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.
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:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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%.
Most authors agree that this vulnerable population (≤ 30 days old) should always be admitted for observation if they are febrile.
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.
Landon A. Jones; Carl E. Barus; Richard M. Cantor
October 1, 2012