The Role Of Biomarkers In Common Pediatric Emergency Department Complaints: An Evidence-Based Approach

Table of Contents

 

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal Of The Literature
5. Biomarkers
   1. Erythrocyte Sedimentation Rate
   2. C-Reactive Protein
   3. Interleukin-6
   4. Procalcitonin
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. History And Physical Examination
9. Diagnostic Studies
   1. Meningitis
      1. Erythrocyte Sedimentation Rate For Meningitis
      2. C-Reactive Protein For Meningitis
      3. Interleukin-6 For Meningitis
      4. Procalcitonin For Meningitis
      5. Biomarker Summary For Meningitis
   2. Serious Bacterial Infection
      1. Erythrocyte Sedimentation Rate For Serious Bacterial Infection
      2. C-Reactive Protein For Serious Bacterial Infection
      3. Interleukin-6 For Serious Bacterial Infection
      4. Procalcitonin For Serious Bacterial Infection
      5. Biomarker Summary For Serious Bacterial Infection
   3. Appendicitis
      1. Erythrocyte Sedimentation Rate For Appendicitis
      2. C-Reactive Protein For Appendicitis
      3. Interleukin-6 For Appendicitis
      4. Procalcitonin For Appendicitis
      5. Biomarker Summary For Appendicitis
   4. Septic Arthritis
      1. Erythrocyte Sedimentation Rate For Septic Arthritis
      2. C-Reactive Protein For Septic Arthritis
      3. Interleukin-6 For Septic Arthritis
      4. Procalcitonin For Septic Arthritis
      5. Biomarker Summary For Septic Arthritis
10. Special Circumstances
11. Controversies And Cutting Edge
12. Summary
13. Risk Management Pitfalls For Biomarkers
14. Case Conclusion
15. Tables and Figures
    1. Table 1. Biomarker Characteristics
    2. Table 2. Inappropriate Settings To Apply Biomarkers
16. References

Abstract

Inflammatory markers are a subset of biomarkers that may help practitioners identify diseases earlier and more accurately. Establishing specific biomarker levels in healthy and sick patients may help differentiate sick children who require medical intervention from those who do not. These interventions can include surgical treatment or the decision to administer antibiotics. This review evaluates the literature on 4 biomarkers, including: (1) erythrocyte sedimentation rate, (2) C-reactive protein, (3) interleukin-6, and (4) procalcitonin, and reviews these biomarkers' diagnostic ability when applied to 4 common pediatric clinical scenarios, including: (1) acute meningitis, (2) serious bacterial infection, (3) appendicitis, and (4) septic arthritis. The results of major studies are presented, along with recommendations for the use of these biomarkers for diagnostic decision making regarding these clinical scenarios in the emergency department.

Case Presentations

It is a busy Monday evening shift and you encounter an 8-year-old boy who was brought in by his mother. Mom says he has been complaining of “tummy pain” since last night before bed and is walking “hunched over.” The boy tells you that the pain started at the belly button and has now moved down into his right lower abdomen. When you question him about food, he states that he is hungry and denies any nausea. He has had no fever at home, and there has been no diarrhea. Acetaminophen has minimally improved his pain, but he is lying uncomfortably on the bed. Your examination reveals stable vital signs, and he is afebrile. His heart and lung examination is normal. His abdominal examination reveals right lower quadrant tenderness without rebound or guarding. He has a positive obturator sign and negative psoas and Rovsing signs. The genitourinary exam is benign. The nurse places a peripheral IV, and you control his pain. As you walk away, you are thinking:

• Does this patient have an acute appendicitis?
• Are there any blood tests that could change my suspicion for an acute appendicitis?
• If the ultrasound is inconclusive, do I need to perform a CT of the abdomen?

Introduction

The “perfect” biomarker in the emergency department (ED) setting would be a laboratory test that is easily obtained from blood or another bodily fluid. It would track disease activity quickly and be easily detectable, allowing for earlier diagnosis. Additionally, it would be relatively inexpensive, and levels between sick patients and healthy patients would be easily distinguishable.

This issue of Pediatric Emergency Medicine Practice presents an evidence-based synopsis of 4 biomarkers: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT) and evaluates these biomarkers' diagnostic ability when applied to 4 common clinical scenarios: (1) acute meningitis, (2) serious bacterial infection, (3) appendicitis, and (4) septic arthritis. For each scenario, we discuss how each biomarker could potentially change an emergency clinician's decision-making practice. The primary characteristics of these 4 biomarkers are summarized in Table 1.

Critical Appraisal Of The Literature

A literature search was performed using both PubMed and Ovid MEDLINE^®. Searches were limited to those studies published in English involving human subjects. Search terms included: C-reactive protein, CRP, erythrocyte sedimentation rate, ESR, procalcitonin, PCT, interleukin-6, IL-6, appendicitis, serious bacterial infection, SBI, meningitis, septic arthritis, pediatrics, children, meta-analysis, systematic review, and biomarkers. Pertinent articles and their references were explored for any potentially missed relevant studies. Additionally, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews were explored. The American College of Emergency Physicians and the American Academy of Pediatrics have no guidelines incorporating these biomarkers and diagnoses. No guideline consensus statements regarding these biomarkers and their relationship to appendicitis, serious bacterial infection, septic arthritis, or meningitis could be found. Overall, there was also a paucity of meta-analyses and systematic reviews addressing the relationship of disease diagnosis and the aforementioned biomarkers.

Risk Management Pitfalls For Biomarkers

1. “My patient recently underwent chemotherapy, but I would like to use a biomarker to help facilitate the diagnosis.“

   Studies examining the diagnostic ability of biomarkers nearly always exclude immunocompromised patients. Practitioners should not apply biomarkers to the clinical scenarios discussed in this review if the patient is potentially immunocompromised.

2. “I know he has been on antibiotics for the last 24 hours, but I am still going to draw a PCT level.”

   In nearly every study addressed here, patients were excluded if they had received antibiotics recently. Applying biomarkers, particularly PCT, in these settings is not recommended and can falsely reassure the practitioner with their very low values.

3. “I thought that a normal WBC and a normal CRP ruled out acute appendicitis.”

   While this may be true in the adult literature, this statement is untrue in the pediatric population. A normal WBC and normal CRP significantly decrease the posttest probability of having an acute appendicitis, but it does not rule out the disease.

4. ”In that child with hip pain, I didn't think I needed a blood culture if the CRP and ESR came back normal.“

   A low CRP and low ESR decreases—but does not exclude—the likelihood of a septic joint. While joint cultures are the gold standard in diagnosing septic arthritis, joint aspirates can be negative and many of these infections are hematogenously spread. For these reasons, always get a blood culture in any patient who has septic arthritis in the differential diagnosis.

5. “If the PCT level comes back normal, I don’t need to do a lumbar puncture, even though he’s got a fever and headache.”

   Biomarkers must be applied appropriately. A normal PCT can help differentiate bacterial from viral meningitis, but it cannot exclude other etiologies of headache and neck pain. This statement is an inappropriate application of PCT in this clinical setting.

6. “I am going to get some labs and send this kid home quickly. He’s only had pain for a couple of hours.”

   Biomarkers are an adjunct to the emergency clinician’s decision-making process, not a replacement. The duration of symptoms should factor into the clinician’s assessment. Refer to Table 1 for biomarker time to onset.

7. “If the child has hip pain, a high ESR, and elevated WBC, it has to be a septic joint.”

   Not true. Some studies only show a PPV ranging from 72% to 93% with these 3 criteria. If the child also has a fever, then the PPV is much higher and septic arthritis is much more likely.

8. “So the child has viral meningitis. Send him home.”

   Before sending home any child with meningitis, assess the overall clinical picture. Viral meningitis patients, while not requiring antibiotics, can be very ill and require hospitalization.

9. “The CRP and ESR are normal. It can’t be a septic joint.”

   Studies finding patients with a normal CRP, normal ESR, normal WBC, no limp, and no fever have still shown a PPV of septic arthritis ranging from 0.2% to 16.9%.

10. “The 2-week-old girl has a fever but looks great. The PCT is normal. I think I’m just going to send her home with her mom.”

    Most authors agree that this vulnerable population (≤ 30 days old) should always be admitted for observation if they are febrile.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study will be included in bold type following the references, where available. The most informative references cited in this paper, as determined by the author, will be noted by an asterisk (*) next to the number of the reference.

1. Colombet I, Pouchot J, Kronz V, et al. Agreement between erythrocyte sedimentation rate and C-reactive protein in hospital practice. Am J Med. 2010;123(9):863. (Retrospective study, 5777 patients)
2. Sox HCJr, Liang MH. The erythrocyte sedimentation rate. Guidelines for rational use. Ann Intern Med. 1986;104(4):515-523. (Review article)
3. Saadeh C. The erythrocyte sedimentation rate: old and new clinical applications. South Med J. 1998;91(3):220-225. (Review article)
4. Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J. 1997;16(8):735-746. (Review article)
5. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111(12):1805-1812. (Review article)
6. Abernethy TJ, Avery OT. The occurrence during acute infections of a protein not normally present in the blood : I. distribution of the reactive protein in patients’ sera and the effect of calcium on the flocculation reaction with C polysaccharide of pneumococcus. J Exp Med. 1941;73(2):173-182. (CRP characterization study)
7. Flood RG, Badik J, Aronoff SC. The utility of serum C-reactive protein in differentiating bacterial from nonbacterial pneumonia in children: a meta-analysis of 1230 children. Pediatr Infect Dis J. 2008;27(2):95-99. (Meta- analysis; 1230 patients)
8. Herzum I, Renz H. Inflammatory markers in SIRS, sepsis and septic shock. Curr Med Chem. 2008;15(6):581-587. (Review article)
9. * Nathan BR, Scheld WM. The potential roles of C-reactive protein and procalcitonin concentrations in the serum and cerebrospinal fluid in the diagnosis of bacterial meningitis. Curr Clin Top Infect Dis. 2002;22:155-165. (Review article)
10. Ho KM, Lipman J. An update on C-reactive protein for intensivists. Anaesth Intensive Care. 2009;37(2):234-241. (Review article)
11. Stearman M, Southgate HJ. The use of cytokine and C-reactive protein measurements in cerebrospinal fluid during acute infective meningitis. Ann Clin Biochem. 1994;31( Pt 3):255-261. (Prospective study; 48 patients)
12. Hsieh CC, Lu JH, Chen SJ, et al. Cerebrospinal fluid levels of interleukin-6 and interleukin-12 in children with meningitis. Childs Nerv Syst. 2009;25(4):461-465. (Prospective study; 95 patients)
13. Fida NM, Al-Mughales J, Farouq M. Interleukin-1alpha, interleukin-6 and tumor necrosis factor-alpha levels in children with sepsis and meningitis. Pediatr Int. 2006;48(2):118-124. (Prospective study; 86 patients)
14. Murakami M, Nishimoto N. The value of blocking IL-6 outside of rheumatoid arthritis: current perspective. Curr Opin Rheumatol. 2011;23(3):273-277. (Review article)
15. Houssiau FA, Bukasa K, Sindic CJ, et al. 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 (2):320-323. (Prospective study; 218 patients)
16. Deis JN, Creech CB, Estrada CM, et al. Procalcitonin as a marker of severe bacterial infection in children in the emergency department. Pediatr Emerg Care. 2010;26(1):51-60. (Review article)
17. Carcillo J, Planquois J, Goldstein B. Early markers of infection and sepsis in newborns and children. Adv Sepsis. 2006;5(4):118-127. (Review article)
18. Butbul-Aviel Y, Koren A, Halevy R, et al. Procalcitonin as a diagnostic aid in osteomyelitis and septic arthritis. Pediatr Emerg Care. 2005;21(12):828. (Prospective study; 44 patients)
19. Assicot M, Gendrel D, Carsin H, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341(8844):515-518. (Prospective study; 88 patients)
20. van Rossum AM, Wulkan RW, Oudesluys-Murphy AM. Procalcitonin as an early marker of infection in neonates and children. Lancet Infect Dis. 2004;4(10):620-630. (Review article)
21. Snider RH,Jr, Nylen ES, Becker KL. Procalcitonin and its component peptides in systemic inflammation: immunochemical characterization. J Investig Med. 1997;45(9):552-560. (Cross-sectional comparison study; 15 patients)
22. Gendrel D, Bohuon C. Procalcitonin as a marker of bacterial infection. Pediatr Infect Dis J. 2000;19(8):679-687. (Prospective study)
23. Dandona P, Nix D, Wilson MF, et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab. 1994;79(6):1605-1608. (Prospective study; 7 patients)
24. Valmari P. White blood cell count, erythrocyte sedimentation rate and serum C-reactive protein in meningitis: magnitude of the response related to bacterial species. Infection. 1984;12(5):328-330. (Prospective study; 61 patients)
25. Kirimi E, Tuncer O, Arslan S, et al. Prognostic factors in children with purulent meningitis in Turkey. Acta Med Okayama. 2003;57(1):39-44. (Prospective study; 48 patients)
26. Sormunen P, Kallio MJ, Kilpi T, et al. C-reactive protein is useful in distinguishing Gram stain-negative bacterial meningitis from viral meningitis in children. J Pediatr. 1999;134(6):725-729. (Prospective study; 325 patients)
27. Clarke D, Cost K. Use of serum C-reactive protein in differentiating septic from aseptic meningitis in children. J Pediatr. 1983;102(5):718-720. (Prospective study; 35 patients)
28. Dubos F, Moulin F, Gajdos V, et al. Serum procalcitonin and other biologic markers to distinguish between bacterial and aseptic meningitis. J Pediatr. 2006;149(1):72-76. (Retrospective study; 167 patients)
29. Knudsen TB, Larsen K, Kristiansen TB, et al. Diagnostic value of soluble CD163 serum levels in patients suspected of meningitis: comparison with CRP and procalcitonin. Scand J Infect Dis. 2007;39(6-7):542-553. (Prospective study; 55 patients)
30. Alkholi UM, Abd Al-Monem N, Abd El-Azim AA, et al. Serum procalcitonin in viral and bacterial meningitis. J Glob Infect Dis. 2011;3(1):14-18. (Prospective study; 40 patients)
31. Ibrahim KA, Abdel-Wahab AA, Ibrahim AS. Diagnostic value of serum procalcitonin levels in children with meningitis: a comparison with blood leukocyte count and C-reactive protein. J Pak Med Assoc. 2011;61(4):346-351. (Prospective study; 38 patients)
32. Prat C, Dominguez J, Rodrigo C, et al. Use of quantitative and semiquantitative procalcitonin measurements to identify children with sepsis and meningitis. Eur J Clin Microbiol Infect Dis. 2004;23(2):136-138. (Prospective study; 90 patients)
33. Gerdes LU, Jorgensen PE, Nexo E, Wang P. C-reactive protein and bacterial meningitis: a meta-analysis. Scand J Clin Lab Invest. 1998;58(5):383-393. (Meta-analysis; 790 patients)
34. Azuma H, Tsuda N, Sasaki K, et al. Clinical significance of cytokine measurement for detection of meningitis. J Pediatr. 1997;131(3):463-465. (Prospective study; 33 patients)
35. Torre D, Zeroli C, Ferraro G, et al. Cerebrospinal fluid levels of IL-6 in patients with acute infections of the central nervous system. Scand J Infect Dis. 1992;24(6):787-791. (Prospective study; 20 patients)
36. Lopez-Cortes LF, Cruz-Ruiz M, Gomez-Mateos J, et al. Interleukin 6 in cerebrospinal fluid of patients with meningitis is not a useful diagnostic marker in the differential diagnosis of meningitis. Ann Clin Biochem. 1997;34( Pt 2):165-169. (Prospective study; 98 patients)
37. Tsai ML, Chen WC, Wang YC, et al. Cerebrospinal fluid interleukin-6, interleukin-8, and tumor necrosis factor-alpha in children with central nervous system infections. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1996;37(1):16 -21. (Prospective study; 53 patients)
38. Chavanet P, Bonnotte B, Guiguet M, et al. High concentrations of intrathecal interleukin-6 in human bacterial and nonbacterial meningitis. J Infect Dis. 1992;166(2):428-431. (Retrospective study; 84 patients)
39. Matsuzono Y, Narita M, Akutsu Y, et al. Interleukin-6 in cerebrospinal fluid of patients with central nervous system infections. Acta Paediatr. 1995;84(8):879-883. (Prospective study; 54 patients)
40. Perrella O, Rescigno C, Guarnaccia D, et al. Cerebrospinal fluid interleukin-6 and IgE in bacterial and viral meningitis. Acta Neurol (Napoli). 1992;14(1):6-9. (Prospective study; 30 patients)
41. Mukai AO, Krebs VL, Bertoli CJ, et al. TNF-alpha and IL-6 in the diagnosis of bacterial and aseptic meningitis in children. Pediatr Neurol. 2006;34(1):25-29. (Prospective study; 35 patients)
42. Shimetani N, Shimetani K, Mori M. Levels of three inflammation markers, C-reactive protein, serum amyloid A protein and procalcitonin, in the serum and cerebrospinal fluid of patients with meningitis. Scand J Clin Lab Invest. 2001;61(7):567-574. (Prospective study; 42 patients)
43. * Dubos F, Korczowski B, Aygun DA, et al. Serum procalcitonin level and other biological markers to distinguish between bacterial and aseptic meningitis in children: a european multicenter case cohort study. Arch Pediatr Adolesc Med. 2008;162(12):1157-1163. (Retrospective multicenter; 198 patients)
44. Ray P, Badarou-Acossi G, Viallon A, et al. Accuracy of the cerebrospinal fluid results to differentiate bacterial from non-bacterial meningitis, in case of negative gram-stained smear. Am J Emerg Med. 2007;25(2):179-184. (Prospective study; 151 patients)
45. * Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: systematic review and meta-analysis. Clin Infect Dis. 2004;39(2):206-217. (Meta-analysis; 1386 patients)
46. * Sanders S, Barnett A, Correa-Velez I, et al. Systematic review of the diagnostic accuracy of C-reactive protein to detect bacterial infection in nonhospitalized infants and children with fever. J Pediatr. 2008;153(4):570-574. (Meta-analysis; 2046 patients)
47. Van den Bruel A, Thompson MJ, Haj-Hassan T, et al. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. BMJ. 2011;342:d3082. (Systematic review; 3981 patients)
48. Thompson M, Van den Bruel A, Verbakel J, et al. Systematic review and validation of prediction rules for identifying children with serious infections in emergency departments and urgent-access primary care. Health Technol Assess. 2012;16(15):1-100. (Meta-analysis; 11,045 patients)
49. Pulliam PN, Attia MW, Cronan KM. C-reactive protein in febrile children 1 to 36 months of age with clinically undetectable serious bacterial infection. Pediatrics. 2001;108(6):1275-1279. (Prospective study; 77 patients)
50. * Manzano S, Bailey B, Gervaix A, et al. Markers for bacterial infection in children with fever without source. Arch Dis Child. 2011;96(5):440-446. (Prospective study; 328 patients)
51. Olaciregui I, Hernandez U, Munoz JA, et al. Markers that predict serious bacterial infection in infants under 3 months of age presenting with fever of unknown origin. Arch Dis Child. 2009;94(7):501-505. (Retrospective study; 347 patients)
52. Lacour AG, Zamora SA, Gervaix A. A score identifying serious bacterial infections in children with fever without source. Pediatr Infect Dis J. 2008;27(7):654-656. (Prospective study; 202 patients)
53. Galetto-Lacour A, Zamora SA, Andreola B, et al. Validation of a laboratory risk index score for the identification of severe bacterial infection in children with fever without source. Arch Dis Child. 2010;95(12):968-973. (Prospective study; 406 patients)
54. Lacour AG, Gervaix A, Zamora SA, et al. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs. Eur J Pediatr. 2001;160(2):95-100. (Prospective study; 124 patients)
55. Saladino R, Erikson M, Levy N, et al. Utility of serum interleukin-6 for diagnosis of invasive bacterial disease in children. Ann Emerg Med. 1992;21(12):1413-1417. (Prospective study; 70 patients)
56. Jones AE, Fiechtl JF, Brown MD, et al. Procalcitonin test in the diagnosis of bacteremia: a meta-analysis. Ann Emerg Med. 2007;50(1):34-41. (Meta-analysis; 2008 patients)
57. Phillips RS, Wade R, Lehrnbecher T, et al. Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer. BMC Med. 2012;10:6. (Meta-analysis; 3585 patients)
58. Fernandez Lopez A, Luaces Cubells C, Garcia Garcia JJ, et al. Procalcitonin in pediatric emergency departments for the early diagnosis of invasive bacterial infections in febrile infants: results of a multicenter study and utility of a rapid qualitative test for this marker. Pediatr Infect Dis J. 2003;22(10):895-903. (Prospective study; 445 patients)
59. Chandel V, Batt SH, Bhat MY, et al. Procalcitonin as the biomarker of inflammation in diagnosis of appendicitis in pediatric patients and prevention of unnecessary appendectomies. Indian J Surg. 2011;73(2):136-141. (Prospective study; 40 patients)
60. Sack U, Biereder B, Elouahidi T, et al. Diagnostic value of blood inflammatory markers for detection of acute appendicitis in children. BMC Surg. 2006;6:15. (Prospective study; 211 patients)
61. Peng YS, Lee HC, Yeung CY, et al. Clinical criteria for diagnosing perforated appendix in pediatric patients. Pediatr Emerg Care. 2006;22(7):475-479. (Retrospective study; 274 patients)
62. Moon HM, Park BS, Moon DJ. Diagnostic value of C-reactive protein in complicated appendicitis. J Korean Soc Coloproctol. 2011;27(3):122-126. (Retrospective study; 128 patients)
63. Vaughan-Shaw PG, Rees JR, Bell E, et al. Normal inflammatory markers in appendicitis: evidence from two independent cohort studies. JRSM Short Rep. 2011;2(5):43. (Retrospective study; 297 patients)
64. Paajanen H, Mansikka A, Laato M, et al. Novel serum inflammatory markers in acute appendicitis. Scand J Clin Lab Invest. 2002;62(8):579-584.(Prospective study; 80 patients)
65. Sand M, Trullen XV, Bechara FG, et al. A prospective bicenter study investigating the diagnostic value of procalcitonin in patients with acute appendicitis. Eur Surg Res. 2009;43(3):291-297. (Prospective study; 103 patients)
66. Sengupta A, Bax G, Paterson-Brown S. White cell count and C-reactive protein measurement in patients with possible appendicitis. Ann R Coll Surg Engl. 2009;91(2):113-115. (Prospective study; 98 patients)
67. John SK, Joseph J, Shetty SR. Avoiding negative appendectomies in rural surgical practice: Is C-reactive protein estimation useful as a diagnostic tool? Natl Med J India. 2011;24(3):144-147. (Prospective study; 238 patients)
68. Siddique K, Baruah P, Bhandari S, et al. Diagnostic accuracy of white cell count and C-reactive protein for assessing the severity of paediatric appendicitis. JRSM Short Rep. 2011;2(7):59. (Prospective study; 204 patients)
69. Erkasap S, Ates E, Ustuner Z, et al. Diagnostic value of interleukin-6 and C-reactive protein in acute appendicitis. Swiss Surg. 2000;6(4):169-172. (Prospective study; 102 patients)
70. Gronroos JM. Do normal leucocyte count and C-reactive protein value exclude acute appendicitis in children? Acta Paediatr. 2001;90(6):649-651. (Prospective study; 200 patients)
71. Gronroos P, Huhtinen H, Gronroos JM. Normal leukocyte count and C-reactive protein value do not effectively exclude acute appendicitis in children. Dis Colon Rectum. 2009;52(5):1028-1029; author reply 1029. (Editorial)
72. * Andersson RE. Meta-analysis of the clinical and laboratory diagnosis of appendicitis. Br J Surg. 2004;91(1):28-37. (Meta-analysis; 5833 patients)
73. Kharbanda AB, Cosme Y, Liu K, et al. Discriminative accuracy of novel and traditional biomarkers in children with suspected appendicitis adjusted for duration of abdominal pain. Acad Emerg Med. 2011;18(6):567-574. (Prospective study; 280 patients)
74. Groselj-Grenc M, Repse S, Dolenc-Strazar Z, et al. Interleukin-6 and lipopolysaccharide-binding protein in acute appendicitis in children. Scand J Clin Lab Invest. 2007;67(2):197-206. (Prospective study; 82 patients)
75. Turkyilmaz Z, Sonmez K, Karabulut R, et al. Sequential cytokine levels in the diagnosis of appendicitis. Scand J Clin Lab Invest. 2006;66(8):723-731. (Prospective study; 105 patients)
76. Anielski R, Kusnierz-Cabala B, Szafraniec K. An evaluation of the utility of additional tests in the preoperative diagnostics of acute appendicitis. Langenbecks Arch Surg. 2010;395(8):1061-1068. (Prospective study; 132 patients)
77. Chakhunashvili L, Inasaridze A, Svanidze S, et al. Procalcitonin as the biomarker of inflammation in diagnostics of pediatric appendicular peritonitis and for the prognosis of early postoperative complications. Georgian Med News. 2005;(129)(129):78-81. (Prospective study; 43 patients)
78. Kouame DB, Garrigue MA, Lardy H, et al. Is procalcitonin able to help in pediatric appendicitis diagnosis? Ann Chir. 2005;130(3):169-174. (Prospective study; 70 patients)
79. Blab E, Kohlhuber U, Tillawi S, et al. Advancements in the diagnosis of acute appendicitis in children and adolescents. Eur J Pediatr Surg. 2004;14(6):404-409. (Prospective study; 1156 patients)
80. Kwan KY, Nager AL. Diagnosing pediatric appendicitis: Usefulness of laboratory markers. Am J Emerg Med. 2010;28(9):1009-1015. (Prospective study; 209 patients)
81. Goergens E, McEvoy A, Watson M, et al. Acute osteomyelitis and septic arthritis in children. J Paediatr Child Health. 2005;41(1‐2):59-62. (Retrospective study; 149 patients)
82. Al Saadi MM, Al Zamil FA, Bokhary NA, et al. Acute septic arthritis in children. Pediatrics International. 2009;51(3):377-380. (Retrospective study; 65 patients)
83. Klein DM, Barbera C, Gray ST, et al. Sensitivity of objective parameters in the diagnosis of pediatric septic hips. Clin Orthop Relat Res. 1997;(338):153-159. (Retrospective study; 26 patients)
84. Kallio MJ, Unkila-Kallio L, Aalto K, et al. Serum C-reactive protein, erythrocyte sedimentation rate and white blood cell count in septic arthritis of children. Pediatr Infect Dis J. 1997;16(4):411-413. (Prospective study; 100 patients)
85. Levine MJ, McGuire KJ, McGowan KL, et al. Assessment of the test characteristics of C-reactive protein for septic arthritis in children. Journal of Pediatric Orthopaedics. 2003;23(3):373. (Retrospective study; 133 patients)
86. Del Beccaro MA, Champoux AN, Bockers T, et al. Septic arthritis versus transient synovitis of the hip: the value of screening laboratory tests. Ann Emerg Med. 1992;21(12):1418-1422. (Retrospective study; 132 patients)
87. Eich G, Superti-Furga A, Umbricht F, et al. The painful hip: evaluation of criteria for clinical decision-making. Eur J Pediatr. 1999;158(11):923-928. (Retrospective study; 89 patients)
88. Kocher MS, Zurakowski D, Kasser JR. Differentiating between septic arthritis and transient synovitis of the hip in children: An evidence-based clinical prediction algorithm. J Bone Joint Surg. 1999;81(12):1662-1670. (Retrospective study;168 patients)
89. * Kocher MS, Mandiga R, Zurakowski D, et al. Validation of a clinical prediction rule for the differentiation between septic arthritis and transient synovitis of the hip in children. J Bone Joint Surg. 2004;86-A(8):1629-1635. (Prospective study; 154 patients)
90. * Caird MS, Flynn JM, Leung YL, et al. Factors distinguishing septic arthritis from transient synovitis of the hip in ChildrenA prospective study. J Bone Joint Surg. 2006;88(6):1251-1257. (Prospective study; 53 patients)
91. Luhmann SJ, Jones A, Schootman M, et al. Differentiation between septic arthritis and transient synovitis of the hip in children with clinical prediction algorithms. J Bone Joint Surg. 2004;86(5):956-962. (Retrospective study; 165 patients)
92. Sultan J, Hughes PJ. Septic arthritis or transient synovitis of the hip in children: the value of clinical prediction algorithms. J Bone Joint Surg Br. 2010;92(9):1289-1293. (Review article)
93. Carpenter CR, Schuur JD, Everett WW, et al. Evidence-based diagnostics: adult septic arthritis. Acad Emerg Med. 2011;18(8):781-796. (Systematic review; 32 studies)
94. Reed L, Baskett A, Watkins N. Managing children with acute non-traumatic limp: the utility of clinical findings, laboratory inflammatory markers and X-rays. Emerg Med Australas. 2009;21(2):136-142. (Retrospective study; 350 patients)
95. Singhal R, Perry DC, Khan FN, et al. The use of CRP within a clinical prediction algorithm for the differentiation of septic arthritis and transient synovitis in children. J Bone Joint Surg Br. 2011;93(11):1556-1561. (Retrospective study; 311 patients)
96. Jeng GW, Wang CR, Liu ST, et al. Measurement of synovial tumor necrosis factor-alpha in diagnosing emergency patients with bacterial arthritis. Am J Emerg Med. 1997;15(7):626-629. (Prospective study; 75 patients)
97. Söderquist B, Jones I, Fredlund H, et al. Bacterial or crystal-associated arthritis? discriminating ability of serum inflammatory markers. Scand J Infect Dis. 1998;30(6):591-596. (Retrospective study; 88 patients)
98. Margaretten ME, Kohlwes J, Moore D, et al. Does this adult patient have septic arthritis? JAMA. 2007;297(13):1478-1488. (Meta-analysis; 6242 patients)
99. Butbul-Aviel Y, Koren A, Halevy R, et al. Procalcitonin as a diagnostic aid in osteomyelitis and septic arthritis. Pediatr Emerg Care. 2005;21(12):828-832. (Prospective study; 44 patients)
100. * Faesch S, Cojocaru B, Hennequin C, et al. Can procalcitonin measurement help the diagnosis of osteomyelitis and septic arthritis? A prospective trial. Ital J Pediatr. 2009;35:33-39. (Prospective study; 339 patients)