Guideline for wireless capsule endoscopy in children and adolescents: A consensus document by the SEGHNP (Spanish Society for Pediatric Gastroenterology, Hepatology, and Nutrition) and the SEPD (Spanish Society for Digestive Diseases)

1130-0108/2015/107/12/714-731 Revista española de enfeRmedades digestivas CopyRight © 2015 aRán ediCiones, s. l. Rev esp enfeRm dig (Madrid) Vol. 107, N.º 12, pp. 714-731, 2015 Guideline for wireless capsule endoscopy in children and adolescents: A consensus document by the SEGHNP (Spanish Society for Pediatric Gastroenterology, Hepatology, and Nutrition) and the SEPD (Spanish Society for Digestive Diseases) Federico Argüelles-Arias1, Ester Donat2, Ignacio Fernández-Urien3, Fernando Alberca4, Federico Argüelles-Martín1, María José Martínez5, Manuel Molina6, Vicente Varea7, Juan Manuel Herrerías-Gutiérrez1 and Carmen Ribes-Koninckx2 1Hospital Universitario Virgen Macarena. Sevilla, Spain. 2Hospital Universitario y Politécnico La Fe. Valencia, Spain. 3Complejo Hospitalario de Navarra. Pamplona, Spain. 4Hospital Universitario Virgen de la Arrixaca. Murcia, Spain. 5Hospital Universitario Infantil Niño Jesús. Madrid, Spain. 6Hospital Universitario La Paz. Madrid, Spain. 7Hospital San Joan de Deu. Barcelona, Spain ABSTRACT Introduction: Capsule endoscopy (CE) in children has limitations based mainly on age. The objective of this consensus was reviewing the scientific evidence. Material and methods: Some experts from the Spanish Society of Gastroenterology (SEPD) and Spanish Society for Pediatric Gastroenterology, Hepatology, and Nutrition (SEGHNP) were invited to answer different issues about CE in children. These sections were: a) Indications, contraindications and limitations; b) efficacy of CE in different clinical scenarios; c) CE performance; d) CE-related complications; e) Patency capsule; and f) colon capsule endoscopy. They reviewed relevant questions on each topic. Results: The main indication is Crohn’s disease (CD). There is no contraindication for the age and in the event that the patient not to swallow it, it should be administered under deep sedation with endoscopy and specific device. The CE is useful in CD, for the management of OGIB in children and in Peutz-Jeghers syndrome (in this indication has the most effectiveness). The main complication is retention, which should be specially taken into account in cases of CD already diagnosed with malnutrition. A preparation regimen based on a low volume of polyethylene glycol (PEG) the day before plus simethicone on the same day is the best one in terms of cleanliness although does not improve the results of the CE procedure. Conclusions: CE is safe and useful in children. Indications are similar to those of adults, the main one is CD to establish both a diagnosis and disease extension. Moreover, only few limitations are detected in children. Key words: Capsule endoscopy. Children. Guideline. Spanish Society for Digestive Diseases. Spanish Society for Pediatric Gatroenterology, Hepatology and Nutrition. INTRODUCTION Since the introduction of Capsule endoscopy (CE) in 2000 the approach to small bowel diseases has been revolutionized (1). There is no doubt that CE has represented a great advance in the study of small bowel diseases in adults. Similarly, in the pediatric age, given that it is a non-invasive technique, which avoids general anesthesia and ionizing radiation in the majority of patients, CE represents a real advantage and has therefore experienced a significant advance. Thus, its use has expanded progressively and is nowadays considered an important diagnostic method in pediatric gastroenterology, although the literature on this topic is not as extensive as in adults. The United States Food and Drug Administration (FDA) approved the use of CE for the evaluation of small bowel diseases in adults in 2001. In 2004, the CE was approved for patients 10 to 18 years of age and finally, in September 2009, both the use of CE and the Patency Capsule was approved for children older than 2 years (2). The most popular device for wireless endoscopy is the Given Imaging´s System (PillCam™ Platform; Yoqneam, Israel). There are other devices commercially available such as MiroCam (Intromedic, South Korea), OMOM (Chongqing, China), EndoCapsule (Olympus, Japan) and CapsoCam (Capso Vision Saratoga, CA, United States). However, most of CE published papers refer to the PillCam™ system. The use of CE in children has some limitations and since the pediatric literature, as mentioned above, is not as profuse as in adults, many questions remain unanswered. Consequently, this Consensus aims to provide a worldwide perspective on the use of CE in children and to respond some key questions regarding the implementation of this diagnostic tool. Argüelles-Arias F, Donat E, Fernández-Urien I, Alberca F, Argüelles-Martín F, Martínez JM, Molina M, Varea V, Herrerías-Gutiérrez JM and Ribes-Koninckx C. Guideline for wireless capsule endoscopy in children and adolescents: A consensus document by the SEGHNP (Spanish Society for Pediatric Gastroenterology, Hepatology, and Nutrition) and the SEPD (Spanish Spanish Society for Digestive Diseases). Rev Esp Enferm Dig 2015;107:714-731. Received: 08-07-2015 Accepted: 21-08-2015 Correspondence: Federico Argüelles-Arias. Hospital Universitario Virgen Macarena. Avda. Doctor Fedriani, 3. 41071 Sevilla, Spain e-mail: [email protected] ORIGINAL PAPERS Vol. 107, N.º 12, 2015 GUIDELINE FOR WIRELESS CAPSULE ENDOSCOPY IN CHILDREN AND ADOLESCENTS: A CONSENSUS DOCUMENT 715 BY THE SEGHNP (SPANISH SOCIETY FOR PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY, AND NUTRITION) AND THE SEPD (SPANISH SOCIETY FOR DIGESTIVE DISEASES) Rev esp enfeRm Dig 2015; 107 (12): 714-731 METHODS This document sets out the current Consensus reached by a group of national experts in the field of CE jointly by the SEGHNP (Spanish Society for Pediatric Gastroenterology, Hepatology and Nutrition) and the SEPD (Spanish Society for Digestive Diseases). The experts have been selected based on their experience in the management of CE in children and adults as well as on their publications on this subject. CR-K, ED, MM, MJM, VV, MM, and FA-M are pediatricians specialized in pediatric gastroenterology, and FA-A, IF-U, FA, and JMH-G are adult gastroenterologists involved in pediatric CE. The content of the present Consensus has been categorized into six sections based on the topics to be covered: a) Indications, contraindications and limitations; b) efficacy of CE in different clinical scenarios; c) CE performance; d) CE-related complications; e) Patency Capsule; and f) colon capsule endoscopy. The strategy to reach the Consensus involved seven steps. The expert panel devised relevant questions on each topic. 1. The questions focused on current practice and were sent to participants. The authors were asked to answer these questions based on evidence from the literature (Delphi procedure) as well as on their experience. In appendix 1 is specified which topic was answered by each expert. 2. A systematic literature search of each topic was conducted using Medline/ PubMed/EMBASE and the Cochrane database as well as their own files. The evidence level (EL) was graded (Table I) according to the Oxford Centre for Evidence-Based Medicine system. 3. The authors wrote provisional guideline statements on each topic based on the answers to the questionnaire as well as on the literature search and these were circulated among participants. 4. The panel of 10 participants then met in Valencia on July 13th 2014 to agree on the final version of each guideline statement. Statements were revised until a consensus was reached. Consensus was defined as an agreement by > 80% of participants, termed a Consensus Statement. Each recommendation was graded according to the Oxford Centre for Evidence-Based Medicine system based on the corresponding level of evidence (Table I). 5. The members of the working party wrote the final document on their assigned topic. 6. Two external assessors reviewed the manuscript and suggested corrections and modifications. 7. The final text is presented here. Each Consensus guideline statement is followed by comments on the underlying evidence and by the expert’s opinion as well. This guideline is based on the current evidence published in the literature, so it should be updated after 5 years. WHICH ARE THE MAIN INDICATIONS, LIMITATIONS AND CONTRAINDICATIONS FOR THE USE OF CE IN PEDIATRIC POPULATION? THE AGE’S ISSUE General indications – Statement 1: The main indication for CE in children is the assessment of Crohn´s disease (CD). Evidence level 3b. Recommendation grade B. Table I. Levels of evidence Level Diagnosis 1a Systematic review (with homogeneity) of Level 1 diagnostic studies; or a clinical decision rule with 1b studies from different clinical centers 1b Validating cohort study with good reference standards; or clinical decision rule tested within one clinical center 1c Absolute SpPins And SnNouts (An Absolute SpPin is a diagnostic finding whose Specificity is so high that a Positive result rules-in the diagnosis. An Absolute SnNout is a diagnostic finding whose Sensitivity is so high that a Negative result rules-out the diagnosis) 2a Systematic review (with homogeneity) of Level > 2 diagnostic studies 2b Exploratory cohort study with good reference standards; clinical decision rule after derivation, or validated only on splitsample or databases 3a Systematic review (with homogeneity) of 3b and better studies 3b Non-consecutive study; or without consistently applied reference standards 4 Case-series (and poor quality cohort and case-control studies) 5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" Grades of recommendation A consistent level-1 studies B consistent level-2 or -3 studies or extrapolations from level-1 studies C level-4 studies or extrapolations from level-2 or -3 studies D level-5 evidence or troublingly inconsistent or inconclusive studies of any level “Extrapolations” are where data are used in a situation that potentially has clinically important differences as compared to the original study situation. 716 F. ARGÜELLES-ARIAS ET AL. Rev esp enfeRm Dig (maDRiD) Rev esp enfeRm Dig 2015; 107 (12): 714-731 Table II. Indications for small bowel CE in children Small-bowel Crohn´s disease Diagnosis and extent evaluation Occult or obscure intestinal bleeding/ferropenic anemia Small-bowel polyps Familial and other polyposis Malabsorption and protein-losing enteropathies Celiac disease Eosinophilic and food-allergic enteropathies Intestinal lymphangiectasia Chronic abdominal pain Small bowel tumors Lymphoma, leiomyoma, carcinoid, and other tumors Transplantation Intestinal graft versus host disease in bone marrow transplant recipients According to the available scientific evidence, the most frequent indication for CE in children is inflammatory bowel disease (IBD), both for diagnosis and disease extension assessment. On the other hand, obscure gastrointestinal bleeding (OGIB) (including chronic ferropenic anemia), malabsorption and protein-losing enteropathies, abdominal pain, small bowel polyps, tumors and, in general, as in adults, all the situations where small bowel pathology is suspected, are other reported indications for CE in pediatric population (3-11). Table II shows the main indications for CE in the pediatric population. Overall, when comparing the use of CE in pediatric and adult patients, CE is more frequently indicated for the evaluation of Crohn´s disease (CD) in pediatric patients and more frequently indicated for OGIB in adults (12). A recent report on the use of CE in childhood compared indications for CE amongst 1.013 procedures in pediatric patients and 22,840 procedures in adults and the conclusion was that, in pediatric patients, 63% of CE had been performed for CD, 15% for OGIB, 10% for abdominal pain/diarrhea and 8% for polyposis (13). In contrast, in adults 66% of CE had been performed for OGIB and 10% for CD (14). However, it has to be noted that OGIB is more frequent than CD in pediatric patients younger than 8 years of age (12). Moreover, case reports are regularly reported on the effectiveness of CE for the diagnosis of a wide variety of diseases in young children and infants. Hence, the contribution of CE to the diagnosis of rare diseases such as peritoneal lipomatosis (15), lymphangioendotheliomatosis (8) or primary intestinal lymphangiectasia (16,17). Likewise, CE allows detecting intestinal microvascular malformations (18) or small bowel hemangiomas difficult to detect by conventional imaging techniques (19,20). CE has also shown small bowel involvement in patients without overt evidence of gastrointestinal disease such as patients with cystic fibrosis (21). Finally, it is important to consider that a recent review and meta-analysis showed positive small bowel findings in 58% to 72% of patients after CE, which is comparable to those results obtained in adults (14). Contraindications and limitations – Statement 2: The main contraindication for the use of CE is the suspicion of intestinal obstruction. Complications, including capsule retention, may be related to the underlying pathology rather than to patient age. Evidence level 3b. Recommendation grade B. – Statement 3: CE is feasible in young infants of 8 months of age and older or in young infants weighing over 8 kg. Evidence level 3b. Recommendation grade B. There are very few contraindications for the use of CE in adults and most of them are exceptional in pediatric age. Cardiac pacemakers and implantable cardioverter defibrillators are no longer a contraindication for the use of CE (22). Pregnancy also represents no contraindication for CE as was recently proven (23). Anyway, they are exceptional conditions in pediatric age. On the other hand, CE should not be performed in cases of confirmed bowel obstruction or when a strong suspicion of obstruction exists (24). The presence of previous digestive surgery should be taken into account before indicating CE, but it is not considered an absolute contraindication in absence of obstructive symptoms (25). The main drawback of CE in children could be the difficulty to be swallowed by children and the possibility of capsule retention based on patient age. The first issue could be solved by placing the capsule endoscopically into the duodenum (see sections “How to proceed with E in children?” and “What are the main complications of CE in pediatrics?”). Based on Consensus experience, the capsule can be voluntarily ingested by children older than 8 years of age. Nevertheless, as other authors point out, success depends more on the child’s confidence and the physician’s calm than on chronological age as some older children and teenagers refuse even to attempt to swallow the capsule and, on the contrary, children as young as 6 years of age will do it satisfactorily (27). Regarding the second issue, there are no studies whose main aim was to main objective was to analyze the lowest age or weight at which it is possible to use the capsule in children. A single case report was published on the successful use of the capsule in a 10-month-old infant weighing 11.5 kg (8). And in a recent retrospective study, CE was used in a child weighing only 7.9 kg (26). The key studies available including young children are listed in table III. If the possibility of capsule retention based on patient age is suspected, certain anatomical considerations must Vol. 107, N.º 12, 2015 GUIDELINE FOR WIRELESS CAPSULE ENDOSCOPY IN CHILDREN AND ADOLESCENTS: A CONSENSUS DOCUMENT 717 BY THE SEGHNP (SPANISH SOCIETY FOR PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY, AND NUTRITION) AND THE SEPD (SPANISH SOCIETY FOR DIGESTIVE DISEASES) Rev esp enfeRm Dig 2015; 107 (12): 714-731 be taken into account. The proximal duodenum is acutely angulated, limiting the view of the posteromedial wall and the diameter of the empty small bowel (duodenum, jejunum, and ileum) in newborns measures 10 to 15 mm (28). The colonic diameter in newborns is approximately 10 mm and around 17 mm in the cecum (29). These measures should be considered when performing an endoscopic technique in children and consequently, it must be noted that Given Imaging´s and Olympus capsules measure 11x26 mm, MiroCam capsules measure 10.8x24 mm, OMOM capsules are somewhat larger (13x27.9 mm) and finally, CapsoCam capsules are the largest and measure 11x31 mm (30). Based on these sizes, there is no retention risk according to age. Moreover, post-mortem studies have revealed that capsules can go through the pylorus and ileocecal valve of infants 1 year of age (3). WHICH IS THE DIAGNOSTIC ACCURACY OF CE IN THE PEDIATRIC POPULATION? Pediatric CD An increased incidence of pediatric IBD is being observed in Western countries, including Spain. A recently published registry –year 1996 till 2009– found an increase from 0.97 to 2.8 per 100,000 individuals (31). It is well known that a definitive diagnosis of IBD is based on clinical, endoscopic, histopathologic and imaging data. Moreover, establishing the subtype of IBD –CD, ulcerative colitis (UC) or inflammatory bowel disease unclassified (IBDU)– is essential to determine not only the treatment of choice but also the prognosis (32). The main indications for using CE in IBD in the pediatric age are suspected CD and established IBD –to assess the extent and activity of the condition or to reclassify IBDU–. Suspected CD – Statement 1: CE is a useful method to identify small bowel lesions compatible with CD. It should be recommended in suspected cases of CD when conventional endoscopy and imaging tools are not feasible or have been non-diagnostic and no bowel obstructive symptoms are present. Evidence level 3b. Recommendation grade B. – Statement 2: A normal CE study has a high specificity for excluding small bowel CD. Evidence level 4. Recommendation grade C. – Statement 3: CE may be superior to magnetic resonance enterography (MRE) for the detection of mucosal lesions consistent with CD, especially in those cases where proximal or mild lesions are present. Evidence level 3b. Recommendation grade B. CD is a chronic inflammatory disorder associated to mucosal and transmural inflammation of the bowel wall. It is well known that CD can affect the entire gastrointestinal tract from the mouth to the anus, although the most common location is the ileum, the colon or both (50% of cases) (33). Therefore, ileocolonoscopy and biopsies of the terminal ileum and every colonic segment to look for microscopic evidence of CD, are the first-line procedures to establish a diagnosis (34). However, it has been observed that up to 30% of patients have only small bowel involvement (35,36). Jejunal lesions are also detected in more than half of patients with CD, and the prevalence of jejunal lesions is higher when the terminal ileum is involved (37). As such, CE is undoubtedly a very useful diagnostic tool to observe small bowel lesions undetectable by conventional endoscopy or radiologic studies in presumed CD cases. Some studies have assessed the role of capsule endos copy in children with suspected Crohn’s disease (Table IV). In one of the earliest studies, CE was performed in 12 patients with a clinical Table III. Summary of main publications regarding young infants Author n Age (range) Youngest patients (months and/or weight) Diagnosis Oikawa-Kawamoto (26) 26 10 m-16 y 7.9 kg Gortani (17) CR CR 48 m Lymphangiectasia Nuutinen (108) 100 8-188 m 8 m OGIB Dupont-Lucas (99) 79 2.2-18 y 26 m Jensen (8) 117 10 m-22.4 y 10 m, 11.5 kg Lymphangio-endotheliomatosis Orendain (146) CR CR 22 m OGIB Fritscher-Ravens (3) 83 1.5-8 y 18 m OGIB de’ Angelis (6) 87 18 m-18 y 18 m OGIB Kavin (19) CR CR 30 m Jejunal angiomatosis OGIB: Obscure gastrointestinal bleeding; CR: Case report; y: Years; m: Months. 718 F. ARGÜELLES-ARIAS ET AL. Rev esp enfeRm Dig (maDRiD) Rev esp enfeRm Dig 2015; 107 (12): 714-731 suspicion of CD after normal gastroscopy, colonoscopy, and small bowel follow-through series (38). Ileoscopy was also performed in 50% of patients and no lesions were observed. In this study, CE identified lesions suggestive of CD in 7 out of 12 patients (58.3%) and the majority of lesions were located at the ileum. In another study in 10 out of 20 children with suspected CD who had negative small bowel series and colonoscopy, CE demonstrated multiple erosions and ulcers consis tent with CD (7). Similar to adults, and this is quite important, all these findings resulted in a change of medical therapy in 75-92% of new or known CD patients in some reported series (6,10,39). In addition, due to the high negative predictive value of a normal examination, small bowel CD can be excluded in most of patients with a negative capsule study (40). On the other hand, minor mucosal lesions may not be specific for CD and such lesions may be found in other settings such as Behçet’s disease, vasculitis or drug-induced enteropathy, particularly in patients using NSAIDs. However, these conditions are less frequent in the pediatric population than in adults (41,42). Although the presence of more than 3 ulcers has been used to diagnose CD by CE (43), based on the comments above, the diagnosis should be made using a combination of clinical, endoscopic, radiographic, histological, and biochemical tests. In order to improve the efficacy of CD identification by CE, patients should be selected based on additional features such as typical symptoms, extraintestinal manifestations, inflammatory markers like fecal calprotectin, or abnormal findings in small bowel imaging techniques such as abdominal ultrasound (44,45). Table IV. Summary of pediatric series on CE and IBD Author Patients/Disorder Age (range) CD diagnosis Design Argüelles (38) 12 suspected CD 12-16 y 7/12 (58.3%) Retrospective Guilhon de Araujo Sant´Anna (7) 30 patients 20 suspected CD 10-18 y 10/20 (50%) Prospective Nuutinen (108) 100 patients 26 CD suspicion 9 CD evaluation 24 UC 10 y (8 m-15.6 y) 16/26 (61%) 5/9 (55.5%) 1/24 (4%) Retrospective Fritscher-Ravens (3) 83 patients 12 CD suspicion 20 CD evaluation 1.5-7.9 y 3/12 (25%) 11/20 (55%) Prospective Kovanlikaya (46) 23 patients 15 y (8-21 y) Sensitivity CE 77.8% MRE 75% Retrospective Lai (47) 55 patients 12 m-16 y Sensitivity CE 94.6% MRE 85.7% Retrospective Casciani (48) 37 patients 14 y (6-18 y) Sensitivity CE 91.9% MRE 100% Prospective Di Nardo (52) 117 patients 18 CD suspicion 44 CD evaluation 29 UC 26 IBDU 4-17 y (11.2 y) *** 9/18 (50%) 18/44 (40%) 0/29 (0%) 16/26 (61.5%) Prospective Cohen (39) 21 CD evaluation 5 UC 2 IBDU 4.2 y 13/21 (61%) 4/5 (80%) 1/2 (50%) Retrospective Min (53) 83 patients 17 CD suspicion 50 CD evaluation 16 UC or IBDU 12.5 y 1/17(6%) 35/50 (70%) 4/16 (25%) Retrospective Gralnek (54) 18 patients 10 CD suspicion 4 CD evaluation 4 UC or IBDU 13.8 y 8/10 (80%) 2/4 (50%) 2/4 (50%) Prospective CD: Crohn´s disease; UC: Ulcerative colitis; IBDU: Inflammatory bowel disease undetermined; y: Years; m: Months; ***CE vs. imaging techniques (p < 0.05). Vol. 107, N.º 12, 2015 GUIDELINE FOR WIRELESS CAPSULE ENDOSCOPY IN CHILDREN AND ADOLESCENTS: A CONSENSUS DOCUMENT 719 BY THE SEGHNP (SPANISH SOCIETY FOR PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY, AND NUTRITION) AND THE SEPD (SPANISH SOCIETY FOR DIGESTIVE DISEASES) Rev esp enfeRm Dig 2015; 107 (12): 714-731 The diagnostic yield of CE for small bowel lesions is higher than that of ileocolonoscopy, small bowel followthrough (SBFT), and CT enterography. In a meta-analysis by Cohen and Klevens (14) the diagnostic yield of CE ranged from 58% to 72%, while it was 0-33% for SBFT and 0-61% for ileocolonoscopy; the authors analyzed data from 15 studies with 740 CE procedures and reported that 69.4% of the examinations resulted in a new diagnosis, and that in 68.3% they led to therapy changes. Recently, the ESPGHAN Revised Porto Criteria for the diagnosis of IBD in children and adolescents (32) consider the CE as a basic tool for CD diagnosis. On the other hand, the ECCO guidelines for the diagnosis of CD in adults with suspected CD and negative ileocolonoscopy, recommends that CE may be the initial diagnostic modality for the evaluation of the small bowel in the absence of obstructive symptoms or known stenosis and in patients with obstructive symptoms or known stenosis, Patency Capsule (see “What are the main complications of CE in pediatrics?”) or a cross-sec- tional imaging modality such as MRE or CT enterography should precede CE (44). It has to be taken into account that CE may also be superior to MRE, particularly for early mucosal injuries and for proximal bowel lesions. In different reports the sensitivity and specificity of CE range from 77.8% to 94.6%, while MRE shows a sensitivity of 75-85.7% (46) and a specificity of 70% (47). Anyway, both MRE and CE should be considered complementary and accurate methods in patients with suspected CD (48). Established CD – Statement 4: CE is valuable in revealing small bowel lesions previously undetected in patients with CD and torpid clinical evolution and/or inconsistent laboratory data. Evidence level 2b. Recommendation grade B. – Statement 5: The finding of small bowel lesions may also be helpful for reclassifying some IBDU patients into CD patients. Evidence level 2b. Recommendation grade B. – Statement 6: In suspected or established CD there is an increased risk for capsule retention. MRE or Patency Capsule should precede CE in order to identify strictures that may cause capsule retention in case of obstruction symptoms. Evidence level 2b. Recommendation grade B. – Statement 7: CE may be helpful in assessing CD recurrence and mucosal healing after treatment for CD. Evidence level 3b. Recommendation grade B. The ability to accurately classify pediatric IBD patients and to determine the presence and/or extent of small bowel involvement may improve medical decision-making and patient outcome (39). There are higher rates of IBDU in younger patients as compared to adults, and thus a more extensive small bowel evaluation may be helpful to differentiate CD from UC (51). In a prospective study, Di Nardo et al. performed CE in 117 children with IBD in order to clarify symptoms and laboratory signs not fully explained by conventional endoscopy and also to reclassify some IBDU patients. Out of 44 CD patients, MRE and/ or small intestine contrast ultrasonography showed small bowel lesions in 8 cases (18%) and CE revealed lesions not detected by imaging tools in 18 children (41%, p < 0.01). Of 26 unclassified IBD cases, small bowel lesions typical of CD were detected by imaging in 7 and by CE in 16 cases (p < 0.05) (52). In two retrospective studies CE reclassified UC/IBDU into CD in 50-75% of cases (39,53). In another prospective cohort of pediatric patients CE reclassified 50% of patients from UC/IBDU to CD, and in 50% of subjects with known CD, CE evidenced a more proximal small bowel mucosal disease than previously recognized. Furthermore, treating physicians reported that CE had helped diagnose CD in 15 of 18 (83.3%) subjects, and influenced medical decision-making in 13 of 18 (72.2%), leading to a change in medical management for 14 of 18 (77.8%) (54). CE may also be considered in the assessment of postoperative recurrence in cases where ileocolonoscopy is contraindicated or unsuccessful (55,56). The potential role of CE in the assessment of mucosal healing after drug therapy has also been investigated (57,58). In a recent prospective study in 9 pediatric patients, mucosal response after a dietary treatment was evaluated using CE (59). Finally, it should be mentioned that an important point to consider is the risk of capsule retention in pediatric patients with known IBD, which is highest when compared to other indications (5.2%) (49). Thus, SBFT, CT, RNM, or Patency Capsule examinations should be performed first to exclude strictures in patients with suspected or established CD if bowel obstruction symptoms are present (11,50). Nevertheless, and especially in children, since CT and SBFT have the potentially detrimental effect of radiation and given the low sensitivity of SBFT, Patency Capsule or MRE procedures seem reasonable first-line options (60). OGIB and ferropenic anemia – Statement 1: CE is useful for the management of OGIB in children. Evidence level 3b. Recomendation grade B. – Statement 2: CE should be performed in the early stages of the disorder. Evidence level 4. Recomendation grade C. – Statement 3: CE performs better than barium studies for the study of OGIB. Evidence level 3b. Recomendation grade B. 720 F. ARGÜELLES-ARIAS ET AL. Rev esp enfeRm Dig (maDRiD) Rev esp enfeRm Dig 2015; 107 (12): 714-731 No studies have been conducted specifically addressing the indication or performance of CE in children with OGIB. In fact, only 2 prospective studies have been published regarding CE, OGIB and children. The first one included 4 patients in whom CE was indicated because of OGIB, but with the primary goal of comparing CE to other imaging techniques. CE was able to detect pathological findings in 3 (75%) out of 4 children (7). The second study is a prospective European multicenter study in children younger than 8 years that aimed to determine what findings are obtained according to CE indication; moreover, different methods for capsule introduction were evaluated. Overall, 30 patients had OGIB and positive findings were observed only in 16 cases (53%) (3). In another study, Thomson and co-workers reported positive CE findings in 6 (100%) patients with negative gastroscopy and colonoscopy assessment (5). In several publications including children with OGIB, intestinal lesions accounting for the bleeding episodes were found in 51.5% of cases (103 positive results in 200 patients); this is similar to the 42% positivity reported in the unique meta-analysis published so far (14). In some series gastric and duodenal findings are reported whereas in others gastroduodenal findings are not analyzed. Thus, results vary widely when comparing different series (60). Furthermore, it is important to take into account that active bleeding lesions are more likely detected when CE is used in the first 3 days (95.1%) or 2 weeks (93.1%) after the bleeding event, as compared to later CE procedures (57.1% after 2 weeks, p = 0.003) (61). Tables V and VI summarizes all OGIB and chronic anemia reports available in pediatric population. Vascular lesions are the most frequently reported pathological findings in patient series (36 out of 106; 33.96%), followed by IBD (27 out of 106; 25.47%), polyps (9 out of 106; 8.49%) gastroduodenal lesions undetected by endoscopy (6 out of 106; 5.66%), nonspecific enteritis (5 out of 106; 4.71%), intestinal tumors (5 out of 106; 4.71%), Meckel´s diverticulum unnoticed by gammagraphy (4 out of 106; 3.77%), villous atrophy (3 out of 106; 2.83%), ileal nodular hyperplasia (3 out of 106; 2.83%), ulcus due to anti-inflammatory drugs (3 out of 106) and complications related to bone marrow transplantation (3 out of 106). Antao et al. (9) have specifically compared CE to other techniques and reported that CE is superior to SBFT, to combined gastroscopy and colonoscopy, to enteroscopy, and to gammagraphy. No studies analyze the value of CE as first diagnostic method replacing gastroscopy and colonoscopy. The effectiveness of CE is evaluated as a rescue diagnostic approach when other methods have failed, but not when a diagnosis has already been confirmed; thus, conclusions are of relative value. Table V. Summary of pediatric series on CE and OGIB Author Patients (n) Procedures (n) OGIB indications OGIB findings Diagnostic yield (%) Evidence Barth (115) 11 11 11 9 81.81 2+ Guilhon (7) 30 30 4 3 75 2+ De´Angelis (6) 87 87 21 15 71.42 2+ Antao (9) 37 37 7 7 100 2+ Moy (10) 45 46 8 NA 2+ Urbain (90) 17 17 10 5 50% 2+ Thompson (5) 29 29 6 6 100% 2+ Ge (11) 16 16 12 9 75% 2+ Atay (49) 207 207 15 NA 2+ Fritscher-Ravens (3) 83 87 30 16 53.33 2+ Dupont-Lucas (99) 70 79 30 10 33.33 2+ Jensen (8) 117 123 18 12 66.66 2+ Tokuhara (4) 12 19 2 2 100 2+ Nuutinen (108) 100 100 18 9 50% 2+ Cohen (14) 277 284 27 NA 2+ Bass (147) 17 17 8 NA 2+ 878 905 227 103 OGIB: Obscure gastrointestinal bleeding; NA: Not applicable. Vol. 107, N.º 12, 2015 GUIDELINE FOR WIRELESS CAPSULE ENDOSCOPY IN CHILDREN AND ADOLESCENTS: A CONSENSUS DOCUMENT 721 BY THE SEGHNP (SPANISH SOCIETY FOR PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY, AND NUTRITION) AND THE SEPD (SPANISH SOCIETY FOR DIGESTIVE DISEASES) Rev esp enfeRm Dig 2015; 107 (12): 714-731 Polyposis syndromes – Statement 1: CE is a feasible, safe and accurate tool for the detection of small bowel polyps. It may be useful as a screening and surveillance method in Peutz-Jeghers syndrome (PJS). Evidence level 3b. Recommendation grade B. – Statement 2: CE is better than barium enterography to detect small polyps in Peutz-Jeghers syndrome (PJS). Evidence level 1b. Recommendation grade A. The role of CE in the diagnosis of small bowel tumors is relevant (62). PJS is an autosomal dominant condition characterized by the association of gastrointestinal polyposis, mucocutaneous pigmentation and cancer predisposition (63). It is the most frequent polyposis syndrome during childhood. Hamartomatous polyps are more common in the small bowel but may also appear in the stomach, large bowel and extraintestinal sites (64). They may result in chronic bleeding, chronic anemia and may also cause recurrent bowel obstruction and intussusception requiring surgery. Polyp-related complications could develop in childhood. One third of children develop symptoms by the age of 10 years and one half by 20 years (65). However, current guidelines on polyp screening vary and suggest starting at age 8 to 10 years with gastroscopy or CE only, even though new advances in small-bowel imaging –including CT enterography, MRE, and balloon-assisted enteroscopy– have improved the diagnosis of this condition and allow the removal of deep small bowel polyps (65,66). On the other hand, follow-up interval recommendations vary from every year to every 5 years (65-67). CE has been demonstrated to be useful for small bowel polyps detection. Gastineau et al. observed jejunal polyps in 72% and ileal polyps in 55% of CE procedures in children with PJS. They concluded that CE is feasible for PJS assessment but the practice of systematic and repeated procedures needs to be validated prospectively (68). Antunes et al. describe the usefulness of CE in a single case in which PJS was suspected because she had hyperpigmented macules on her lips and bucal mucosa and her father had been diagnosed with PJS after previous surgical interventions for intestinal occlusion (69). Based on a recent review of their casuistry, initial screening at age 4 to 5 years with CE, EGD, and colonoscopy, and an evaluation of boys for Sertoli cell tumors is recommended by Goldstein et al. (70). A case of Gardner fibroma has been also described in which CE was performed to observe polyps in the jejunum (71). In adults many studies have been reported, also comparing CE with other imaging techniques (72-75). There is only one study comparing CE with traditional imaging methods in children. Postgate et al. compared the yield of CE with that of barium enterography (BE) in children with PJS. Children with PJS (ages 6.0-16.5 years) were prospectively recruited and underwent BE followed by CE, the results being reported by expert reviewers blinded to the alternate modality. The number of “significant” (> 10 mm) lesions and the total number of polyps were both recorded. There was no significant difference in the detection of polyps > 10 mm, but significantly more polyps < 10 mm were identified by CE than by BE -61 versus 6 (p = 0.02). They concluded that CE is a feasible, safe and accurate tool for small bowel polyp surveillance in children with PJS (76). Moreover, the assessment of polyposis syndromes has the highest ratio of diagnosis to indication by CE in children. Findings are observed in 80.2% of procedures that is more than in adults (13,76). Hence, CE should be considered as a first line diagnostic method in small bowel polyposis syndromes. Table VI. Diagnoses for OGIB using CE Diagnosis Case reports (n) Series (n) Total Meckel’s diverticulum 6 4 10 Schonlein-Henoch purpura 1 0 1 Vasculitis 1 0 1 Angiodysplasias 3 26 29 Hemangiomas 1 0 1 Tumors 2 5 7 Polyps 0 9 9 Celiac disease 0 14 14 Ulcerative jejunoileitis 0 13 13 Gastroduodenitis 0 6 6 Anastomosis ulcer 0 1 1 NSAID-related ulcer 0 3 3 Lymphoid nodular hyperplasia 1 3 4 Villous atrophy 0 3 3 GVHD 0 2 2 Thrombotic microangiopathy 0 1 1 Non-specific enteritis 0 5 5 Eosinophilic enteritis 1 0 1 Intestinal varices 0 4 4 Blue rubber bleb nevus syndrome 2 4 6 Isolated hemangioma 3 2 5 Intestinal duplication 0 1 1 Total 21 106 127 OGIB: Obscure gastrointestinal bleeding; NSAID: Non-steroidal anti-inflamma- tory drug; GVHD: Graft versus host disease. 722 F. ARGÜELLES-ARIAS ET AL. Rev esp enfeRm Dig (maDRiD) Rev esp enfeRm Dig 2015; 107 (12): 714-731 Miscellanea CE may be useful in several gastrointestinal disorders of childhood such as celiac disease, protein-losing enteropathy, intestinal lymphangiectasia, graft-versus-host disease, chronic abdominal pain and failure to thrive. However, regarding these conditions only data on isolated case reports have been published and evidence is low. In addition, the fact that biopsies are required for histopathologic disease confirmation in most of these cases, brings about dependence on additional diagnostic procedures. Malabsorption/celiac disease/eosinophilic enteritis – Statement 1: CE has nowadays a secondary role for the diagnosis of celiac disease in the pediatric population. It may be of some value for patient follow-up when refractory disease is suspected. Evidence level 4. Recommendation grade C. The gold standard for the diagnosis of celiac disease in children is the histological assessment of the intestinal mucosa. Thus, except for selected cases in which histology may be skipped (77), performing small bowel biopsies is mandatory. As no biopsy can be taken through CE, this tool has no role in the diagnostic work-up except, maybe, for children who refuse to undergo upper endoscopy. Nonetheless, typical mucosal changes related to celiac disease, such as scalloping, nodularity, loss of mucosal folds and mosaicism, may be observed with CE. A recent meta-analysis found that CE has a sensitivity of 89% and a specificity of 95% for celiac disease diagnosis (78). CE may also be of benefit in those with known celiac disease on a glutenfree diet who have ongoing symptoms or alarm symptoms to exclude complications such as ulcerative jejunitis and small bowel lymphoma (79,80). A child with ulcerative jejunitis associated to untreated celiac disease has been reported recently; healing was achieved after one year on a gluten-free diet, which suggests that ulcerative jejunitis is not associated with a poorer prognosis (81-83). There are no specific data on CE in other malabsorption syndromes or in eosinophilic enteritis. Protein-losing enteropathy/intestinal lymphangiectasia – Statement 2: In patients with protein-losing enteropathy of unknown etiology CE may be helpful to detect underlying lesions such as intestinal lymphangiectasia or CD. Evidence level 4. Recommendation grade C. – Statement 3: In patients with intestinal lymphangiectasia CE is helpful in establishing disease location and extension. Evidence level 4. Recommendation grade C. Few CE studies in children with protein-losing enteropathy have been reported. In these studies, the most common finding was intestinal lymphangiectasia (16,17,84), although other pathologies such as CD have been described (85). The macroscopic lymphangiectasia lesions observed with CE are characteristic (swollen villi and edematous aspect of small intestine mucosa) and for that reason CE is useful not only to diagnose but also to evaluate disease extension (3,17). Recurrent abdominal pain – Statement 4: CE is not useful for diagnostic purposes in pediatric patients with isolated chronic or recurrent abdominal pain not accompanied by other clinical and/or laboratory findings. Evidence level 4. Recommendation grade C. Recurrent abdominal pain is one of the most common pathologies in children, occurring in 9% to 15% of patients in the pediatric age (86). The etiology of this condition is not clear. While in the majority of cases no organic cause may be found, which suggests a functional disorder, with the techniques currently available an organic process is sometimes identified and can explain the reported symptoms. It is not, however, until numerous tests have been performed, some of them radiological or invasive in nature, that a diagnosis can be reached, resulting in frustration and worry both for patients and their families. Several papers have discussed the usefulness of CE in adult patients with recurrent abdominal pain reaching different conclusions. Bardan et al. found no benefit from performing CE examinations in patients with chronic abdominal pain (87). In a recent systematic review it was concluded that CE provides a noninvasive diagnostic tool for patients with unexplained chronic abdominal pain, but with a limited diagnostic yield (20.9%). Among patients with positive CE, inflammatory lesions are the most common findings (88). In children CE has been evaluated in different studies and has been found to be superior to other investigation methods, including upper endoscopy (89). In one of them, CE showed relevant findings in 43% of patients with chronic and recurrent abdominal pain (90). Tokuhara et al. confirmed the absence of small bowel involvement by CE in 3 out of 4 patients with recurrent abdominal pain, although one patient had nodular lymphoid hyperplasia (4) and in another study, the lesion most commonly found was the presence of numerous hyperplastic lymphoid nodules in the terminal ileum (91). In a recent study (92) seventy-two patients with chronic abdominal pain with/without diarrhea underwent CE. 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