CHRONIC IDIOPATHIC CONSTIPATION IN CHILDREN GUIDELINE. Appendix J - EVIDENCE TABLES

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1 CHRONIC IDIOPATHIC CONSTIPATION IN CHILDREN GUIDELINE Appendix J - EVIDENCE TABLES Key Component of the Hitory Taking and the Phyical Examination in Children with chronic contipation Bibliographic Borowitz et al. Precipitant of contipation during early childhood Journal of the American Board of Family Practice 16[3], United State. Borowitz, 2003 Study type & level Study type: Cae-control level: III Study aim: To determine the precipitant to contipation in early childhood patient & prevalence 220 children Incluion Aged 2y 0m to 6y 11m, at leat average intelligence - patient: Firt time preentation to phyician with contipation - control: no hitory of contipation Excluion Underlying medical condition, medication that could account for contipation Population Characteritic 220 children - n=125 mean age (month): 44±13 49% male -Control n=95 mean age (month): 46±18 54% male Country: USA Setting: 26 primary care facilitie (15 paediatrician, 11 family medicine centre) Type of tet and Reference tandard Tet Hitory of event occurring in the 3 month prior to onet of contipation: -large/painful bowel movement -toilet training -tarted day care -travelling -liquid to olid food -breat to bottle -family move -vomiting /dehydration -new medication -parental eparation -birth of a ibling -tent camping -high fever -urgery -extended bed ret -trauma in Senitivity, Specificity, PPV and NPV Degree of difficulty with toilet training (mean ± SD) (0=none, 4=extreme) : 2.1±1.3 Control: 1.4±1.1 p<0.001 Degree of difficulty paing ome bowel movement (% children) None: patient 3, control 49 Mild: patient 86, control 49 Moderate: patient 80, control 10 Extreme: patient 76, control 5 p<0.001 (patient a compared to control in each category) Degree of pain paing ome bowel movement (% children) None: patient 5, control 56 Mild: patient 82, control 40 Reviewer comment Additional information from tudy Contipation defined a paage of < 3 bowel movement each week for at leat 2 conecutive week 22 non-patient ibling matched a control, an additional 73 non-ibling control recruited from advertiement Likert cale: 0 to 4. 0 being not at all difficult and 4 being extremely difficult Quetionnaire for parent to fill out decribing children bowel habit. - indication of how difficult toilet training had been for bowel movement uing Likert cale - parent to indicate if any of 18 different event occurred in the 3 month preceding the onet of contipation, and which of thee they believed contributed to the onet of contipation Both group comparable regarding age and ex 1

2 Study type & level patient & prevalence Population Characteritic Type of tet and Reference tandard bathroom -exual abue -family death Reference Standard None Senitivity, Specificity, PPV and NPV Moderate: patient 69, control 8 Severe: patient 67, control 6 p<0.001 (patient a compared to control in each category) Children expreing worry about paing bowel movement (% children) Reviewer comment Reviewer comment Potential recall bia Source of funding: NIH grant RO1HD : 75 Control: 8 p<.001 -Family hitory of contipation and initial age of toilet training no ignificantly different between the 2 group -Subgroup analyi: children grouped according to whether they became contipated before or after their econd birthday. The event parent reported having occurred in the 3 month before the onet of contipation were imilar in the two group, with the exception of toilet training having occurred more often before contipation in the older children (40% v. 20%), and making the dietary tranition from breat to bottle and from liquid to olid diet having occurred more often before 2

3 Study type & level patient & prevalence Population Characteritic Type of tet and Reference tandard Senitivity, Specificity, PPV and NPV contipation in the younger children (30% v. 0). Large or painful bowel movement were een by far the mot frequent precipitating event for both age group. Toilet training wa een a more of a precipitant for older onet children (20% v. 10%), wherea tranition from breat to bottle and from liquid to olid food wa een to be more of a problem for younger-onet children (25% v. 0) Reviewer comment 3

4 Freedman et al. The crying infant: Diagnotic teting and frequency of eriou underlying dieae Pediatric 123[3], United State. Freedman, 2009 Study type & level Study type: Retropectiv e cae erie level: III Study aim: To determine the proportion of children evaluated in an emergency department becaue of crying who have a eriou underlying aetiology patient & prevalence 238 patient Incluion - le than 12 month age - afebrile - preenting to ED during 9 month eligibility period with chief complaint of crying Excluion Not tated Population Characteritic 238 patient Male 124 (52%) Median age 2.3 month (range 1.0 to 5.4) Country: Canada Setting: Tertiary care referral hopital Type of tet and Reference tandard Tet Abdominal radiograph Abdominal ultraound Reference Standard Hitory taking and phyical examination Senitivity, Specificity, PPV and NPV -Poitive finding on hitory and/or phyical examination alone uggeted the final diagnoi in 66.4% (158 of 238) of the crying children -11 cae of contipation were diagnoed, all diagnoed by category 1 data ource poitive hitory and phyical examination only Contipation defined a hitory of difficult, infrequent, hard tool, palpation of mall pellet on abdominal examination Abdominal radiograph performed 14 time with 0 poitive finding Abdominal ultraound performed 16 time with poitive finding 2 time (12.5%) contributing only to the diagnoi of intuuception and acute cholecytiti, but not contipation -Hitory and examination were found to be the mot important apect in the evaluation of the crying infant. Invetigation only helpful in 3% of ample in thi tudy Reviewer comment Additional information from tudy preenting with chief complaint of crying identified retropectively by earching electronic databae uing a chief complaint family word root earch for: cry, irritable, fu, cream and colic. Afebrile defined a < 38 C 37,549 ED viit during 9 month eligibility period, of which 238 children met incluion criteria and their final diagnoe grouped into 1-4 categorie according to the ource of data that contributed the diagnoi Data ource categorie: 1) Diagnoi wa baed on the hitory (Hx) and/or phyical examination (PE) alone 2) Diagnoi wa baed on poitive tet reult obtained after the Hx and PE failed to ugget a caue 3) Diagnoi wa baed on tet ordered to invetigate poitive finding from the Hx and/or PE that uggeted a caue 4) Neither Hx, PE nor invetigation were diagnotic Required ample ize calculated to yield table etimate (±5%) of the primary outcome meaure (proportion of infant who had potentially eriou underlying aetiology). Etimated that 10% ample would have underlying eriou aetiologie. Minimum ample of 138 ubject required. Anticipated 4

5 Study type & level patient & prevalence Population Characteritic Type of tet and Reference tandard Senitivity, Specificity, PPV and NPV Reviewer comment follow-up telephone call repone rate of only 75%. Final ize after adjutment:: 245 Reviewer comment No data on follow up care of accuracy of contipation cae Minimum ample ize required not achieved Source of funding: Not tated 5

6 Lewi et al. Diagnoing Hirchprung' dieae: increaing the odd of a poitive rectal biopy reult Journal of Pediatric Surgery 38[3], Lewi et al., 2003 Study type & level Study type: Retropectiv e cohort level: III Study aim: To tet the hypothei that key feature in the hitory, phyical examination and radiographic evaluation would allow to avoid unneceary rectal biopie patient & prevalence 315 children Incluion -Cohort 1: Children preenting with contipation to diagnoe Hirchprung dieae (HD) -Cohort 2: idiopathic contipation Excluion undergoing reevaluation fro contipation after pullthrough procedure for HD Population Characteritic 315 children: -265 children who hade undergone rectal biopy -50 children, concurrent elected cohort (cohort 2) Country: USA Type of tet and Reference tandard Tet: Rectal biopy Senitivity, Specificity, PPV and NPV Clinical feature in children with Hirchprung dieae and idiopathic contipation (IC, n=40) -Onet of contipation <1 year old Delayed paage of meconium (%) HD: 65 IC: 13 P< 0.05 Abdominal ditenion (%) HD: 80 IC: 42 P< 0.05 Vomiting (%) HD: 72 IC: 21 P< 0.05 Faecal impaction requiring manual evacuation (%) HD: 6 IC: 30 P< 0.05 Enterocoliti (%) HD: 13 IC: 15 NS Reviewer comment Additional information from tudy Quetionnaire, telephone interview and patient viit ued to compile longterm data. In reporting feature lited in the quetionnaire only patient with definite information were included: the number of patient in each analyi varie to exclude thoe with miing data Delayed paage of meconium defined a failure to pa meconium in the firt 48h of life. Thee data were available in 59% of cae Abdominal ditenion determined from parental repone to quetionnaire or data noted during patient viit Enterocoliti defined a diarrhoea aociated with fever Reviewer comment: Data on clinical feature not available for all children Unclear what kind of rectal biopy wa performed and how the diagnoi of HD wa made Source of funding: Not tated -Onet of contipation >1 year old Delayed paage of meconium (%) 6

7 Study type & level patient & prevalence Population Characteritic Type of tet and Reference tandard Senitivity, Specificity, PPV and NPV HD: 81 IC: 1 P< 0.05 Reviewer comment Abdominal ditenion (%) HD: 53 IC: 7 P< 0.05 Vomiting (%) HD: 23 IC: 0 P< 0.05 Faecal impaction requiring manual evacuation (%) HD: 46 IC: 30 NS Enterocoliti (%) HD: 13 IC: 14 NS Age at onet of ymptom -Hirchprung (HD) (n=46) Mean: 8 month (range 1 day to 9 year) 1rt week of life: 60 % 1rt month of life: 70% 1rt year of life: 87% after 1 year of life: 13% -Idiopathic contipation (IC) (n=40) Mean: 15 month (range 7 day to 16 year) 7

8 Study type & level patient & prevalence Population Characteritic Type of tet and Reference tandard Senitivity, Specificity, PPV and NPV 1rt week of life: 15% 1rt month of life: 55% 1rt year of life: 68% after 1 year of life: 32% Reviewer comment At leat 34% of HD patient had the claic triad (delayed paage of meconium + vomiting + abdominal ditenion). At leat 1 feature of the triad noted in 98% of patient with HD. Only 60% of patient with IC had a hitory of delayed paage of meconium, vomiting or abdominal ditenion. 100 % HD patient v. 64% IC patient had 1 or more of the following: delayed paage of meconium, vomiting, abdominal ditenion and a tranition zone on contrat enema. 36% of IC patient had none of thee feature. 8

9 Diagnotic Value of the Digital Rectal Examination (DRE) Children with Chronic Idiopathic Contipation Bibliographic Beckmann et al. Accuracy of clinical variable in the identification of radiographically proven contipation in children Wiconin Medical Journal 100[1], 33-36United State. Study type & level Study type: Propective cae erie level: III Study aim: to determine whether clinical variable accurately identify children with radiologically proven contipation patient & prevalence 251 children Incluion Children aged 2-12 year old who preented to the Emergency Department (ED) of Children' Hopital of Wiconin with abdominal pain and underwent radiographic evaluation. Excluion previou abdominal urgery, known abdominal pathology, menarche or ickle cell dieae Setting: hopital Population Characteritic Group 1: 141 children with radiologically proven contipation Age: year 63 (25%) male Group 2: 110 children with no radiographic evidence of contipation Age: year 57 (23%) male Country: USA Type of tet and Reference tandard Tet: Clinical variable -Hitory of gatrointetinal problem -Duration of abdominal pain -Stool habit -Straining on defecation -Faecal conitency (normal/hard tool) -Medication -Phyical exam: rebound, rigidity, guarding, tympanic/ditended -Phyical examtenderne: diffue, each of four quadrant, flank, epigatric, periumbilical -Phyical exam: bowel ound, rectal exam Clinical examination (including rectal exam) performed by Senitivity, Specificity, PPV and NPV Clinical variable (a a model) Senitivity: 77% (+) Specificity: 35% (-) PPV 60% NPV: 55% Only the following clinical variable were ignificantly different between the two group: Hitory of normal/hard tool conitency: Group 1: 74% (100/135) Group 2: 61% (61/99) p: Abence of rebound tenderne Group 1: 98% (138/141) Group 2: 90% (99/110) p: Preence of left lower quadrant tenderne: Reviewer comment Abdominal radiograph wa either a ingle flatplate or a flatplate with upright view, ordered by the ED attending phyician baed on cutomary practice. The ED phyician ordering the radiograph were blinded to tudy objective 32% of the enrolled ubject did not undergo rectal exam A clinical diagnoe previou to radiology wa made and reported. However it wa not clear how many of the clinical variable needed to be preent to diagnoe contipation. Furthermore, the phyical exam wa completed by one of everal paediatric ED phyician and no aement of inter-rater reliability wa performed. Official radiologic diagnoi wa provided by a ingle board certified paediatric radiologit blinded to the tudy. Thi wa compared with the ED phyician interpretation of the radiograph and the patient were divided into the two group, but it i not clear on the bai of what thi deciion wa made. A data heet with demographic-clinical 9

10 Study type & level patient & prevalence Emergency Department Population Characteritic Type of tet and Reference tandard the ED phyician Reference tet: Abdominal radiograph Radiological diagnoe of contipation (baed on faecal loading core originated and validated by Barr et al and later revied by Blethyn et al) -Normal, grade 0: faece in rectum and cecum only -Grade 1, mild contipation: faece in rectum, cecum and dicontinuou elewhere -Grade 2, moderate contipation: faece in rectum, cecum with continuou faece affecting all egment but allowing for ga -Grade 3, evere contipation: continuou faece with dilated colon and rectal impaction Senitivity, Specificity, PPV and NPV Group 1: 20% (19/96) Group 2: 9% (6/69) p: Stool preent in rectal vault a per rectal exam: Group 1: 69% (70/102) Group 2: 43% (29/68) p: Reviewer comment data wa required before an abdominal radiograph wa ordered, but in 159 patient no data-heet wa ubmitted for variou reaon. Thee patient were excluded from the tudy and the lack of data make impoible to tell whether they differed from the group of included patient Source of funding: Not reported 10

11 Rockney et al. The plain abdominal roentgenogram in the management of encoprei Archive of Pediatric and Adolecent Medicine 149[6], Study type & level Study type: Retropectiv e cae erie level: III Study aim: to determine whether faecal retention in encopretic children can be aeed objectively uing the plain abdominal roentgenogr am and whether roentgenogr aphic evidence of faecal retention i aociated with clinical finding on preentation in encopretic children patient & prevalence 60 encopretic children Incluion/ excluion criteria Encoprei a defined by the DSM Revied Third Edition: repeated involuntary (or, much more rarely, intentional) paage of faece into place not appropriate for that purpoe (e.g., clothing or floor) the event mut occur at leat once a month for at leat 6 month, the chronological and mental age of the child mut be at leat 4 year, and phyical diorder that can caue faecal incontinence, uch a Population Characteritic Age: 4-11 year old Group 1 47 encopretic children with faecal retention by roentgenogram criteria on preentation Male ex: 74.5% Group 2 13 encopretic children without faecal retention by roentgenogram criteria on preentation Male ex: 61.5 % Country: USA Type of tet and Reference tandard Tet: Rectal examination Reference tet: Plain abdominal roentgenogram Three radiologit, two paediatric and one general, at three eparate intitution, blind to the identity of the ubject evaluated the plain abdominal Rx twice: a "ubjective" reading aeed faecal content a markedly exceive, moderately exceive or normal and a "ytematic" reading where a tool retention rating record wa completed and a core aigned (0-25) reflecting the everity of faecal retention (core of 10 or greater indicate faecal retention, cale validated by Barr et al.) Final reult were taken from the ytematic reading Senitivity, Specificity, PPV and NPV Value for rectal examination: a) When the diagnoi of retention by abdominal RX, ytematic reading wa agreed by at leat two radiologit: (%) Senitivity: 88.6 Specificity: 41.6 Poitive predictive value: 84.8 Negative predictive value: 50 b) When the diagnoi of retention by abdominal RX, ytematic reading wa agreed by the three radiologit: (%) Senitivity: 91.7 Specificity: 71.4 Poitive predictive value: 94.3 Negative predictive value: 62.5 Not all data were available for every ubject Reviewer comment 78 encopretic children originally enrolled but only 60 children for whom Rx could be retrieved were included in analyi. There were no ignificant difference between encopretic children whoe abdominal Rx were reviewed for the tudy and thoe who did not have a Rx or whoe Rx could not be retrieved. There were no ignificant difference in patient characteritic at the two ite. Not all data were available for every ubject Children with retention (a per Rx) were ignificantly more likely to have tool in the rectum on preentation (p 0.015) and were ignificantly le likely to have parent report a difficult toilet training (p 0.018). There were no other ignificant difference between the two group regarding the ret of the variable meaured. Each patient medical record wa reviewed eparately by one of the author and a reearch aitant. When dicrepancie exited chart were reviewed again conjointly and dicrepancie reolved for both reviewer atifaction. The reliability of the radiologit aement wa teted by two different procedure. Overall agreement among the three radiologit wa 77.8% for the ubjective aement, k=0.53 (z=7.04, 11

12 Study type & level patient & prevalence aganglionic megacolon, mut be ruled out Children younger than 4 year old and children who had a oiling frequency of le than once a month or who had recently topped oiling were excluded Setting: two paediatric incontinence clinic, one located in the ambulatory care facility of a tertiary care hopital and the other at a community hopital Population Characteritic Type of tet and Reference tandard only. At leat two radiologit had to agree in order to claify roentgenogram either a in the retention or nonretention category Preence of tool in rectal examination wa recorded in the patient record a none, mall, moderate or large amount. with moderate or large amount of tool on rectal examination were claified a having tool in the rectum for ubequent analyi. The pecific profeional qualification of the peron who performed the rectal examination wa not reported Senitivity, Specificity, PPV and NPV Reviewer comment p<0.0001). Agreement uing the ytematic aement wa 87.4%, k=0.65 (z=7.2, p<0.0001). There were no difference in interrater reliabilitie between pair of radiologit. The tudy from which the ytematic coring ytem wa derived ha not been replicated, and the cut-off point of 10, might not be valid for all population Source of funding: Primary Care Faculty Development Fellowhip Programme at Michigan State Univerity, Eat Laning. 12

13 Prevalence of Coeliac Dieae and Hypothyroidim in children with Chronic Idiopathic Contipation Bibliographic Bonamico et al. Prevalence and clinical picture of celiac dieae in Italian down yndrome patient: A multicenter tudy Journal of Pediatric Gatroenterolog y and Nutrition 33[2], United State. Study type & level Study type: Propective cohort level: 2+ Study aim: To etimate the prevalence of coeliac dieae (CD) in patient with Down yndrome and to define the clinical characteriti c of CD among Down Syndrome patient patient 1202 patient Incluion Down yndrome Excluion IgA deficiency Setting: Community Population Characteritic 1202 patient 609 male 1110 children age range: 15 month to 18 year 92 adult age range 18 to 46 year Country: Italy -Group 1: 55 CD patient diagnoed by ESPGHAN Criteria (36 male, aged 4 to 46 year) -Group 2: 55 IgA AGA-poitive EMA negative DS patient (33 male, aged 3 to 40 year) -Group 3: 57 IgA AGA-negative EMA-negative DS patient (34 male, Type of tet () Tet: -Coeliac dieae: Revied European Society of Paediatric Gatroenterology, Hepatology and Nutrition (ESPGHAN) criteria elected for intetinal biopy on the bai of EMA poitivity, AGA IgA poitivity, or both in children < 2 year of age (AGA: antigliadin antibodie; EMA: antiendomyium antibodie; IgA: immunoglobulin A) -Down yndrome: confirmed by cariotype in all cae Sign/ymptom (%): -Group 1 (n=55): Growth failure 52.7 Diarrhoea 41.8 Vomiting 20 Anorexia 18.2 Contipation 29.1 Ditended abdomen Group 2 (n=55): Growth failure 10.9 Diarrhoea 1.8 Vomiting 1.8 Anorexia 1.8 Contipation 14.5 Ditended abdomen Group 3 (n=57): Growth failure 7 P < Diarrhoea 6.9 P < Vomiting 1.7 P < Anorexia 3.4 P < 0.01 Contipation 8.8 P < 0.05 Reviewer comment Additional information from tudy of IgA AGA were meaured by enzymelinked immunoorbent aay by the Alfa-gliatet (Europital, Triete, Italy). of EMA IgA were evaluated by an indirect immunofluorecence method (Europital, Triete, Italy). Section from the dital portion of monkey oeophagu were ued a a ubtrate, and fluorecein-labeled goat antihuman IgA antibody wa ued a the econd antibody. The patient erum wa diluted 1:5 in phophate buffer at ph 7.2. The preence of a brilliant green network pattern under a fluorecence microcope wa taken a a poitive reult. Intetinal biopie performed by Waton capule or by paediatric or adult endocope elected for intetinal biopy on the bai of both EMA poitivity and AGA IgA poitivity in children < 2 year of age, becaue in thi age group, EMA poitivity may have a fale-negative reult A detailed quetionnaire wa completed to obtain information about familial gatroenterologic hitory with pecial attention to feeding habit (breat milk 13

14 Study type & level patient Population Characteritic aged 4 to 38 year) Type of tet () Ditended abdomen 15.5 NS P value are the reult of comparing group 1 v. group 2 and group 3 Reviewer comment or formula, age of introduction of glutencontaining food); gatrointetinal function, particularly the feature of CD, uch a chronic diarrhoea, vomiting, failure to thrive, and anorexia; preence of autoimmune or neoplatic condition All patient were receiving a glutencontaining diet. Weight and height were evaluated uing Down yndrome percentile chart (DSPC) The clinical feature of 55 CD patient diagnoed by ESPGHAN Criteria (group 1) were compared with thoe oberved in 55 IgA AGA-poitive EMA negative DS patient (group 2) and in 57 IgA AGA-negative EMA-negative DS patient (group 3). Group 2 and group 3 patient were elected randomly from among the creened patient to be age and gender matched to group ymptomatic patient belonging to group 2 underwent intetinal biopy and howed normal mall bowel mucoa Parent of 8 EMA poitive children and 2 EMA-poitive adult did not give permiion for intetinal biopy to be performed and were not included among the 55 CD patient Reviewer comment: It i unclear whether ome patient had EMA and other had AGA IgA meaured alternatively, or whether all patient had both EMA and AGA IgA 14

15 Study type & level patient Population Characteritic Type of tet () Reviewer comment meaured at the ame. Thi conidered it i alo unclear why only IgA AGApoitive EMA-negative patient and IgA AGA-negative EMA-negative patient were choen a control group and there i no mention of the EMA-poitive IgA AGA-negative group Source of funding: Not tated 15

16 Bingley et al. Undiagnoed coeliac dieae at age even: Population baed propective birth cohort tudy Britih Medical Journal 328[7435], United Kingdom. Study type & level Study type: Propective cohort level: 2+ Study aim: to etablih the prevalence of undiagnoed coeliac dieae in the general population at age even and to look for any aociated clinical feature patient 5470 children Incluion Children aged 7.5 year participating In the Avon Longitudinal Study of Parent and Children (ALPASC), a population baed birth cohort tudy etablihed in 1990 Excluion Not tated Setting: Community Population Characteritic 5470 children age: 7.5 year gender not reported Country: UK Type of tet () Tet: -Coeliac dieae: Two tage creening: 1. Senitive initial radioimmunoaa y for antibodie to tiue tranglutaminae (endomyial antigen) (ttg antibodie) 2. If poitive to previou, erum IgA antiendomyial antibodie (IgA- EMA) by indirect inmunofluorecen ce -Contipation: Clinical variable Any contipation reported at age 6.75 year (No, %): -ttg antibody negative control (n=4285 quetionnaire): 435 (10) -IgA-EMA poitive (n=42 quetionnaire): 6 (14) odd ratio (95% CI): 1.48 (0.62 to 3.52) Other ymptom reported at age 6.75 year (No, %): -ttg antibody negative control (n=4285 quetionnaire): any diarrhoea: 1450 (34) any vomiting: 1933 (45) any tomach pain: 2557 (60) 3 GI ymptom: 931 (22) -IgA-EMA poitive (n=42 quetionnaire): any diarrhoea: 21 (50) odd ratio (95% CI): 1.96 (1.06 to 3.59) any vomiting: 23 (55) odd ratio (95% CI): 1.47 (0.80 to 2.71) any tomach pain: 28 (66) Reviewer comment Additional information from tudy Children with ttg antibodie < 97.5 th centile were defined a antibody negative Detail of gatrointetinal ymptom and pecial diet collected by routine quetionnaire at age 6.75 year Total ttg antibody negative control (n=5333 children). Total IgA-EMA poitive children (n=54) (1.0%; 95% confidence interval 0.8 to 1.4) 4324 children (79%) returned quetionnaire An additional 137 children were ttg antibody poitive, but Ig-EMA negative IgA-EMA were more common in girl (OR 2.12; 1.20 to 3.75). IgA-EMA poitive children were horter and weighted le than thoe who teted negative fro ttg antibody (p< for all comparion) Since ALPASC i an obervational tudy baed on analyi of anonymou ample, confirmatory biopy wa not poible Reviewer comment: Unclear how the ymptom contipation wa defined in the firt place No data regarding clinical ymptom at 16

17 Study type & level patient Population Characteritic Type of tet () odd ratio (95% CI): 1.35 (0.71 to 2.57) 3 GI ymptom: 17 (40) odd ratio (95% CI): 2.45 (1.33 to 4.5) Reviewer comment 6.75 year for 21% of the total ample Source of funding: Coeliac UK, Medical Reearch Council, Wellcome Trut, UK government department, and variou charitable organiation and commercial companie, ALSPAC i part of the WHO initiated European Longitudinal Study on Pregnancy and Childhood 17

18 Cataldo et al. Epidemiological and clinical feature in immigrant children with coeliac dieae: An Italian multicentre tudy Digetive and Liver Dieae 36[11], United State. Study type & level Study type: Retropectiv e cae erie level: 3 Study aim: To evaluate the prevalence of immigrant children with coeliac dieae (CD) in Italy, the clinical finding in thee patient and the poible relationhip between immigration, dietary habit and CD in childhood patient 1917 children Incluion Italian and immigrant children conecutively diagnoed a having CD between January 1999 to December 2001 Excluion Not tated Setting: Hopital (multicentre) Population Characteritic Total: 1917 children with CD 36 immigrant children with CD 15 male age range 6 month to 15 year (mean 7.3) 1881 Italian children 891 male age range 6 month to 16 year (mean 7.9) Country: Italy Type of tet () Tet: -coeliac dieae: diagnoi baed on the revied criteria of the European Society of Paediatric Gatroenterology and Nutrition (ESPGAN): 1. Finding of a flat mall intetinal mucoa with the feature of hyperplatic villou atrophy on hitological examination of a biopy pecimen, while the patient i eating adequate amount of gluten 2. Clear cut clinical remiion on a trict gluten free diet with relief of all ymptom of the dieae. Thi repone hould be reaonably rapid occurring within a matter of week rather than many month Clinical pattern and preenting ymptom at diagnoi (n=36) -Claical form (25/36) (69.4%): No child with contipation reported -Atypical form (9/36) (25%): Abdominal pain with contipation : 2/9 -Silent form (2/36) (5.5%): No child with contipation reported Reviewer comment Additional information from tudy Claical form not clearly defined, but included the following ymptom: chronic diarrhoea, weight lo, abdominal ditenion and vomit Atypical form included: iron-deficiency anaemia, hort tature, delayed puberty, recurrent oral aphtae Silent form included: erological creening of firt degree relative, lo of Kerckring fold at endocopy Clinical pattern in Italian children were imilar to thoe of immigrant children Reviewer comment: Unclear how the ymptom contipation wa defined in the firt place Preenting ymptom at diagnoi were not reported for Italian children Source of funding: Study upported by grant of Minitero dell Univerita e della Ricerca Scientifica e Tecnologica (MURST) 60% di F.C. 18

19 Study type & level patient Population Characteritic Type of tet () Reviewer comment 3. The finding of circulating antibodie (IgA gliadin, antireticulin, and antiendomyiun) at time of diagnoi and their diappearance when the patient i taking a gluten free diet add weight to the diagnoi 19

20 Egan-Mitchell et al. Contipation in childhood coeliac dieae Archive of Dieae in Childhood 47[252], Study type & level Study type: Retropectiv e cae erie level: 3 Study aim: To ae the incidence of contipation in coeliac dieae patient 112 children Incluion Coeliac dieae Excluion Not tated Setting: Regional and univerity hopital Population Characteritic 112 children 12 children with contipation: 6 male, age range 6 to 102 month Country: Ireland Type of tet () Tet: -Coeliac dieae 1. Clinical variable: undernutrition and retarded growth. 2. Jejunal biopy: Grade 2/3 or grade 3 jejunal mucoal damage -Contipation: Clinical variable: paage of tool of harder conitency than normal, or the clinical obervation of impaction of abnormal amount of hard (uually pale) faece in colon and rectum Incidence of contipation: 12 children contipated at ome tage before diagnoe: -9 of thoe children preented with contipation and faecal impaction, of thee 5 had intermittent diarrhoea and contipation but 4 never had diarrhoea. Of thee 4, 3 children preented at around 1 year of age with anorexia, failure to thrive and faecal impaction -the 3 children who did not have faecal impaction when invetigated had hitorie of contipation alternating with mild diarrhoea and all had been given laxative frequently for their contipation Reviewer comment Additional information from tudy Growth retardation aeed on the graph of Tanner and Whitehoue (1959) and ubequently confirmed by catch-up growth following treatment with gluten-free diet Mucoal damage according to author claification (normal mucoa grade 0; mild non-pecific change grade 1; grade 2 and 3 correpond to moderate and evere villou atrophy) Reviewer comment: Unclear whether author claification ytem for jejunal mucoa damage ha been validated Source of funding: The main author wa receiving a grant from the Medical Reearch Council of Ireland 20

21 Diagnotic Value of the Anorectal Manometry in Children with Chronic Idiopathic Contipation Bibliographic Jarvi et al. Anorectal manometry with reference to operative rectal biopy for the diagnoi/exclu ion of Hirchprung' dieae in children under 1 year of age International Journal of Colorectal Dieae 24[4], Germany. Study type & level Study type: Retropectiv e cae erie level: III Study aim: To report on the value of anorectal manometry (ARM) with reference to operative rectal biopy in the diagnoi/ex cluion of Hirchprun g dieae in children under 1 year of age and on the prognotic ignificance of a normal patient 81 patient Incluion under 1 year of age who preented with delayed paage of meconium, abdominal ditenion and vomiting or contipation who underwent ARM Excluion Other congenital gatrointetinal malformation uch a anorectal anomaly, funnel anu or gatrochii Population Characteritic 81 patient 49 male median age at time of ARM and biopy: 2 month (range 0.1 to 11 month) Country: Finland Type of tet () Tet: -Anorectal manometry: Performed uing a 4-cm long rectal balloon inflated incrementally with 5 to 50 ml of air -Operative rectal biopy: Taken 3 cm above the dentate in the poterior midline, coniting of a generou, longitudinal pecimen extending to the ubmucoa Rectoanal inhibitory reflex (RAIR) and hitology reult -RAIR preent (N=40) HD: no children Normal hitology: 39 children Hypoganglionoi: 1 child -RAIR abent (N=41) HD: 33 children Normal hitology: 8 children Diagnotic variable for ARM and operative rectal biopy in HD (%): -Biopy: Senitivity: 100 Specificity: 100 Poitive predictive value: 100 Negative predictive value: 100 -ARM: Senitivity: 100 Specificity: 83 Poitive predictive value: 80 Reviewer comment Additional information from tudy Record of all patient who met the incluion criteria were reviewed In each cae ARM wa performed under ketamine anaetheia by a conultant paediatric urgeon, and operative rectal biopy wa taken imultaneouly RAIR defined a greater than 25% drop in the anal phincter preure for at leat 5 econd who had HD were ignificantly younger at the time of invetigation than thoe who did not In the cae of patient diagnoed with HD hitology from bowel reected at pull-through operation wa conitent with pre-operative diagnoi in all cae Operative rectal biopy wa adequate and diagnotic in all cae. There wa one cae of rectal bleeding following biopy which required uturing in theatre Reviewer comment: 21

22 Study type & level RAIR in thee patient patient Population Characteritic Type of tet () Reviewer comment Negative predictive value: 100 Unclear how the reviewing proce wa conducted Unclear how the biopy pecimen were proceed and analyed Source of funding: Not tated 22

23 Lee et al. Allergic proctiti and abdominal ditention mimicking Hirchprung' dieae in infant Acta Paediatrica, International Journal of Paediatric 96[12], United Kingdom. Study type & level Study type: Retropectiv e cae erie level: III Study aim: To evaluate the incidence and clinical apect of allergic proctiti (AP) in patient with ymptom that mimic Hirchprun g dieae (HD). In addition author determined the enitivity and pecificity of anorectal manometry and uction rectal biopy ued for evaluation of patient 105 children Incluion Infant < 6 month of age with evere abdominal ditenion that mimicked HD referred to department of paediatric and diviion of paediatric urgery and underwent all triple tet including barium enema, anorectal manometry and rectal uction biopy. Some patient had aociated ymptom like contipation, poor oral intake, vomiting, poor weight gain and diarrhoea Excluion Coeliac dieae and cytic fibroi not Population Characteritic 105 children 61 boy Mean age: 2.1 ± 0.9 month Country: Korea Type of tet () Tet: -Anorectal manometry: Performed by paediatrician uing a ilicon rubber catheter with an array of 8 channel of enor. Sedation with chloral hydrate for the procedure wa ued -Suction rectal biopy: Taken from 4 different ite uing a rectal uction biopy tube. Biopy ite were 3cm and 5 cm for anal verge. When ganglion cell were oberved to be preent with normal appearance on haematoxylineoin taining HD wa excluded. HD wa finally diagnoed with full thickne Rectoanal inhibitory reflex (RAIR) and hitology reult -RAIR abent (N=48) HD: 34 Normal hitology: 10 AP: 2 IND: 2 -RAIR preent (N=57 ) HD: 5 Normal hitology: 43 AP: 5 IND: 4 Diagnotic variable for ARM and rectal uction biopy in HD (%): -Biopy: Senitivity: 92.31% (CI: to 97.35) Specificity: 100 % (94.50 to ) Poitive predictive value 100% Negative predictive value: 95.65% -ARM: Senitivity: 87.18% (CI: to 94.90) Specificity: 78.79% (CI: to 86.92) Reviewer comment Additional information from tudy Severe abdominal ditenion defined a an abdominal wall that protruded, wa hiny and tene upon palpation Reviewer comment: Unclear how the reviewing proce wa conducted Unclear what wa the order in which invetigation were carried out Source of funding: Not tated 23

24 Study type & level HD patient conidered in the differential diagnoi becaue are extremely rare in Korea Population Characteritic Type of tet () biopy Poitive predictive value: 70.83% Negative predictive value: 91.23% Reviewer comment 24

25 Kong et al. Screening Hirchprung' dieae by anorectal manometry Chinee Journal of Gatroenterolog y 10[1], 29-32Taiwan, Province of China. Study type & level Study type: Retropectiv e cae erie level: III Study aim: To evaluate the poibility of uing anorectal manometry (ARM) for creening Hirchprun g dieae (HD) patient 39 patient Incluion Children with contipation or upected HD Excluion Sytemic dieae like hypothyroidim or neurologic diorder Population Characteritic 39 patient age range: 3 day to 9 year (no other detail provided) Country: Taiwan Type of tet () Tet: -Anorectal manometry: Double lumen tainle teel manometric probe with internal diameter of 6 mm ued. Entire ytem cloed and water filled. Multiplechannel recorder ued for recording reult. No previou bowel preparation. Stimulu balloon placed from 3 to 5 cm from anal verge, depending on ize of patient. For uncooperative patient intramucular injection with mixture of chlorpromazine, promethazine and meperidine with or without intravenou diazepam wa given Rectoanal inhibitory reflex (RAIR) and hitology reult -RAIR abent (N=18) HD: 15 Normal hitology: 3 -RAIR preent (N=18) HD: 0 Normal hitology: 18 -RAIR inconcluive (N=3) HD: 0 Normal hitology: 3 Diagnoi variable ARM (%): Accuracy: 90 Senitivity: 100 Specificity: 86 PPV: 83 NPV: 100 Reviewer comment Additional information from tudy A normal reflex (RAIR) wa preent when rythmicity of internal phincter contractility wa totally inhibited by rectal ditenion accompanied by a imultaneou drop of internal phincteric preure fro 5mmHg or more. A poitive rectoanal repone conited of 3 ucceive preure fall, each immediately following upon rectal ditenion by balloon. When rythmicity and internal phincter preure remained unchanged following rectal ditenion, the amount of air wa increaed gradually to 10 cc fro neonate and 50 cc for children. If RAIR wa abent, a negative repone wa recorded The final diagnoi of HD wa made by patient clinical hitory, barium enema and rectal uction biopy Inconcluive reult with manometry due to poor tracing of internal phincter contraction a a reult of overedation (n=2) and to anal tenoi (n=1) Reviewer comment: No definition of contipation given Inufficient detail on how HD wa diagnoed It i not completely clear whether or not all patient underwent rectal biopy but it look a thi wa probably the cae 25

26 Study type & level patient Population Characteritic Type of tet () - Rectal uction biopy (no other detail provided) Reviewer comment The 3 children in whom manometry wa inconcluive were not included in the calculation of the diagnotic variable and thi introduce bia Source of funding: Not tated 26

27 Penninckx et al. Pitfall and limitation of teting the rectoanal inhibitory reflex in creening for hirchprung' dieae Pediatric Surgery International 5[4], Germany. Study type & level Study type: Propective cae erie level: III Study aim: To better acertain the trap and limitation of teting the rectoanal inhibitory reflex (RAIR), how frequently they occur and the poible explanation fro equivocal or fale reult patient 261 patient Incluion referred for anorectal manometry in order to confirm or exclude Hirchprung dieae. All patient had preented with contipation varying from light to intractable, with highly differing duration ranging from neonatal ileu to chronic contipation in adult Excluion Not tated Population Characteritic 261 patient -gender not reported for all patient -Age: < 6 month: 94 (36%) 6 month to 6 year: 106 (41%) 6 to 15 year: 47 (18%) 2 adolecent and 12 adult (5%) Country: Belgium Type of tet () Tet: -Anorectal manometry No pecial bowel preparation given. if a coniderable amount of faecal impaction wa found, patient were ent back for evacuating enema () and reexamination planned for the next day. Children not edated. Entire ytem filled with degaed water. Multiple-channel recorder ued for recording reult - Superficial biopy of rectal mucoa and ubmucoa taken with a laryngeal biopy forcep. Frozen ection biopie tained for acetylcholinetera e and nicotinamide adenine dinucleotide- Rectoanal inhibitory reflex (RAIR) and hitology reult -RAIR equivocal reult (abent?): 9 children HD: 4 Normal hitology: 5 -RAIR equivocal reult (preent?): 8 children HD: 2 Normal hitology: 6 -RAIR confident interpretation: 232 children RAIR+: 207 RAIR-: 25 Of the previou 54 children underwent either biopy or repeated manometry. Only fale reult reported: -RAIR preent and HD: 2 children -RAIR abent and normal hitology: 4 children Incidence of fale reult and age of patient at firt manometry Reviewer comment Additional information from tudy In no cae the reult of a rectal biopy wa known at the time of manometry RAIR conidered to be preent if the anal preure decreaed on rectal ditenion followed by recovery of the baal tone. RAIR wa alo conidered to be preent if the typical anal preure wave were clearly abolihed Confident interpretation of the RAIR wa made in 232/261 patient (89%): RAIR preent in 207 cae and abent in 25. The reult of thi firt manometric evaluation wa verified either by biopy or by repeated manometry in 54 cae. In other cae the clinical evolution did not warrant further invetigation. Manometrically the following factor prevented examiner from reaching a definite concluion: low anal tone (n=8), retlene of patient (n=7), reflex external phincter contraction partially or completely making poible RAIR (n=4), preence of megarectum (n=3), artifact (n=1), untable RAIR (n=6) Reviewer comment: Not all children underwent both manometry and biopy: 261 patient underwent manometry and only 24 underwent biopy Detail of both the manometry and biopy reult were reported only in cae where the RAIR wa equivocal in 27

28 Study type & level patient Population Characteritic Type of tet () reduced diaphorae. Aganglionoi with hypertrophic bundle wa diagnotic for HD -In <1 month old: 5/22 (22.7.8%) -In > 1 month old: 4/239 (1.7%) Incidence of equivocal reult and age of patient at firt manometry -In <1 month old: 4/22 (18.2%) -In > 1 month old: 25/239 (10.4%) Reviewer comment the firt manometry and in thoe children where the reult proved to be fale (either negative or poitive). Conidering thi it i not poible to calculate the enitivity, pecificity, poitive and negative predictive value of the anorectal manometry The incidence of fale reult in manometry performed by different examiner i reported in the paper, but there are miing data not accounted for and therefore we do not report it here Source of funding: Not tated 28

29 Low et al. Accuracy of anorectal manometry in the diagnoi of Hirchprung' dieae Journal of Pediatric Gatroenterolog y and Nutrition 9[3], Study type & level Study type: Propective cae erie level: III Study aim: To ae the accuracy of anorectal manometry in the diagnoi of Hirchprun g dieae (HD) uing hitological aganglionoi a the reference point for final diagnoi patient 50 children Incluion Children referred conecutively to one of the author for anorectal manometric tudie Excluion Not tated Population Characteritic 50 children (data available for 45 children) 31 male 14 female Age range birth to 11 month Country: Singapore Type of tet () Tet: -Anorectal manometry Performed a a ide-room procedure. All children under 4 year of age who were unable to cooperate were teted after oral edation with chloral hydrate -Suction rectal biopy Suction rectal biopie obtained without anaetheia by paediatric urgeon on outpatient bai. Biopie taken at 4 cm from the anal verge with a Noblet or Quinton biopy et. Rectoanal inhibitory reflex (RAIR) and hitology reult -RAIR abent (N=16) HD: 15 Normal hitology: 1 -RAIR preent (N= 34) HD: 4 Normal hitology: 30 Diagnotic variable for ARM, total ample N=50 (%): Accuracy: 90 Senitivity: 79 Specificity: 97 Poitive predictive value: 94 Negative predictive value: 88 Diagnotic variable for ARM, neonate N=10 (%): Accuracy: 90 Senitivity: 86 Specificity: 100 Poitive predictive value: 100 Negative predictive value: 75 Diagnotic variable for ARM, infant N=18 (%): Accuracy: 94.4 Senitivity: 90 Specificity: 100 Poitive predictive value: 100 Reviewer comment Additional information from tudy 5 children (10%) required repeat fullthickne biopy for inadequate ampling All children underwent both manometry and biopy. Biopy pecimen prepared in paraffin ection and tained with haematoxylin and eoin. Up to 60 6-μm-thick erial ection of each pecimen were examined hitologically by pathologit for ganglion cell and hypertrophied nerve bundle. Specimen not including the ubmucoal layer were conidered inadequate and repeat full-thickne operative rectal biopie were taken A normal reflex wa preent when rythmicity of internal phincter contractility wa totally inhibited by rectal ditenion accompanied by imultaneou drop in internal phincteric preure. Rythmicity and tone recovered when rectal ditenion wa removed. When rythmicity and internal phincter preure remained virtually unchanged after rectal ditenion a negative repone wa recorded No complication encountered with manometry in all 50 children tudied Reviewer comment: No definition of contipation/idiopathic contipation given 29

30 Study type & level patient Population Characteritic Type of tet () Negative predictive value: 89 Reviewer comment Unclear what infant meant for author Source of funding: Reearch grant (RP53/81) from the National Univerity of Singapore, Singapore 30

31 Diagnotic Value of the Plain Abdominal Radiography in Children with Chronic Idiopathic Contipation Bibliographic Reuchlin- Vroklage et al. Diagnotic value of abdominal radiography in contipated children: a ytematic review Archive of Pediatric and Adolecent Medicine 159[7], Study type & level Study type: Sytematic Review level: 1+ Study aim: to evaluate the additional diagnotic value of the plain abdominal radiography in the diagnoi of contipation in children patient & prevalence 6 tudie (3 cae erie, 2 cae-control tudie, 1retropective re-examination of abdominal radiograph Incluion Controlled, obervational tudie invetigating the relationhip between faecal loading on plain abdominal radiography and ymptom and ign related to contipation in otherwie healthy children aged from 1 to 18 year old Excluion Population Characteritic Otherwie healthy children aged from 1 to 18 year old with ign and ymptom related to contipation. Some tudie included children with oiling or encoprei, while other exclude thi group Country: The Netherland Type of tet and Reference tandard Tet and Reference Standard (tudie could treat either tet a the reference tandard) -Faecal loading on plain abdominal radiography according to a predefined coring ytem (reference tet in 3 tudie) -Clinical diagnoi of contipation according to the preence or abence of predefined ymptom and ign (reference tet in 3 tudie) In the 6 tudie Senitivity, Specificity, PPV and NPV Diagnotic value: (LR: Likelihood ratio) -Ability of the abdominal radiography to dicriminate between clinically contipated and non contipated children (4 tudie): 1. Senitivity: 76 (95% CI: 58 to 89) Specificity: 75 (95% CI: 63 to 85) LR: 3.0 (95% CI: 1.6 to 4.3) 2. Senitivity: 60 (95% CI: 46 to 72) Specificity: 43 (95% CI: 18 to 71) LR: 1.0 (95% CI: 0.5 to 1.6) 3. Senitivity: 80 (95% CI: 65 to 90) Specificity: 90 (95% CI: 74 to 98) LR: 8.0 (95% CI: 0.7 to 17.1) Reviewer comment MEDLINE earched from inception to April 2004, earch term reported and comprehenive. Reult of thi earch combined with earch trategy pecific to identify diagnotic tudie. Reference lit of review article and included tudie checked for further relevant article. Expert in the field contacted and aked to identify publihed and unpublihed tudie. No language retriction applied Two reviewer independently creened the title and abtract f tudie identified by the earche for eligibility. All potentially relevant tudie were retrieved a full paper and independently creened by two reviewer. Any diagreement were reolved through conenu or by arbitration of a third reviewer Methodological quality of tudie aeed uing the QUADAS tool. An overall methodological quality value wa aigned to tudie by calculating the number of poitive core (maximum value 14). Studie with core of 9 or higher >60%) were arbitrarily regarded a being of high 31

32 Study type & level patient & prevalence Lack of control group, no data on diagnotic value preented, ymptom of contipation not related to the outcome of a plain abdominal radiography Setting: all 6 tudie hopital baed Population Characteritic Type of tet and Reference tandard included, 3 different coring ytem for aeing impaction on abdominal radiography were ued: 3 tudie: Barrcore 2 tudie: revied Barr-core 1 tudy: author own coring ytem Senitivity, Specificity, PPV and NPV 4.Accuracy 80% (95% CI: 50 to 100) Ability of the clinical examination to dicriminate between radiographically contipated and non contipated children (1 tudy): Senitivity: 77 (95% CI: 70 to 84) Specificity: 35 (95% CI: 27 to 44) LR: 1.2 (95% CI: 1.0 to 1.4) Reviewer comment methodological quality. Two reviewer independently aeed the methodological quality of the independent tudie. Any diagreement were reolved by conenu or through conultation with third reviewer. Reviewer cored 84 item and agreed on 65 item (77.4%, k=0.54) Structured data extraction performed independently by two reviewer and any diagreement reolved by conenu Source of funding: Not reported -Aociation between a hitory of hard tool and faecal impaction on radiography: LR: 1.2 (95% CI, 1.0 to 1.4) -Aociation between a finding of abence of rebound tenderne and faecal impaction on radiography: LR: 1.1 (95% CI, 1.0 to 1.2) -Aociation between tool preent on rectal examination and faecal impaction on abdominal radiography: LR: 1.6 (95% CI, 1.2 to 2.0) LR: 1.5 (95% CI, 0.8 to 2.3) 32