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Keywords:

  • inflammatory bowel disease;
  • pediatrics;
  • serologic tests

Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Background:

Our purpose was to study the concordance of serological tests for inflammatory bowel disease with clinical diagnosis established by traditional testing in children.

Methods:

All children seen in our division who had IBD Diagnostic System (ie, pANCA, ASCA IgA, and ASCA IgG) performed over a 21-month period (June 1998 to February 2000) were identified. Their medical records were reviewed for basic demographics, test results (endoscopy, histology, and radiology), IBD Diagnostic System results, and patient symptoms/medications. Results of the IBD Diagnostic System were compared with several patient characteristics including age, sex, absence/presence of symptoms, medication use, disease activity and duration.

Results:

One hundred seven patients were divided into 6 groups based on clinical diagnosis and IBD Diagnostic System results. The sensitivity, specificity and +/− predictive values of the IBD Diagnostic System for ulcerative colitis were 69.2, 95.1, 90.0, and 87.1%, respectively, and for Crohn's disease were 54.1, 96.8, 90.9, and 80.8%, respectively. Overall, the results of the IBD Diagnostic System were concordant with the clinical diagnosis in 76 of the 107 (71%) patients.

Conclusions:

In our experience, the specificity of IBD Diagnostic System is better than the sensitivity; the sensitivity is better for ulcerative colitis than Crohn's disease (69.2% vs 54.1%). The low sensitivity, especially for Crohn's disease, precludes the possibility that the IBD Diagnostic System can replace traditional studies when evaluating for inflammatory bowel disease. Though we do not exclude inflammatory bowel disease solely by IBD Diagnostic System results, it is reassuring to note that all patients without clinical evidence of inflammatory bowel disease also had negative IBD Diagnostic System results.

A combination of tests is used when evaluating for possible inflammatory bowel disease (IBD), and no one test can diagnose IBD with absolute certainty. 1–3 The testing starts with a detailed history, comprehensive physical examination, and a panel of laboratory studies that include nonspecific markers of inflammation. The next steps involve endoscopic examinations of the upper and lower gastrointestinal tracts, careful examination of endoscopically obtained tissue specimens, and contrast radiography of the small bowel. A diagnosis of IBD is made or excluded based on results of these tests, and, if present, the IBD is classified as Crohn's disease (CD), ulcerative colitis (UC) or, infrequently, indeterminate colitis (IC).

Various biologic markers have been studied in patients with IBD over the last several years. 4 Antineutrophil cytoplasmic antibody (ANCA) has shown promise, and studies indicate that ANCA with a perinuclear staining pattern (pANCA) is present in 60% to 80% of patients with UC versus 3% to 4% of healthy individuals. 4–6 Elevated titers of IgA and IgG antibodies directed against the phosphopeptidomannan part of the cell wall of Saccharomyces cerevisiae (baker's yeast) (anti–Saccharomyces cerevisiae antibody, ASCA) are found in 50% to 80% of CD patients and are rarely found in patients with UC (<10%) or healthy controls (<5%). 4,5 Main et al 7 initially correlated ASCA with CD in 1988.

Technologically refined serological tests for IBD are now commercially available. One such test is the IBD Diagnostic System (IDS) (Prometheus Laboratories, Inc., San Diego, CA). The IDS examined for pANCA, ASCA IgA, and ASCA IgG until recently when another component, namely αOmpC, was added to the panel. We wished to study the concordance of IDS with the clinical diagnosis established by traditional tests in children. We also examined the correlation between IDS and several patient characteristics.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patients

The study patients were under the age of 19 years who had been seen by the Division of Gastroenterology at the James Whitcomb Riley Hospital for Children, Indiana University Medical Center, Indianapolis during a 21-month period (June 1998 through February 2000) and had the IDS performed. No specific inclusion/exclusion criteria were used to select patients with IBD who underwent the IDS test. Data was collected from patient medical records and included basic demographics (eg, age and sex), endoscopic findings, biopsy findings, interpretation of radiographic studies, and the final clinical diagnosis. The IDS results were recorded, as were symptoms and medications at the time of these tests. An IBD activity score was calculated using the scoring system developed by Lloyd-Still and Green. 8

Clinical Diagnosis

These were made using established criteria, 1–3 independent of the IDS results. Specifically, UC was diagnosed by the presence of continuous mucosal disease involving the rectum and extending proximally for variable distances, as assessed by endoscopy, and histologic changes consistent with UC. A diagnosis of CD was established by the presence of appropriate endoscopic (eg, aphthoid ulcers, serpiginous ulcers, cobblestone appearance, and skip lesions/noncontiguous disease), histologic (eg, granulomas), and radiologic (eg, small bowel disease) data. A diagnosis of IC was entertained when there was endoscopic, histologic, and radiologic evidence of IBD, but features of both UC and CD were present. 1,5,9 The colonic findings in the patients classified as IC were consistent with a diagnosis of UC; yet their biopsies, often from the upper gastrointestinal tract, contained multinucleated giant cells.

IBD Diagnostic System

The test was performed by Prometheus Laboratories, Inc. (San Diego, CA) using techniques previously described. 5

Statistical Analysis

Statistical analysis was performed utilizing Sigmastat software, version 2.03 (SPSS, Inc). A p value of <0.05 was considered significant. Result analysis between the groups with positive or negative IDS was by the one-way ANOVA with a 95% confidence interval. This was applied for comparison of the six patient groups based on patient age, sex, and IBD activity score.

The z-test comparison of proportions was used to determine if occurrences were significantly different among the various patient groupings. The z-test was performed to compare the likelihood of a positive or negative IDS based on patient age (≤12 years old vs >12 years of age), male or female sex, absence/presence of clinical symptoms, use of medications, disease activity based on IBD activity score (inactive, mild, moderate, severe), and diagnosis duration (done in three parts: average duration for entire group, established patients alone, and newly diagnosed patients alone). These analyses were performed for the entire group and also for patients with CD alone, UC alone or IC alone. The analysis for specificity, sensitivity, positive predictive value and negative predictive value were performed using all patients except group 5.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

During the study period, 112 patients (56/112 males) had the IDS ordered with a mean age of 12.57 years (range 0.16–18.43 years); 5 patients were excluded due to incomplete evaluation. The remaining 107 patients were divided into 6 groups based on clinical diagnosis and results of the IDS test (Table 1). The results of the first IDS were used when the patients had IDS performed more than once (12 patients).

Table 1. Patients Were Divided into Five Groups Based on Clinical Diagnosis (CLD) and IBD Diagnostic System (IDS)
Group (n)CLD/IDSMale % (N)Mean Age (Years) (Range)
  • *

    IDS either negative for both pANCA/ASCA (n = 9) or positive for both pANCA/ASCA (n = 3).

  • **

    IDS either negative for both pANCA/ASCA (n = 14) or )ANCA+/ASCA- (n = 3).

1(27)UC+/UC+44.4 (12)13.03(7.83–18)
2(20)CD+/CD+60.0(12)13.34 (6–18.33)
3(12)UC+/UC-*66.7(8)14.25 (9.75–16.17)
4(17)CD+/CD-**47.1(8)12.66 (9.08–17.67)
5(7)Indeterminate colitis28.6(2)10.42 (1.83–15.67)
6(24)Control (−/−)50.0(12)10.78 (0.16–15.67)

The 27 patients in group 1 carried a clinical diagnosis of UC that was confirmed by IDS; their pANCA titer was elevated and they were negative for ASCA (IgA/IgG). The 20 patients in group 2 had a clinical diagnosis of CD and the IDS results supported this; they were negative for pANCA and their ASCA (IgA and/or IgG) was elevated. The 12 patients in group 3 were clinically felt to have UC, but their IDS test was discordant, that is, either negative for both pANCA/ASCA (9 patients) or positive for both pANCA/ASCA (3 patients, one of whom was later re-classified as CD based on pouchitis with granuloma on tissue specimens following colectomy). The clinical data in the 17 patients in group 4 were consistent with CD, but the IDS results were either negative for both pANCA/ASCA (14 patients) or pANCA+/ASCA− (three patients, all of whom were felt to have CD based on the endoscopic findings and/or the presence of granulomas on biopsies). Group 5 consisted of seven children who were clinically diagnosed with IC. The IDS was pANCA+/ASCA− in five of these children and negative for both pANCA/ASCA in the other two, who were pANCA+/ASCA− on repeat testing. Lastly, the 24 patients in group 6 served as controls. They were not thought to have IBD clinically, and this was supported by a negative IDS (pANCA-/ASCA−). Their final diagnoses included irritable bowel syndrome (n = 6), infectious illness (n = 5), nonspecific recurrent abdominal pain (n = 6), and one each with granulomatous gastritis, rectal ulcer, allergic colitis, eosinophilic ileocolitis, lactase deficiency, Helicobacter pylori infection, and hyperthyroidism. The mean age, sex distribution, and mean IBD activity scores were similar between disease groups.

In 54 of the 83 patients with IBD (Groups 1–5), a diagnosis of IBD had been established prior to the IDS being performed, including all 7 patients with IC. In the remaining 29 patients, the IDS was performed at the time of initial evaluation (ie, endoscopic studies). Of these 29 patients, 21 had a definitive clinical diagnosis of UC or CD, and their IDS was consistent with the clinical diagnosis [UC (n13; group 1) and CD (n8; group 2)]. In the remaining eight children, we established a clinical diagnosis of IBD [UC (n1) or CD (n7)], but their IDS was negative for both pANCA and ASCA.

The specificity of IDS was excellent for UC and CD, but the sensitivity was poor (Table 2). These results may be affected by the retrospective nature of the study and the potential for selection bias. The likelihood of this, however, is diminished by the fact that our results for specificity and positive and negative predictive values were similar to those provided by Prometheus Laboratories, Inc.; their sensitivity was 61.1% for UC and 67.1% for CD (personal communication). The probability of an abnormal IDS was not related to patient age, gender, absence/presence of symptoms, use of medications to treat IBD, diagnosis duration, or IBD activity score (Table 3), except that the IDS was more likely to be abnormal in a naive UC patient compared with one in whom the diagnosis had already been established (p 0.042).

Table 2. Statistical Analysis of IBD Diagnostic System for UC and CD
 Ulcerative ColitisCrohn's Disease
Sensitivity69.254.1
Specificity95.196.8
+ Predictive value90.090.9
- Predictive value87.180.8
Table 3. Selected Patient Characteristics at Time of IBD Diagnostic System Testing
     Diagnosis Duration in Months    
 Age (Years)    Disease Activity (No. Patients)
Group (n)≤12 (%)>12(%)On Medications No. (%)*Symptomatic. No. (%)All Patients*Established Patients Mean Duration (Range) [n]InactiveMildModerateSevere
  • *

    Varying combinations of corticosteroids, azathioprine/6-mercaptopurine, and 5-ASA preparation.

  • *

    Established and newly diagnosed patients together.

  • Based on IBD Activity Score.

1(27)10(37)17(63)13(48.2)24(88.9)20.539.5(4–162)[n = 14]1269
2(20)7(35)13(65)12(60.0)15(75.0)11.519.1(2–67)[n = 12]6581
3(12)3(25)9(75)10(83.3)10(83.3)29.231.9(1–114)[n = 11]633
4(17)8(47)9(53)9(52.9)13(76.5)12.924.0(1–112)[n = 9]6182
5(7)3(43)4(57)6(85.7)6(85.7)36.436.4(2–81)[n = 7]331

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

A diagnosis of IBD may be difficult to establish, and accurate classification of the IBD subtype may be even more challenging. For example, it was the teaching that involvement of the non-colonic GI tract argues strongly against UC, but a number of patients with UC have been found to have pathology in their upper gastrointestinal tracts. 10–12 It was hoped that availability of a serological test would allow more precise identification and classification of patients with IBD.

We performed the IDS in a large cohort of children and adolescents—both with IBD and non-IBD (controls). We found the test to have a high specificity but poor sensitivity, similar to other adult and pediatric reports. 5,13–17 The sensitivity of the test is better for UC than for CD. We were not able to demonstrate any correlation between the serological markers and patient age or sex, presence or absence of symptoms, medications, diagnosis duration (except for newly diagnosed UC who were more likely to be pANCA positive compared with established UC), or IBD activity score, as in other reports. 5,18–20 Three of our 37 CD patients (8%) were pANCA+/ASCA−, which is lower than most other reports, including pediatric studies, where the incidence has been 0%–40%. 5,15,21–23 The reasons for this discrepancy are unclear, especially as the laboratory methods are similar. Furthermore, none of our three pANCA+ CD patients had a “UC-like state.” 21 This is in contrast to the results of Ruemmele et al, 5 where 10 of the 17 (59%) pANCA+ CD patients had UC–like symptoms, and Vasiliauskas et al, 21 where 38 of 69 (55%) pANCA+ CD patients had a UC-like state.

Sandborn et al 20 reported that patients with treatment-resistant left sided UC are more likely to be pANCA+ than those with treatment-responsive left-sided UC and/or UC historical controls (90% vs 62% and 60%). We were unable to reproduce these results in children; clinical features of our pANCA+ and pANCA− UC patients were similar. The discrepancy between our results and adult studies is intriguing and could be due to sample size. Other pediatric studies, however, also do not report the associations noted in adult patients. 5,15

Ten percent to 15% of children with colitis have an indeterminate form, 2,3 and 2% to 4% of patients undergoing colectomy for UC are later diagnosed with CD. 24,25 Seven of 107 patients (6.5%) in our study were thought to have IC (group 5), 5 of whom were pANCA+/ASCA− on initial IDS. Two were initially negative for both pANCA and ASCA, but became pANCA+/ASCA− on repeat testing. Our results are similar to those of Olives et al 19 who reported five patients with IC, four of whom were pANCA+. In contrast, Ruemmele et al 5 had nine patients with IC and only two were pANCA+. None of our IC patients were ASCA+. Gupta et al 26 studied 41 children with IC and 19 had histologic findings suggestive of UC. Thirteen of the 19 patients were pANCA+ and 3 were ASCA+. A recent study of adults with IC found a higher number of patients to be ASCA+ than pANCA+. 27 As such, whereas in our experience patients with IC generally test positive for pANCA, the role of ASCA and pANCA measurements in IC is yet to be settled. 1,6,28

In summary, the low sensitivity of IDS reduces its value in screening and diagnosis and precludes its ability to replace traditional studies when evaluating a patient with suspected IBD. 13–15,17 The IDS may serve as an adjunct to the clinical workup. For example, if a patient is felt to have UC and is doing poorly, it would be worthwhile to measure the serological markers to ensure that the patient does not have serological evidence of CD, which would influence further management considerations. Will the role of these serological markers be to define the clinical and genetic/immunologic heterogeneity of IBD rather than be a screening/diagnostic tool for IBD? Further studies are needed to examine these issues and assess the cost-effectiveness of using IDS in combination with other tests for screening/testing for IBD in children. As our experience with, and knowledge of, these serological markers increases, we may find them to be more useful in predicting disease patterns rather than the disease itself.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The authors thank our nurses Gail Waltz, Debbie Horn, Libby Mitchell, Ann Klipsch Eye, Sara Campbell, and Pam Doll for their assistance with patient care and Donna Morley for patient identification. We also wish to extend our gratitude to Vicki Haviland-Wilhite for her assistance with manuscript preparation.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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