Pir Quiz Pediatrics N Review Answers Inflammatory Bowel Disease 2011 January

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Open Access

Peer-reviewed

Research Article

Diagnostic test strategies in children at increased risk of inflammatory bowel disease in primary intendance

• Gea A. Holtman,
• Yvonne Lisman-van Leeuwen,
• Boudewijn J. Kollen,
• Obbe F. Norbruis,
• Johanna C. Escher,
• Laurence C. Walhout,
• Angelika Kindermann,
• Yolanda B. de Rijke,
• Patrick F. van Rheenen,
• Marjolein Y. Berger

x

• Published: December vi, 2017
• https://doi.org/10.1371/journal.pone.0189111

Figures

Abstruse

Groundwork

In children with symptoms suggestive of inflammatory bowel disease (IBD) who present in principal care, the optimal test strategy for identifying those who require specialist care is unclear. We evaluated the following 3 test strategies to determine which was optimal for referring children with suspected IBD to specialist care: ane) alarm symptoms alone, two) alarm symptoms plus c-reactive protein, and 3) alarm symptoms plus fecal calprotectin.

Methods

A prospective cohort study was conducted, including children with chronic gastrointestinal symptoms referred to pediatric gastroenterology. Effect was defined as IBD confirmed by endoscopy, or IBD ruled out by either endoscopy or unremarkable clinical 12 month follow-upwardly with no indication for endoscopy. Examination strategy probabilities were generated past logistic regression analyses and compared by expanse nether the receiver operating feature curves (AUC) and determination curves.

Results

We included 90 children, of whom 17 (xix%) had IBD (due north = 65 from primary care physicians, n = 25 from general pediatricians). Adding fecal calprotectin to alarm symptoms increased the AUC significantly from 0.80 (0.67–0.92) to 0.97 (0.93–one.00), simply adding c-reactive protein to alarm symptoms did non increase the AUC significantly (p > 0.05). Decision curves confirmed these patterns, showing that alert symptoms combined with fecal calprotectin produced the diagnostic examination strategy with the highest net do good at reasonable threshold probabilities.

Conclusion

In primary care, when children are identified as being at loftier risk for IBD, adding fecal calprotectin testing to alarm symptoms was the optimal strategy for improving adventure stratification.

Commendation: Holtman GA, Lisman-van Leeuwen Y, Kollen BJ, Norbruis OF, Escher JC, Walhout LC, et al. (2017) Diagnostic test strategies in children at increased take a chance of inflammatory bowel disease in master care. PLoS 1 12(12): e0189111. https://doi.org/10.1371/journal.pone.0189111

Editor: Seungil Ro, Academy of Nevada Schoolhouse of Medicine, Us

Received: November nine, 2016; Accustomed: Nov twenty, 2017; Published: December 6, 2017

Copyright: © 2017 Holtman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted employ, distribution, and reproduction in any medium, provided the original author and source are credited.

Information Availability: All relevant data are inside the newspaper and its Supporting Information files.

Funding: This study was funded by a grant from the netherlands Fonds NutsOhra (grant number 0802-099) and a grant from the University Medical Centre Groningen doelmatigheidsonderzoek (grant number 689 302). The funders had no function in written report design, data collection and assay, determination to publish, or preparation of the manuscript.

Competing interests: The authors take declared that no competing interests exist.

Introduction

Abdominal pain is a mutual gastrointestinal symptom in children that prompts a visit to the general practitioner [1–3]. In virtually children, intestinal symptoms are attributed to functional gastrointestinal disorders (FGIDs), and in a few children to an organic disease [4–6]. This distinction is important because children with FGIDs have no structural or biochemical abnormalities and can exist managed in primary care [7,eight]; moreover, excessive testing can sustain complaints and subtract patient well-existence [nine,x]. However, a thorough differential diagnosis is necessary to avert delaying diagnosis and appropriate handling of serious organic affliction, such equally inflammatory bowel illness (IBD) [11].

Differentiation between FGID and IBD is difficult, all the same, considering symptoms are not-specific and frequently overlap. The absence of alarm symptoms (e.g., weight loss and rectal blood loss) may assistance full general practitioners to exclude IBD and prevent the unnecessary referral of children with FGIDs [12]. However, these alert symptoms are mutual and are often related to illnesses that could exist safely managed in primary care (due east.m., rectal haemorrhage caused by anal fissuring related to constipation). The trade-off between the benefits (early recognition of IBD) and harms (referral of FGIDs) of referral and the lack of acceptable tools to discriminate children with IBD, triggers full general practitioners to either refer children with abdominal symptoms for further diagnostic piece of work-upwardly or perform not-valid tests [4].

In primary care, evaluating alarm symptoms and claret markers is the most commonly used diagnostic strategy for triaging children with chronic gastrointestinal symptoms before referral to specialist intendance [13]. C-reactive poly peptide has shown the all-time diagnostic performance of blood markers, but evaluation of its diagnostic value is express to highly selected children [14,xv]. More recently, fecal calprotectin has been shown to be a useful, simple, and non-invasive examination that can exclude IBD in chief care [16]. Although test characteristics such equally sensitivity, specificity, and expanse under the receiver operating characteristic curve (AUC) accept been presented, the added value of c-reactive protein, or fecal calprotectin to alarm symptoms are unknown [17]. In decision, there is petty evidence to recommend additional testing in children with chronic gastrointestinal symptoms in main intendance.

In this study, we aim to determine the optimal diagnostic examination strategy supporting decisions for referral to specialist intendance in children with suspected IBD by evaluating the added diagnostic performance of c-reactive protein and fecal calprotectin across alarm symptoms. For that purpose, we compared three test strategies: 1) alert symptoms solitary, 2) alarm symptoms plus c-reactive protein, and three) alarm symptoms plus fecal calprotectin.

Materials and methods

Setting and participants

We conducted a prospective cohort written report betwixt July 2011 and September 2014 in kingdom of the netherlands. All children were followed for 12 months. We recruited 2 cohorts of children with chronic gastrointestinal symptoms: ane) children initially seen in one out of 38 participating general practices (chief care cohort) and 2) children initially referred past either a general practitioner or general pediatrician to one of the participating medical centers (4 general hospitals and three bookish centers) (referred cohort). Children included in the primary intendance cohort were likewise included in the referred accomplice when they had ≥1 alarm symptom or an aberrant claret test (Table ane), in accord with the written report protocol [18]. For this study we only included children in the referred cohort.

For inclusion, children had to be aged 4–xviii years and presenting with chronic diarrhea (soft or watery stool, matching scores 5–7 of the Bristol Stool nautical chart, for ≥two weeks or ≥2 episodes in the past half dozen months) [19] or recurrent intestinal pain or discomfort (≥ii episodes in the by 6 months) [12,xiii]. An episode was defined as symptoms during three days or more than. Participants were excluded if they had a known diagnosis of chronic organic gastrointestinal disease, had undergone endoscopic evaluation or fecal calprotectin measurement within the preceding six months, or had cognitive impairment or language problems that caused difficulty in understanding questionnaires. Furthermore, we excluded children with chronic use (>3 months) of antibiotics, not-steroid anti-inflammatory drugs (NSAID), or oral corticosteroids, equally well as children anile nether 4 years, considering the calprotectin levels of these groups take been shown to be higher than those observed in good for you older children and adults [20,21].

The Medical Ethics Commission of the University Medical Centre Groningen, the netherlands, approved the report. Parents of all children provided written informed consent, equally did children anile 12 years or older.

Baseline measurements

At baseline, the general practitioner or pediatrician performed a structured physical examination to place the vi alarm symptoms, using a standardized form [12,13]. A blood sample was taken from all patients to mensurate iv blood markers at local laboratories (c-reactive poly peptide, hemoglobin, erythrocyte sedimentation rate, and platelet count). Direct afterwards baseline, all children nerveless a stool sample that was sent to a laboratory for storage at –fourscore°C. At the finish of the data collection period (September 2014), calprotectin was measured in the department of clinical chemistry at Erasmus MC Rotterdam, using a commercially available quantitative enzyme-linked immunosorbent assay (Phical test, CALPRO Every bit, Oslo, Norway). Alarm symptoms and the thresholds for claret markers and fecal calprotectin are presented in Table i. All physicians, researchers, and patients were blinded to the effect of the fecal calprotectin test, merely not to the results of alarm symptoms or blood analyses. The technicians in all laboratories were blinded to the clinical characteristics and diagnoses of patients.

Patient flow

After baseline assessment, a pediatric gastroenterologist decided whether to perform an endoscopy or not, based on estimation of baseline findings and examination of the child. All children were followed for 12 months, and every 3 months a symptom questionnaire was completed past parent or child (if aged ≥10 years). The symptom questionnaire was developed in cooperation with experienced pediatric gastroenterologists and general practitioners (S1 Text. Children'due south symptom questionnaire). At 12 months, either the full general practitioner or pediatrician performed a structured physical examination of all children who still had chronic gastrointestinal symptoms and who had non received a diagnosis of IBD during the report. Children with at least one alarm symptom at this exam were seen once more by the pediatric gastroenterologist who evaluated the need for endoscopy. If a child was lost to follow-up, the general practitioner or pediatrician was contacted to provide updated information on relevant diagnoses (IBD or other organic diseases) during the 12 months later baseline.

Outcome

The diagnosis of IBD was confirmed by esophagogastroduodenoscopy and ileocolonoscopy, with histology, according to the Porto criteria [12]. Absence of IBD was divers as no endoscopic and histopathologic evidence of IBD or no indication for endoscopy within or at 12 months' follow-upward. Endoscopy was not considered to be indicated if there were no alert symptoms for IBD or if the pediatric gastroenterologist considered that the identified alarm symptoms were not related to IBD.

Statistical analyses

We calculated the test characteristics of alarm symptoms, blood markers and fecal calprotectin with 95% confidence intervals (CIs). In addition, we calculated the AUC for claret markers and fecal calprotectin.

Nosotros used logistic regression analysis to construct a bones model predicting the presence of IBD. The dependent variable was the IBD diagnosis (dichotomous). For the independent variable, we totaled the alarm symptoms into one variable (continuous) to comply with the number of events per variable (EPV) rule for obtaining adequate statistical power [25,26]. Nosotros added weighting scores to the alarm symptoms, because the symptoms are known to have unlike predictive values [12,13].

To evaluate the added value of c-reactive protein and fecal calprotectin (both continuous scaled) to alarm symptoms lone (basic model), the variables were added to the bones model and their probabilities were compared to those of the basic model past computing differences between AUCs, using the method described by DeLong [27]. The models were likewise assessed with goodness-of-fit tests and calibration plots.

Nosotros used decision curve analysis to evaluate the clinical usefulness of decision-making based on the three diagnostic strategies [28–30]. We chose a range of threshold probabilities with an upper limit of twoscore%, considering it is unrealistic that whatsoever general practitioner would accept more than than a 40% risk of IBD for a referral to be justified [17]. Strategies with the highest net benefit at a particular threshold were considered preferable to alternative strategies.

To evaluate the verification pattern of which children received endoscopy at baseline, nosotros compared baseline characteristics and risk of IBD in children with and without endoscopy at baseline. We expected that peculiarly children at high risk would be subjected to an endoscopy.

If the distribution between variables in patients with and without missing data was different, the data were considered missing at random (MAR) [31]. In that case, we conducted multiple imputations (fully conditional specification, predictive mean matching, [32] 20 iterations, twenty datasets), using patient characteristics, symptoms, tests and effect as predictors [33]. We used Rubin's rule to summate the pooled AUC [34]. We presented results of the non-imputed (complete case analysis) and imputed dataset. Statistical analyses were performed with IBM SPSS, Version 24 (IBM corp., Armonk, New York, USA) and STATA/SE 13 (STATA Corp, College station, TX, USA).

Results

Participants

Fig 1 summarizes the patient catamenia in this study. Children referred to the pediatric gastroenterologist by a general pediatrician (n = 25) were older, more than oft had alarm symptoms, and were more than likely to have IBD compared with children who were referred past a general practitioner (n = 65). Children who were subject to endoscopy at baseline (due north = 25) more oft had alarm symptoms, positive laboratory markers, and a loftier hazard for IBD compared with children who underwent no endoscopy at baseline (north = 65) (Table 2).

Diagnoses

IBD was confirmed in 17 patients (nineteen%), of whom seven had Crohn's disease, viii had ulcerative colitis, and 2 had unclassified IBD. Of the 72 children (80%) with other diagnoses, 66 (73%) had a FGID, 3 (3%) had gastroenteritis (salmonella enteric [n = two]; Giardia lamblia [north = 1]), 1 (i%) had reflux esophagitis, 1 (ane%) had celiac disease, and 1 (1%) had a solitary rectal ulcer. In one patient, the diagnosis was not known because the child, who was aged 16 years, refused endoscopic evaluation at baseline and evaluation by a general practitioner at 12 months.

Examination characteristics

All tests were performed before endoscopy. The median fourth dimension intervals between blood sampling and endoscopy were 34 and 69 days for children with and without IBD, respectively. The median time interval betwixt stool sampling and endoscopy was four days for children with IBD and was 8 days for children without IBD. Of the 29 children who underwent endoscopy, xi (2 missing) had a delay of more than one month. Overall, 25 children had missing data for one or more variable of interest. The children with and without missing data were comparable in all baseline characteristics, except for actress-intestinal symptoms and setting (S1 Table). To reduce the probability of selection bias, we imputed the missing information [31]. The results of the non-imputed and imputed dataset were similar (Table iii), therefore bias is less likely and we presented the results of the non-imputed dataset in the text.

The diagnostic characteristics of alert symptoms, blood markers, and fecal calprotectin are shown in S2 Table. The AUC of fecal calprotectin was 0.98 (0.96–1.00), which was significantly higher than that for all blood markers individually (p < 0.05).

Added value of C-reactive protein and fecal calprotectin

The AUC of the basic model was 0.fourscore (0.67–0.92). Adding c-reactive poly peptide or fecal calprotectin to the model increased the AUC to 0.88 (0.78–0.98) and 0.97 (0.93–one.00), respectively. However, this increase was only pregnant for fecal calprotectin (p < 0.05) (Table 3). The goodness-of-fit test was good for all models (Hosmer and Lemeshow examination, p > 0.05). The calibration plots of all models displayed linear cyclopedia betwixt the observed and predicted probabilities of IBD.

Decision bend analysis

The determination bend analysis indicates that all three diagnostic strategies had college net benefit at diagnostic threshold probabilities >5% when compared with the alternative of referring all children (Fig two). Alarm symptoms in combination with fecal calprotectin had the highest net benefit at threshold probabilities between v% and xl%. Table 4 shows that the test strategy of alert symptoms plus fecal calprotectin generated a college reduction in the numbers of referrals without missing a child with IBD at different threshold probabilities compared to all other strategies.

Fig 2. Decision curve for the three models predicting the event of IBD in the non-imputed dataset.

Representative interpretation of the decision curve: the regal line representing the alert symptoms + fecal calprotectin strategy shows a internet benefit of 0.16 at a threshold probability of xx%. In this instance, a threshold probability of twenty% means that a general practitioner would exist willing to refer 5 children to prevent a delay in diagnosis for i child with IBD. The net benefit of 0.16 means that this strategy would lead to the referral of 160 per yard children at run a risk, with all referrals having IBD. Abbreviations: CRP: C-reactive protein, FCal: fecal calprotectin.

https://doi.org/10.1371/journal.pone.0189111.g002

Discussion

In this report, 73% of children referred for evaluation of chronic gastrointestinal symptoms had FGIDs that could be managed in principal care, and the prevalence of IBD was 19%. Interestingly, for children in whom general practitioners considered a referral for further diagnostic work-up, c-reactive poly peptide provided no additional diagnostic value when used in combination with warning symptoms. By contrast, the addition of fecal calprotectin to alarm symptoms significantly improved the AUC. Compared to the strategy of adding c-reactive poly peptide to alarm symptoms, adding fecal calprotectin to alarm symptoms showed the highest net benefit and produced the greatest reduction in the number of referrals for IBD without any false negatives.

In clinical practice, physicians apply diagnostic threshold probabilities to determine when they need to initiate further testing earlier deciding on farther management. The decision curve analysis in this study indicated, that in children with a threshold probability of IBD that was < 5%, testing with c-reactive protein or fecal calprotectin had limited additional value. Therefore, we propose confronting testing c-reactive protein or fecal calprotectin in children with a very low risk for IBD (e.g. without alert symptoms). At threshold probabilities between 5% and 40%, still, the test strategy with alarm symptoms and fecal calprotectin showed highest internet benefit. Moreover, the discriminative power of fecal calprotectin proved to be superior to all blood markers when compared individually. Therefore, on the bases of our results, we conclude that fecal calprotectin is the best laboratory test for use when seeking to further stratify children identified as at risk for IBD past history and physical examination. In our previous study in chief care, we showed that a calprotectin value below 50 μg/thou feces can safely exclude IBD [16]. Therefore, a normal calprotectin value is a very reassuring test result that complements a thorough history and physical test in children with chronic gastrointestinal symptoms. It is important that the GP is aware of factors that increase the fecal calprotectin value: the calprotectin value is increased in children with bacterial gastroenteritis, younger than 4 years, or using NSAIDs or antibiotics [21].

There are few publications about the added value for fecal calprotectin in children with symptoms suggestive of IBD. A study evaluating the added value of fecal calprotectin using the "clinical center" of the pediatrician showed that fecal calprotectin reduced the need for referral to a pediatric gastroenterologist, with only a low gamble of missing a child with IBD [23]. However, we could not determine how this approach incorporated warning symptoms and blood markers. Other researchers constructed a model to predict the take a chance of having IBD based on fecal calprotectin and age,[35] and correctly identified 85.v% of children with a sensitivity of 0.81 and specificity of 0.92 (AUC 0.92). However, important predictors, such as alarm symptoms and blood markers, were not included in their model.

It is important to realize that our study included patients referred by general practitioners and general pediatricians. Although it was assumed that these represent the same patient population, the children referred by a pediatrician were more probable to have IBD, were older, and had more than alarm symptoms compared with children referred past their general practitioner. This consequence is to be expected in the Dutch healthcare system, because pediatricians can but be consulted if patients are referred past a general practitioner, but pediatric gastroenterologists can exist consulted if children are referred by either a general practitioner or a general pediatrician. Healthcare systems in the Britain, Scandinavia, Canada, New Zealand, and Australia are similar [36].

A limitation of our study is that alarm symptoms are routinely assessed with claret markers in children with symptoms suggestive of IBD. Consequently, the reference standard was interpreted with prior knowledge of the test results of alarm symptoms and blood markers, which might have acquired review bias and overestimation of the diagnostic accuracy of the alarm symptoms and blood markers [37]. Some other limitation is that we did not perform endoscopies in children with a low likelihood of IBD, because this was considered unethical. There are two of import aspects to consider when assessing whether the apply of 2 reference standards pb to biased accuracy estimates: the verification design and the ceremoniousness of the follow-upwards [38]. Although the verification pattern was based on the clinical judgment of the pediatric gastroenterologist, and was thereby somewhat subjective, our results did show that children who received endoscopy at baseline were at higher risk for IBD than children who received follow-up. Therefore, if the test strategies were but evaluated in the children who received endoscopy at baseline, the results would probably be biased [39]. Although IBD is not a self-limiting disease and it is very rare for it to stay in remission for one yr,[23] in that location is a very small chance that we missed a kid with IBD; such information could alter the diagnostic values reported for the tests. Yet, follow-up is the all-time achievable pick given the reality of clinical intendance [40].

Given that there were few children with IBD in our study (northward = 17), we combined the weighted alarm symptoms into i variable based on the subjective opinions of 85 physicians. Despite this, the AUC of the combined alarm symptoms without weighting was comparable to that with weighting. We also evaluated the added value of two important markers based on 8 events per variable; although it is recommend to accept at least ten events per variable information technology has been shown that 5 events per variable is advisable [25]. A larger study with more than events is needed for the development of a prediction model for IBD based on single alarm symptoms, claret markers, and fecal calprotectin results [29]. Moreover, an exploration of whether age influences the prediction model is needed.

Conclusions

The add-on of fecal calprotectin to an evaluation of alarm symptoms was the optimal strategy for stratifying children identified as being at risk of IBD past their general practitioner. This strategy is different to that published in several guidelines, which recommend testing for c-reactive protein and other blood markers of inflammation when alarm symptoms are present [13,41]. It should be noted that we focused on IBD alone in this study, whereas general practitioners must evaluate whether symptoms are related to any organic illness, including celiac disease. Further studies are therefore needed to investigate whether the new test strategy combining the assessment of alarm symptoms with testing for fecal calprotectin can improve decision-making in clinical practice. These studies should also include a cost–benefit analysis.

Supporting information

Acknowledgments

We thank the full general practitioners and pediatricians involved in this study for recruiting patients, and we thank all participants for their contribution. The belittling support of Sascha Smit, Erasmus MC, was highly appreciated. Nosotros thank Dr Robert Sykes (www.doctored.org.united kingdom of great britain and northern ireland) for his editorial help.

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Source: https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0189111

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