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Abstract

  1. Top of page
  2. Abstract
  3. Continuing Medical Education
  4. Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusions
  9. References

ACADEMIC EMERGENCY MEDICINE 2011; 18:568–574 © 2011 by the Society for Academic Emergency Medicine

Abstract

Objectives:  The objective was to assess the accuracy of novel and traditional biomarkers in patients with suspected appendicitis as a function of duration of symptoms.

Methods:  This was a prospective cohort study, conducted in a tertiary care emergency department (ED). The authors enrolled children 3 to 18 years old with acute abdominal pain of less than 96 hours and measured serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), white blood cell (WBC) count, and absolute neutrophil count (ANC). Final diagnosis was determined by histopathology or telephone follow-up. Trends in biomarker levels were examined based on duration of abdominal pain. The accuracy of biomarkers was assessed with receiver operating characteristic (ROC) curves. Optimal cut-points and test performance characteristics were calculated for each biomarker.

Results:  Of 280 patients enrolled, the median age was 11.3 years (interquartile range [IQR] = 8.6 to 14.8), 57% were male, and 33% had appendicitis. Median IL-6, median CRP, mean WBC count, and mean ANC differed significantly (p < 0.001) between patients with nonperforated appendicitis and those without appendicitis; median IL-8 levels did not differ between groups. In nonperforated appendicitis, median IL-6, WBC, and ANC levels were maximal at less than 24 hours of pain, while CRP peaked between 24 and 48 hours. In perforated appendicitis, median IL-8 levels were highest by 24 hours, WBC count and IL-6 by 24 to 48 hours, and CRP after 48 hours of pain. The WBC count appeared to be the most useful marker to predict appendicitis in those with fewer than 24 or more than 48 hours of pain, while CRP was the most useful in those with 24 to 48 hours of pain.

Conclusions:  In this population, the serum levels and accuracy of novel and traditional biomarkers varies in relation to duration of abdominal pain. IL-6 shows promise as a novel biomarker to identify children with appendicitis.


Continuing Medical Education

  1. Top of page
  2. Abstract
  3. Continuing Medical Education
  4. Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusions
  9. References

Continuing Medical Education Activity in Academic Emergency Medicine

CCME Editor: Hal Thomas, MD

Authors: Anupam B. Kharbanda, MD, MS, Yohaimi Cosme, MD, Khin Liu, Steven L. Spitalnik, MD, and Peter S. Dayan, MD, MS

Article Title: Discriminative Accuracy of Novel and Traditional Biomarkers in Children With Suspected Appendicitis Adjusted for Duration of Abdominal Pain

If you wish to receive credit for this activity, please refer to the website: http://www.wileyblackwellcme.com.

Accreditation and Designation Statement:

Blackwell Futura Media Services designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Educational Objectives

After completing this exercise, the participant will be able to discuss the indications for and usefulness of various biomarkers to aid in diagnosis of appendicitis.

Activity Disclosures

No commercial support has been accepted related to the development or publication of this activity.

Faculty Disclosures:

CME editor – Hal Thomas, MD: no relevant financial relationships to disclose

Authors – Anupam B. Kharbanda, MD, MS, Yohaimi Cosme, MD, Khin Liu, Steven L. Spitalnik, MD, Peter S. Dayan, MD, MS: No relevant financial relationships to disclose.

This manuscript underwent peer review in line with the standards of editorial integrity and publication ethics maintained by Academic Emergency Medicine. The peer reviewers have no relevant financial relationships. The peer review process for Academic Emergency Medicine is double-blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review.

Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. No relevant financial relationships exist for any individual in control of the content and therefore there were no conflicts to resolve.

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For information on applicability and acceptance of CME credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within an hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication.

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This activity will be available for CME credit for twelve months following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months.

Appendicitis remains a challenging diagnosis in the pediatric population.1 Clinicians increasingly rely on diagnostic imaging, such as computed tomography (CT), to identify patients with appendicitis.2 Although CT is highly accurate, substantial concerns have been raised regarding the overuse of CT, particularly the adverse health effects resulting from exposure to ionizing radiation.3,4

Biomarkers may serve as alternative diagnostic tools to identify patients at high or low risk for appendicitis.5–7 To date, there is no optimal biomarker, or combination of biomarkers, for diagnosing appendicitis. Two recent studies have suggested the prominent role of cytokines (e.g., interleukins [IL-6 and IL-8]) in the inflammatory response of patients with appendicitis.6,8 Previous authors have demonstrated that serum IL-6, a potent inducer of the systemic immune response to a bacterial infection, is up-regulated in appendicitis.9 IL-8, a chemoattractant for neutrophils, is also up-regulated in proportion to the degree of neutrophil invasion in the affected appendix.10,11

Prior studies have revealed conflicting and variable performance of traditional biomarkers such as the white blood cell (WBC) count to diagnose appendicitis, emphasizing the need to explore and study novel biomarkers.1,9,12–14 The limited utility of traditional biomarkers should not be surprising, as appendicitis is a dynamic, evolving process, for which fluctuations in levels might be expected. This theory has been explored by researchers who have demonstrated the diagnostic benefit of repeat laboratory measures (WBC, C-reactive protein [CRP]) in hospitalized, adult patients with acute abdominal pain.15–17

We hypothesized that novel and standard biomarkers would have improved test performance if correlated with a patient’s evolving, inflammatory response to appendicitis. Therefore, we aimed to describe the trends and accuracy in serum levels of novel (IL-6, IL-8) and traditional (WBC, absolute neutrophil count [ANC], and CRP) biomarkers in relation to the duration of abdominal pain in children with suspected appendicitis. By using duration of pain as a surrogate for the degree of inflammation, we sought to identify which biomarkers might be most useful for distinguishing appendicitis from other causes of acute abdominal pain over the course of illness.

Methods

  1. Top of page
  2. Abstract
  3. Continuing Medical Education
  4. Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusions
  9. References

Study Design

We conducted a prospective, observational pilot study. We obtained written informed consent from all parents and assent from children 7 years of age and older. The study was approved by the local institutional review board.

Study Setting and Population

The study site was an urban, tertiary care, pediatric emergency department (ED), with approximately 50,000 visits annually. From August 2008 to November 2009, children 3 to 18 years of age who presented to the ED with acute abdominal pain of less than 96 hours’ duration and who were being evaluated for possible appendicitis were enrolled. We defined “possible appendicitis” as when the treating physician obtained blood tests, radiologic studies (CT and/or ultrasound), or a surgical consultation for the purpose of diagnosing appendicitis. In our ED, it is standard practice to obtain a WBC count with differential for all patients with suspected appendicitis. Radiologic studies or surgical consults are obtained at the discretion of the treating physician. We excluded patients with any of the following conditions: pregnancy, prior abdominal surgery (e.g., gastrostomy tube, abdominal hernia repair), chronic illness that potentially affected the gastrointestinal system (e.g., cystic fibrosis, inflammatory bowel disease, sickle cell anemia, chronic pancreatitis, diabetes, immunosuppression), or a medical condition affecting the provider’s ability to obtain an accurate history (e.g., substantial language or developmental delay). We also excluded patients who had radiologic studies (CT or ultrasound) of the abdomen performed prior to ED arrival or a history of abdominal trauma within 7 days of the ED evaluation.

Study Protocol

Pediatric emergency physicians completed standardized histories and physical examinations prior to knowledge of any radiologic studies, if obtained. As part of the patient history, clinicians categorized the duration of pain in 12-hour intervals. To assess the interobserver reliability of the duration of pain, a second physician assessor was asked to complete an additional data collection tool on a subset of patients within 30 minutes of the first assessor.

The patient’s medical record was abstracted to obtain data from laboratory, radiology, pathology, and operative reports. A single research assistant (YC) abstracted the medical record and entered it into Microsoft Access (Microsoft Corp., Redmond, WA); all data were double-checked for accuracy by one author (ABK), including a review of data interpretation and data entry. We reviewed the daily ED admission log and electronic tracking system to identify potentially eligible patients who were not enrolled (i.e., missed).

Serum Collection and Analysis

We obtained serum WBC count and automated differentials per standard hospital procedure. We obtained an additional aliquot of patient serum (3–5 mL) and placed it into a serum separator tube to measure IL-6, IL-8, and CRP levels. These additional samples were sent to the hospital clinical laboratory within 1 hour of collection where they were spun at a speed of 1300 relative centrifugal force for 10 minutes. During the hours of 0900 to 1600, trained laboratory technicians immediately divided the sample into two aliquots and froze the blood at −80°C. After 1600 on weekdays and at all times on weekends, spun samples were stored at 4°C. The following business day, the laboratory technicians divided the samples into two aliquots and froze the blood at −80 °C. We recorded the time the serum was drawn, delivered to the laboratory, and frozen.

The study laboratory technicians analyzed the serum for IL-6 and IL-8 (R&D Systems, Minneapolis, MN) levels by enzyme-linked immunosorbent assay (ELISA). CRP (Siemens Healthcare Diagnostics, Deerfield, IL) was measured by particle enhanced immunonephelometry. If the initial IL-6 level was at the lower detection limit of 3.12 pg/mL on the primary ELISA assay, an additional hypersensitive IL-6 assay (R&D Systems) was performed to assess the full spectrum of IL-6 levels in patients with acute abdominal pain. The technicians were blinded to the patient’s final diagnosis.

Measures

The primary outcome was the presence or absence of appendicitis, determined by reviewing the written attending pathologist histopathology report for patients who had an appendectomy. A perforated appendix was determined by the attending surgeon’s written postoperative note. For patients who did not have surgery, we determined the outcome by a follow-up telephone call 14 to 21 days following the index ED visit. If the family could not be reached, a review of the hospital electronic record system was conducted to assess for operations (i.e., appendectomy), hospitalizations or ED visits during the follow-up period. Those assessing the outcome were blinded to the biomarker levels.

Data Analysis

For each biomarker, we conducted descriptive analyses, exploring ranges, means with standard deviations (SDs), medians with interquartile ranges (IQRs), and the respective 95% confidence intervals (CIs). We assessed the association between each biomarker and the presence or absence of appendicitis with the unpaired t-test or Mann-Whitney U-test for normally and asymmetrically distributed data, respectively. To assess biomarker trends and accuracy among groups with similar illness severity, we then stratified our analyses by appendicitis status (e.g., perforated appendicitis, nonperforated appendicitis, or no appendicitis). Finally, we constructed receiver operating characteristic (ROC) curves to determine the area under the curve (AUC) for the various serum biomarkers based on the duration of abdominal pain in three clinically relevant time intervals: <24, 24 to 48, and >48 hours of pain. Within each time category, we calculated the cut-point from the ROC curve that maximized sensitivity and specificity (based on the Youden index).18 The test performance characteristics (including likelihood ratio [LR]) for this cut-point were then calculated. We determined the interobserver reliability between physicians for their assessment of duration of abdominal pain using Cohen’s unweighted kappa statistic.19–21 All statistical analyses were performed using SPSS (Version 18.0, SPSS Inc., Chicago, IL.

Results

  1. Top of page
  2. Abstract
  3. Continuing Medical Education
  4. Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusions
  9. References

Study Population

Over the 15-month study period, 380 patients 3 to 18 years of age presented to the ED with acute abdominal pain and were considered for appendicitis. A total of 291 were potentially eligible for participation, 280 were enrolled (96%), and 259 had complete biomarker data available for analysis of trends and discriminative characteristics (Figure 1).

image

Figure 1.  Study patient flow.

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Patient Characteristics

Of the 280 enrolled patients, the median age was 11.3 years (IQR = 8.6, 14.8 years), and 160 (57%) were male. Comparisons between patients with appendicitis and those without revealed no statistical difference by sex, age, duration of abdominal pain, history of right lower quadrant pain, mean temperature in the ED, tenderness on exam, or percentage who underwent imaging (p > 0.05 for all comparisons). Pairs of physicians (n = 41) showed good interobserver agreement on their assessments of the duration of abdominal pain (κ = 0.63).

Ninety-four patients were diagnosed with appendicitis (33%), of whom 22 (23%) had a perforated appendix. We completed telephone follow-up on 177 (99%) of the 179 patients who did not undergo an operation; none had an appendectomy during the follow-up period. Medical records for the two patients lost to telephone follow-up revealed no further ED visits, operations, or hospitalizations within 2 months of enrollment. Compared to enrolled patients, eligible patients who were not enrolled were slightly older (median age = 13.1 years) and more likely to be female (60%), but had similar likelihoods of undergoing CT or ultrasound (73%) and having appendicitis (36%).

Levels of Biomarkers in Patients With and Without Appendicitis

The biomarker levels in patients without appendicitis, with nonperforated appendicitis, and with perforated appendicitis are shown in Table 1. Each serum biomarker level except IL-8 was statistically higher for patients with nonperforated appendicitis compared to those without appendicitis (p < 0.001). The serum levels of all biomarkers differed significantly for children with perforated appendicitis compared to those with nonperforated appendicitis (p < 0.001).

Table 1.    Biomarker Levels Stratified by Appendicitis Status
BiomarkerNo Appendicitis (n = 186)Nonperforated Appendicitis (n = 72)Perforated Appendicitis (n = 22)
  1. ANC = absolute neutrophil count; CRP = C-reactive protein; IL-6 = interleukin-6; IL-8 = interleukin-8; IQR = interquartile range; WBC = white blood cell.

  2. *Mean (±SD). Data for WBC count, ANC, and neutrophil count were normally distributed.

  3. †p < 0.001 for comparisons between no appendicitis and nonperforated appendicitis groups.

  4. ‡p < 0.001 for comparisons between nonperforated appendicitis and perforated appendicitis groups.

  5. §Values in brackets are 95% CIs.

  6. ||Median (IQR). Data for IL-6, IL-8, and CRP levels were skewed and thus not normally distributed.

WBC count (×109/L)* (n = 276)10.4 (±4.8)† [9.7–11.1]§15.8 (±4.5) [14.8–16.9]17.3 (±4.4)‡ [15.3–19.2]
ANC (×109/L)* (n = 262)7.5 (±4.7)† [6.8–8.2]12.7 (±4.6) [11.6–13.8]14.7 (±4.5)‡ [12.6–16.7]
IL-6 (pg/mL)|| (n = 259)4.4 (1.3–16.1)† [2.4–5.7]21.0 (9.8–37.0) [15.7–25.1]122.3 (42.2–388.6)‡ [43.8–250.6]
IL-8 (pg/ml)|| (n = 259)16.3 (11.0–24.2) [13.9–17.5]13.5 (10.6- 21.2) [11.9–16.2]25.2 (19.0–55.6)‡ [19.1–38.2]
CRP (mg/L)|| (n = 260)5.3 (0.49–17.8)† [2.7–7.4]14.1 (4.9–34.4) [7.3–22.9]115.1 (38.3–179.0)‡ [38.5–155]

Relationship of Duration of Abdominal Pain to Biomarker Levels

In Figures 2A–2D, the biomarker levels for IL-6, IL-8, WBCs (ANC results closely approximate the WBC count and are not shown), and CRP are shown for each time interval as stratified by appendicitis status. As seen in each figure, biomarker levels in patients without appendicitis remain low and steadily decline across the time intervals. In comparison, in cases of either nonperforated or perforated appendicitis, biomarker levels rise and reach maximum values at different rates. In nonperforated appendicitis, median IL-6 and WBC levels are maximal by 24 hours of pain, and CRP by 24 to 48 hours, and median IL-8 levels were similar across time categories. In perforated appendicitis, median IL-8 level is highest by 24 hours, WBC count and IL-6 by 24 to 48 hours, and CRP after 48 hours of pain.

image

Figure 2.  (A) WBC levels based on duration of pain and appendicitis status. (B) IL-6 levels based on duration of pain and appendicitis status. (C) IL-8 levels based on duration of pain and appendicitis status. (D) CRP levels based on duration of pain and appendicitis status. CRP = C-reactive protein; IL-6 = interleukin-6; IL-8 = interleukin-8; WBC = white blood cell.

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Time-dependent Accuracy of Biomarkers

Table 2 displays the discriminative ability of the biomarkers studied to distinguish patients with appendicitis (perforated and nonperforated) from those without appendicitis, stratified by duration of abdominal pain. The WBC count, ANC, and IL-6 had relatively similar AUCs for children with less than 24 hours of pain, whereas CRP had a trend toward greater discriminative accuracy (by AUC) in the 24- to 48-hour time period, and the WBC count appeared to be more accurate than other biomarkers in those with longer than 48 hours of abdominal pain. Despite these trends, the 95% CIs for the AUCs of these biomarkers did overlap.

Table 2.    Biomarker Performance Based on Duration of Abdominal Pain
BiomarkerDuration of Pain (Hours)AUC (95% CI)Cut-point Maximizing Overall AccuracySensitivity at Cut-point, % (95% CI)Specificity at Cut-point, % (95% CI)LR+
  1. ANC = absolute neutrophil count; AUC = area under the receiver operating characteristic curve; CRP = C-reactive protein; IL-6 = interleukin-6; IL-8 = interleukin-8; LR+ = likelihood ratio positive; WBC = white blood cell.

WBC count (×109/L)<240.78 (0.70–0.85)14.667.8 (54–79)80.0 (70–87)3.4
24–480.87 (0.78–0.95)10.095.6 (76–100.0)71.4 (55–84)3.3
>480.92 (0.84–0.99)10.0100 (70–100.0)73.3 (58–85)3.8
ANC (×109/L)<240.78 (0.70–0.85)11.069.1 (55–81)74.7 (64–83)2.7
24–480.85 (0.76–0.95)8.490.5 (68–98)80.0 (64–90)4.5
>480.89 (0.80–0.98)6.091.7 (60–100.0)66.7 (50–80)2.8
IL-6 (pg/mL)<240.78 (0.71–0.86)11.3182.1 (69–91)68.5 (58–78)2.6
24–480.87 (0.79–0.95)5.795.6 (76–100.0)71.1 (54–84)3.3
>480.76 (0.60–0.93)2.591.7 (60–100.0)58.5 (42–73)1.3
IL-8 (pg/mL)240.49 (0.40–0.59)64.85.3 (1.8–14.6)81.8 (73–88)0.3
24–480.59 (0.44–0.74)15.965.2 (43–83)63.2 (46–78)1.8
>480.57 (0.36–0.78)24.141.2 (17–71)86.8 (71–95)3.2
CRP (mg/L)<240.64 (0.55–0.73)0.692.9 (82–98)28.1 (19–39)1.3
24–480.89 (0.81–0.97)20.887.0 (65–97)86.8 (71–95)6.6
>480.85 (0.73–0.96)7.0100 (70–99)56.1 (40–71)2.3

Within each time category, we also provide cut-points and test performance characteristics for each biomarker, as calculated from their respective ROC curves. Each biomarker exhibited fluctuations in test performance as a function of duration of pain. For example, the test performance of the WBC count was maximal (LR+ of 3.8) in the >48-hour time period, while for IL-6 and CRP, optimal performance was seen in the 24- to 48-hour time period (LR+ of 3.3 and 6.6, respectively). Based on the LR+, the WBC count appeared to be the most useful marker to predict appendicitis in those with <24 or >48 hours of pain, while CRP was the most useful in those with 24 to 48 hours of pain.

Discussion

  1. Top of page
  2. Abstract
  3. Continuing Medical Education
  4. Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusions
  9. References

In this pilot study, we have demonstrated the fluctuations in serum levels and accuracy of novel and traditional biomarkers for pediatric appendicitis as a function of duration of pain. In patients with nonperforated appendicitis, median serum IL-6, the WBC count, and ANC levels were highest in the 24 hours after symptoms of pain began, while median CRP levels trended higher in those with 24 to 48 hours of pain. Furthermore, we found that the novel biomarker IL-6 had substantial discriminative ability, whereas IL-8 was seemingly less useful for diagnosing nonperforated appendicitis.

We believe that an understanding of the fluctuations in biomarker levels in relation to the duration of abdominal pain may be clinically useful. IL-6 increased early in relation to symptoms of pain, consistent with its role in stimulating the immune system to contain infection, whereas CRP, which is stimulated by IL-6, required 24 to 36 hours for up-regulation. In comparison, the WBC count and ANC showed little fluctuations in patients with nonperforated appendicitis. We found it interesting that the biomarkers studied in this pilot did not necessarily exhibit their best test performance during time periods when their levels would be expected to peak. For example, although overall CRP levels peaked in those with >48 hours of pain, CRP exhibited its best test performance in those with 24 to 48 hours of pain. Similarly, the WBC count revealed improving test performance as duration of pain increased. If further research confirms our findings, clinicians could tailor which laboratory test(s) they obtained in relation to a patient’s history of symptoms. In addition, the thresholds (as described in Table 2) that would trigger further action would also change based on an understanding of these fluctuations. Based on our results, the WBC count appears to be the most useful biomarker in those patients with <24 or >48 hours of pain, while the CRP may be the most useful in those with 24 to 48 hours of pain. In addition, if IL-6 is to be utilized in the diagnosis of appendicitis, it may be most useful in those with symptoms for 24 to 48 hours or it may be used to distinguish which patients with appendicitis have a perforated appendix.

For each of the biomarkers analyzed in this study, serum levels remained low or declined in patients without appendicitis, even as duration of symptoms increased. We believe that the improved overall test performance of the WBC count, as duration of pain increased, can be attributed to the steady decline in the WBC in patients without appendicitis (who likely have conditions that do not illicit as aggressive of an immune response). These findings add to prior literature, in which low levels of the WBC and ANC have provided reassurance for the absence of appendicitis.1,22,23 Furthermore, two recent studies have provided results that would indicate that a normal WBC count combined with a normal CRP value would make the probability of appendicitis low.24,25 Further research is needed to determine whether a combination of the biomarkers analyzed in this study provide marginal benefit over individual biomarkers for the purpose of diagnosing appendicitis when correlated to a patient’s symptoms of abdominal pain.

Similar to our findings, several prior publications have described improved test performance characteristics of CRP in those with several days of symptoms.24,26 In addition, prior researchers have noted the utility of serial CRP measurements with acute abdominal pain, describing that an increasing CRP level over time was concerning for appendicitis.15,17 Although previous authors have noted that the dynamic nature of CRP levels may make serial measurement useful, it may be clinically more feasible to associate a biomarker with duration of symptoms, as serial blood draws can be problematic in the ED setting and in children.17,26 We agree with previous authors that an elevation in CRP (either serial measurements or as correlated to durations of symptoms) in children with acute abdominal pain may aid in the diagnosis of appendicitis.

Our IL-6 findings differ from prior studies in which serum IL-6 levels were only elevated in children with perforated appendicitis.9–11,13 Paajanen et al.10 measured cytokine levels in 80 patients (27 of them younger than 20 years) undergoing surgery for appendectomy and found that IL-6 levels correlated with increasing severity of inflammation seen on histopathology, but that no significant differences were noted in IL-6 levels between patients with nonperforated appendicitis and those without appendicitis. Similarly, Sack et al.9 recently reported on 211 children with suspected appendicitis (189 underwent appendectomies) and found that IL-6 levels in patients without appendicitis and with focal, nonperforated appendicitis by histopathology were both low (median IL-6 levels 2.5 and 5.9 pg/mL, respectively). Our results may have differed due to the inclusion of a population of patients who mostly did not have appendicitis (as opposed to higher rates of appendicitis in previous studies), which provided us a more accurate estimate of IL-6 levels in those without appendicitis. Additionally, we were unable to determine the timing of the biomarker assessments in the previous IL-6 studies. IL-6 is up-regulated by mRNA transcription (which takes 4 to 6 hours), and protein levels peak by 24 hours following the development of a localized inflammatory process.10,11,13 Therefore, diagnostic performance may depend on when in the disease course serum is collected.

Although IL-8 levels were elevated in children with perforated appendicitis, serum levels do not distinguish patients with nonperforated appendicitis from those without appendicitis. We studied IL-8 as recent research demonstrated that IL-8 gene expression was highly elevated in appendicitis and that expression correlated with the degree of inflammation on pathology.6 Although our results were consistent with this finding for those with perforation, it is not clear why serum IL-8 levels were not elevated in patients with nonperforated appendicitis. Similar to our findings, Yoon et al.11 found that serum IL-8 levels were significantly elevated only in patients with perforated appendicitis.

Limitations

  1. Top of page
  2. Abstract
  3. Continuing Medical Education
  4. Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusions
  9. References

The current study has several limitations. First, although a relatively large number of patients were prospectively enrolled, there were a limited number of patients with a longer duration of abdominal pain and nonperforated appendicitis; this resulted in wide 95% CIs for estimates of diagnostic accuracy. Second, the estimates of biomarker accuracy were based on the premise that physicians could reliably determine, and parents and children could reliably report, duration of pain. Although this is a potential source of variability, there was good interobserver reliability between physicians. Additionally, sequential serum samples were not collected from patients; this mimics the routine ED setting where only a single sample would typically be obtained. It should be noted that although we had a very high follow-up rate, two patients were lost to telephone follow-up. We cannot exclude that these patients sought care at an alternative medical facility. Finally, the human IL-6 and IL-8 assay kits are presently intended for laboratory investigation, take many hours to complete, and are not FDA-approved for clinical use. Further work must be done to confirm biomarker utility and to develop assays to provide biomarker results in a clinically useful time frame. Nevertheless, this study provides important baseline information to guide future research on novel biomarkers.

Conclusions

  1. Top of page
  2. Abstract
  3. Continuing Medical Education
  4. Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusions
  9. References

Although interleuken-6, the white blood cell count, the absolute neutrophil count, and C-reactive protein are all increased in patients with appendicitis, levels of these markers fluctuate over the course of illness. Serum interleuken-6 is a potentially useful novel biomarker for patients with suspected appendicitis. Duration of symptoms may be an important variable to consider when interpreting laboratory values in patients with acute abdominal pain.

References

  1. Top of page
  2. Abstract
  3. Continuing Medical Education
  4. Methods
  5. Results
  6. Discussion
  7. Limitations
  8. Conclusions
  9. References