D. Thomson, MD, is linked to the online version of this article at jbjs.org. Predictive Factors for Differentiating Between Septic Arthritis and Lyme Disease of the Knee in Children Keith D. Baldwin, MD, MSPT, MPH, Christopher M. Brusalis, BA, Afamefuna M. Nduaguba, MD, and Wudbhav N. Sankar, MD Investigation performed at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Background: Differentiating between septic arthritis and Lyme disease of the knee in endemic areas can be challenging and has major implications for patient management. The purpose of this study was to identify a prediction rule to dif- ferentiate septic arthritis from Lyme disease in children presenting with knee pain and effusion. Methods: We retrospectively reviewed the records of patients younger than 18 years of age with knee effusions who underwent arthrocentesis at our institution from 2005 to 2013. Patients with either septic arthritis (positive joint ﬂuid culture or synovial white blood-cell count of >60,000 white blood cells/mm3 with negative Lyme titer) or Lyme disease (positive Lyme immunoglobulin G on Western blot analysis) were included. To avoid misclassiﬁcation bias, undiagnosed knee effusions and joints with both a positive culture and positive Lyme titers were excluded. Historical, clinical, and laboratory data were compared between groups to identify variables for comparison. Binary logistic regression analysis was used to identify independent predictive variables. Results: One hundred and eighty-nine patients were studied: 23 with culture-positive septic arthritis, 26 with culture- negative septic arthritis, and 140 with Lyme disease. Multivariate binary logistic regression identiﬁed pain with short arc motion, history of fever reported by the patient or a family member, C-reactive protein of >4 mg/L, and age younger than 2 years as independent predictive factors for septic arthritis. A simpler model was developed that showed that the risk of septic arthritis with none of these factors was 2%, with 1 of these factors was 18%, with 2 of these factors was 45%, with 3 of these factors was 84%, or with all 4 of these factors was 100%. Conclusions: Although septic arthritis of the knee and Lyme monoarthritis share common features that can make them difﬁcult to distinguish clinically, the presence of pain with short arc motion, C-reactive protein of >4.0 mg/L, patient- reported history of fever, and age younger than 2 years were independent predictive factors of septic arthritis in pediatric patients. The more factors that are present, the higher the risk of having septic arthritis. Level of Evidence: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. The Deputy Editor reviewed each revision of the article, and it underwent a ﬁnal review by the Editor-in-Chief prior to publication. Final corrections and clariﬁcations occurred during one or more exchanges between the author(s) and copyeditors. A cute bacterial septic arthritis is most often a surgical present with fever, joint effusion, irritability, and inability to emergency. However, differentiating septic arthritis of the bear weight on the affected extremity. In addition, laboratory knee from Lyme disease in children with symptoms of measurements, including erythrocyte sedimentation rate (ESR), knee pain and swelling can be very challenging. Clinical pre- C-reactive protein (CRP), and peripheral and synovial white sentations of both conditions can be quite similar. Often patients blood-cell (WBC) counts, may be elevated in both conditions1-4. Disclosure: One author of this study (K.D.B.) received funds from JBJS for manuscript preparation. On the Disclosure of Potential Conﬂicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant ﬁnancial relationship in the biomedical arena outside the submitted work. J Bone Joint Surg Am. 2016;98:721-8 d http://dx.doi.org/10.2106/JBJS.14.01331
722 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG d P R E D I C T I O N A L G O R I T H M F O R S E P T I C A R T H R I T I S C O M PA R E D WITH V O LU M E 98 -A N U M B E R 9 M AY 4, 2 016 d d LY M E D I S E A S E O F T H E K N E E I N C H I L D R E N TABLE I Patient Data Groups Lyme Disease Culture-Negative Septic Arthritis Culture-Positive Septic Arthritis No. of cases* 140 26 23 Mean age† (yr) 8.03 ± 4.0 2.1 ± 1.7 5.6 ± 1.6 Sex* Male 93 13 12 Female 47 13 11 *The values are given as the number of patients. †The values are given as the mean and the standard deviation. In spite of the overlap in both clinical presentation and take several days to be ﬁnalized. As a result, frontline clinicians laboratory testing, it is imperative that the treating physician are often faced with a challenging scenario: a child with knee makes an accurate diagnosis because each condition has very pain and effusion and indeterminate serum and synovial lab- different implications for treatment. Because pyogenic septic oratory values. In these circumstances, one must weigh the risk arthritis can result in rapid articular cartilage destruction, of delayed or untreated septic arthritis against the potential for emergent irrigation and drainage in the operating room are an unnecessary surgical procedure or serial aspirations, which warranted. In contrast, Borrelia burgdorferi, the causative organ- are less than ideal in a children’s hospital where anxiety at ism in Lyme disease, stimulates an immune complex-mediated multiple needle sticks is undesirable. inﬂammatory reaction that does not endanger the articular car- In the absence of a quick and accurate test to deﬁni- tilage to the same degree, but does cause systemic immune- tively diagnose Lyme disease, prediction algorithms that driven medical complications5. Standard treatment generally combine multiple clinical and laboratory factors have been involves an appropriate course of antibiotics and observation developed to identify patients at high risk for pyogenic ar- for other sequelae of systemic Lyme disease. thritis and to help to guide treatment decisions 6-9. Although In most pediatric medical centers, conﬁrmatory testing these models have proven helpful in differentiating septic for Lyme disease involves serum Western blot analysis for Lyme arthritis from transient synovitis of the hip, their utility in immunoglobulin G (IgG), but the results of this testing may differentiating septic arthritis from Lyme disease of the knee TABLE II Univariate Analysis of Culture-Positive Septic Arthritis Compared with Lyme Arthritis for Clinical and Laboratory Findings Culture-Positive Septic Arthritis* (N = 23) Lyme Disease* (N = 140) P Value Duration of symptoms (d) 3.2 ± 2.1 6.1 ± 9.3 0.268 History of antibiotic use 21.7% 6.4% 0.019 History of fever 73.9% 40.7% 0.001 Radiographic effusion 78.3% 95% 0.999 Micromotion tenderness 86.4% 6.3%
723 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG d P R E D I C T I O N A L G O R I T H M F O R S E P T I C A R T H R I T I S C O M PA R E D WITH V O LU M E 98 -A N U M B E R 9 M AY 4, 2 016 d d LY M E D I S E A S E O F T H E K N E E I N C H I L D R E N TABLE III Univariate Analysis of Culture-Negative Septic Arthritis Compared with Lyme Arthritis for Clinical and Laboratory Findings Culture-Negative Septic Arthritis* (N = 26) Lyme Disease* (N = 140) P Value Duration of symptoms (d) 4.5 ± 3.2 6.1 ± 9.3 0.625 History of antibiotic use 23.1% 6.4% 0.030 History of fever 76.9% 40.7% 0.001 Radiographic effusion 96.2% 95% 0.999 Micromotion tenderness 58.8% 6.3%
724 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG d P R E D I C T I O N A L G O R I T H M F O R S E P T I C A R T H R I T I S C O M PA R E D WITH V O LU M E 98 -A N U M B E R 9 M AY 4, 2 016 d d LY M E D I S E A S E O F T H E K N E E I N C H I L D R E N Materials and Methods logical testing, blood and joint ﬂuid cultures, Gram stains of the joint ﬂuid, ESR, and CRP. W e conducted a retrospective study of individuals younger than 18 years of age who presented to the emergency department of a large tertiary care children’s hospital between 2005 and 2013 and in whom an arthrocentesis was Statistical Analysis performed for knee joint effusion. The study was approved by our institutional Data were analyzed using SPSS version 22.0 (IBM). Descriptive elements of the board review prior to data collection. Study patients were identiﬁed through a data are presented as means (and ranges) and categorical variables are presented query of the laboratory database of our electronic medical record system for all as counts (and percentages). Cutoff values for continuous variables, CRP of patients in the emergency department for whom joint or synovial ﬂuid analysis >4 mg/L and age younger than 2 years, were determined with receiver operating was ordered. Identiﬁed patients were then cross-referenced with the labo- characteristic curve analysis. Mann-Whitney U tests were used to evaluate ratory results of Gram-staining, microbial culture, and synovial WBC count to differences between groups in continuous or ordinal variables in cases where identify patients with septic arthritis and were cross-referenced with the the data were not normally distributed and to identify variables for multi- results of the Lyme Western blot analysis to identify patients diagnosed with variate analysis. A chi-square test was used to determine signiﬁcance in the Lyme disease. case of binary or categorical data. Level of signiﬁcance was established at a two- The emergency department records of each identiﬁed patient were sided alpha level of p < 0.05. Variables that signiﬁcantly inﬂuenced the diag- reviewed to conﬁrm the diagnosis of either pyogenic septic arthritis or Lyme nosis of septic arthritis were included in a binary logistic regression with a arthritis and to extract clinical and laboratory data. To create the cleanest stepwise backward elimination method (with a cutoff for elimination of 0.1) to cohort to minimize misclassiﬁcation bias, we deﬁned septic arthritis as either determine factors predictive of septic arthritis. Simpler dichotomized models the presence of a positive joint ﬂuid culture irrespective of synovial cell were generated using the risk factors and were conﬁrmed using 22 log like- count (culture-positive septic arthritis) or synovial WBC count of >60,000 lihood methodology. Models were generated for Lyme disease compared with white blood cells/mm3 in a joint with a negative Lyme titer (culture-negative culture-positive septic arthritis and for Lyme disease compared with all cases septic arthritis). Lyme disease was deﬁned as the presence of a positive serum of septic arthritis. Lyme IgG on Western blot based on our reference laboratory deﬁnitions. Patients who did not meet the criteria for a diagnosis of septic arthritis and Patient Demographic Characteristics who did not have a Lyme titer sent within the same emergency department During the study period, a total of 841 children were identiﬁed as having had an evaluation were excluded from the study. To avoid misclassiﬁcation bias, arthrocentesis performed in the emergency department, of which 498 were undiagnosed knee effusions and joints with both a positive culture and positive knee aspirations. After cross-referencing identiﬁed patients with the results Lyme titers were excluded. In patients with multiple peripheral blood of the microbial culture and Lyme disease immunoblot assays and applying analyses and joint aspirations during the same hospitalization, we limited our further exclusion criteria (Fig. 1), we identiﬁed 189 patients as our study data analysis to the ﬁrst peripheral laboratory values and to the initial aspirate cohort (49 with septic arthritis and 140 with Lyme disease) (Table I). sample. Of the 23 patients with culture-positive septic arthritis, organisms in- For each patient, we recorded data on demographic characteristics, cluded methicillin-susceptible Staphylococcus aureus (MSSA) (11 patients), medical comorbidities, historical elements, physical examination ﬁndings, and methicillin-resistant Staphylococcus aureus (MRSA) (4 patients), Propionibacterium results of laboratory testing, including complete blood-cell count, Lyme sero- acnes (2 patients), Clostridium bifermentans (1 patient), Streptococcus pneumoniae Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) diagram of the study population. SA = septic arthritis, CNSA = culture-negative septic arthritis, Dx = diagnosis, WB1 = positive white blood-cell count, and Hx = medical history.
725 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG d P R E D I C T I O N A L G O R I T H M F O R S E P T I C A R T H R I T I S C O M PA R E D WITH V O LU M E 98 -A N U M B E R 9 M AY 4, 2 016 d d LY M E D I S E A S E O F T H E K N E E I N C H I L D R E N TABLE V Univariate Analysis of Operatively Treated Lyme Arthritis Compared with Nonoperatively Treated Lyme Arthritis Operative Group* (N = 46) Nonoperative Group* (N = 94) P-Value Temperature (F) 99.3 ± 1.3 99.1 ± 1.2 0.08 Serum WBC count (·109 cells/L) 11.2 ± 3.6 9.6 ± 2.8 0.010 Absolute neutrophil count (cells/mm3) 5,727 ± 2,122 5,726 ± 2,121 0.061 ESR (mm/hr) 52 ± 21 37 ± 21
726 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG d P R E D I C T I O N A L G O R I T H M F O R S E P T I C A R T H R I T I S C O M PA R E D WITH V O LU M E 98 -A N U M B E R 9 M AY 4, 2 016 d d LY M E D I S E A S E O F T H E K N E E I N C H I L D R E N count alone may lead to a high rate of unnecessary surgical Three previous studies have speciﬁcally sought to identify procedures. Furthermore, the results of Lyme-speciﬁc serologi- predictive factors for differentiating septic arthritis from Lyme cal testing can take several days and therefore are not helpful for disease. Thompson et al.11 evaluated 179 patients with mono- making an urgent surgical decision. As a result, Lyme disease is arthritis of different joints (not just the knee) and identiﬁed often mistaken for culture-negative septic arthritis and is history of fever and elevated CRP to be negative predictors of treated as such with incision and drainage, unnecessarily ex- Lyme arthritis and knee involvement to be a positive predictor posing these patients to the risks of a surgical procedure4. (model sensitivity of 88% and speciﬁcity of 82%). In spite of In the absence of an easily administered test with high this, the authors concluded that there was too much overlap in sensitivity and speciﬁcity for deﬁnitively diagnosing septic ar- the data to create a clinically useful predictive model. Milewski thritis, previous studies have used multiple physical examina- et al.15 compared 123 patients with Lyme disease with 51 pa- tion and laboratory factors to create prediction models that tients with culture-positive septic arthritis, although several help to identify patients at high risk for pyogenic arthritis. different joints were included in their analysis. Based on mul- Kocher et al.8 developed a widely used set of criteria to differ- tivariate analysis, the authors found that refusal to bear weight entiate septic arthritis from transient synovitis of the hip using was the most predictive factor, with weaker predictors being 4 independent clinical variables: history of fever, non-weight- presence of a fever, WBC count of >12 · 1,000/mL, and nu- bearing status, ESR of ‡40 mm/hr, and serum WBC count of cleated cell count of >100,000 cells/mm3. Interestingly, CRP ‡12 · 109 cells/L. This model has since been validated internally and ESR were not found to be useful predictors, although the and externally, and updated to reﬂect the additional diagnostic study was limited by a very low CRP collection rate during the beneﬁt of CRP6. Although the Kocher model is often applied to study period. A recent study by Deanehan et al. is the only multiple joints even in the setting of Lyme disease, this pre- previous one, to our knowledge, that compared predictive dictor was not originally intended to distinguish between factors for Lyme disease with those for septic arthritis speciﬁ- septic arthritis and Lyme disease and was not validated for the cally of the knee10. Unlike the aforementioned studies (and knee. The septic arthritis cohort studied by Kocher et al. con- ours), the authors found ESR to be an independent predictor of sisted of all patients with synovial leukocyte counts in excess of septic arthritis in Lyme disease-endemic areas; the other factor 50,000 cells/mm3 regardless of bacterial culture results and that they found to be predictive was an absolute neutrophil therefore may have inadvertently included patients with Lyme count of ‡10,000 cells/mm3, which we also did not detect in our disease and other misclassiﬁcation biases. Indeed, a recent study study. However, their data were limited by a low CRP collection by Deanehan et al. demonstrated synovial WBC counts in excess rate (77%) and a small number of patients with septic arthritis of 50,000 cells/mm3 to be quite common in Lyme arthritis16, (19). In addition, the Lyme disease cohort included a signiﬁcant and these ﬁndings were reiterated by this current study. proportion of patients (58%) who did not undergo arthrocentesis. Fig. 2 Map of reported cases of Lyme disease in the United States, 2014. (Reproduced from: CDC, National Center for Health Statistics. Lyme Disease. 2015 Oct 2. http://www.cdc.gov/lyme/stats/index.html. Accessed 2016 Jan 26.)
727 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG d P R E D I C T I O N A L G O R I T H M F O R S E P T I C A R T H R I T I S C O M PA R E D WITH V O LU M E 98 -A N U M B E R 9 M AY 4, 2 016 d d LY M E D I S E A S E O F T H E K N E E I N C H I L D R E N These latter types of patients can typically be triaged to ob- To provide a clinically useful prediction model, we de- servation by the treating physician and are rarely, by clinical ﬁned septic arthritis as either the presence of a positive joint examination, suspected of having septic arthritis. These patients culture or as a synovial WBC count of >60,000 white blood may therefore not represent the types of clinical presentations cells/mm3 with negative Lyme serological results. Although there that are easily confused with those having true pyogenic arthritis. is a small risk of misclassiﬁcation bias using this second def- In this present study aimed at differentiating septic ar- inition, ignoring the large number of patients who present to thritis of the knee from Lyme monoarthritis, we found several emergency departments with culture-negative septic arthritis independent predictive factors for pyogenic arthritis: patient or would limit the clinical applicability of any prediction rule. family-reported history of fever, pain with short arc motion, This study had several limitations. First, as a chart review, CRP of ‡4 mg/L, and age younger than 2 years. The probability it had the potential loss of data ﬁdelity associated with retro- of septic arthritis with any one factor present was 18% com- spective analysis. Second, as a single-center study in a Lyme pared with 100% with all 4 factors present. Logistic regression disease-endemic area, the results of this study may not be ap- of predictor variables showed that 87% of cases were correctly plicable to all geographical regions, particularly those with a low predicted with our model. In our series, a patient with no risk prevalence of Lyme disease. The Centers for Disease Control and factors had a 2% chance of being diagnosed with septic ar- Prevention (CDC) has reported that, in 2014, 96% of conﬁrmed thritis, and a patient with 4 factors had a 100% chance of septic cases of Lyme disease occurred in 14 U.S. states, concentrated in arthritis. Notably, of 46 patients with Lyme disease who un- the Northeast and upper Midwest (Fig. 2)17. Therefore, the ﬁnd- derwent a surgical procedure, 11 patients had no clinical pre- ings of this study may be most applicable to these geographic dictors. Thus, applying this clinical prediction rule may have regions. The strengths of the study include rigorous deﬁnitions avoided a surgical procedure in 23.9% of patients in this of the cohorts and data acquisition and statistical analysis methods cohort. Of the remaining 35 patients with Lyme disease who that limit misclassiﬁcation and observer bias. Additionally, to our underwent a surgical procedure, 19 had one clinical predictor, knowledge, our study is the ﬁrst to identify predictive risk factors 14 had 2 predictors, 2 had 3 predictors, and no patient had all that, in our cohort, ensured the diagnosis of septic arthritis when 4 predictors. It is important to note that the results of this study all were present (i.e., the diagnosis was septic arthritis in 100% may not be applicable in a non-endemic area with a lower of cases) and resulted in only one case of septic arthritis when prevalence of Lyme disease. all 4 risk factors were absent (2%). Interestingly, we found pain with short arc motion to be In conclusion, our study offers a useful prediction algo- the most clinically useful test for septic arthritis, with a sensi- rithm for septic arthritis compared with Lyme disease of the tivity of 0.78 and a speciﬁcity of 0.92. Multivariate analysis knee. We believe that a patient older than 2 years of age without showed that the adjusted odds of having septic arthritis with history of fever, no short arc pain, and CRP of
728 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG d P R E D I C T I O N A L G O R I T H M F O R S E P T I C A R T H R I T I S C O M PA R E D WITH V O LU M E 98 -A N U M B E R 9 M AY 4, 2 016 d d LY M E D I S E A S E O F T H E K N E E I N C H I L D R E N 7. Jung ST, Rowe SM, Moon ES, Song EK, Yoon TR, Seo HY. Signiﬁcance of labo- 12. Bennett OM, Namnyak SS. Acute septic arthritis of the hip joint in infancy and ratory and radiologic ﬁndings for differentiating between septic arthritis and transient childhood. Clin Orthop Relat Res. 1992 Aug;(281):123-32. synovitis of the hip. J Pediatr Orthop. 2003 May-Jun;23(3):368-72. 13. Forlin E, Milani C. Sequelae of septic arthritis of the hip in children: a new 8. Kocher MS, Zurakowski D, Kasser JR. Differentiating between septic arthritis and classiﬁcation and a review of 41 hips. J Pediatr Orthop. 2008 Jul-Aug;28(5): transient synovitis of the hip in children: an evidence-based clinical prediction al- 524-8. gorithm. J Bone Joint Surg Am. 1999 Dec;81(12):1662-70. 14. Gillespie R. Septic arthritis of childhood. Clin Orthop Relat Res. 1973 Oct; 9. Molteni RA. The differential diagnosis of benign and septic joint disease in chil- (96):152-9. dren. Clinical, radiologic, laboratory, and joint ﬂuid analysis, based on 37 children 15. Milewski MD, Cruz AI Jr, Miller CP, Peterson AT, Smith BG. Lyme arthritis in with septic arthritis and 97 with benign aseptic arthritis. Clin Pediatr (Phila). 1978 children presenting with joint effusions. J Bone Joint Surg Am. 2011 Feb 2; Jan;17(1):19-23. 93(3):252-60. 10. Deanehan JK, Kimia AA, Tan Tanny SP, Milewski MD, Talusan PG, Smith BG, 16. Deanehan JK, Nigrovic PA, Milewski MD, Tan Tanny SP, Kimia AA, Smith BG, Nigrovic LE. Distinguishing Lyme from septic knee monoarthritis in Lyme disease- Nigrovic LE. Synovial ﬂuid ﬁndings in children with knee monoarthritis in Lyme dis- endemic areas. Pediatrics. 2013 Mar;131(3):e695-701. Epub 2013 Feb 18. ease endemic areas. Pediatr Emerg Care. 2014 Jan;30(1):16-9. 11. Thompson A, Mannix R, Bachur R. Acute pediatric monoarticular arthritis: dis- 17. CDC, National Center for Health Statistics. Lyme Disease. 2015 Oct 2. http:// tinguishing Lyme arthritis from other etiologies. Pediatrics. 2009 Mar;123(3):959-65. www.cdc.gov/lyme/stats/index.html. Accessed 2016 Jan 26.
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