Subtypes of Irritable Bowel Syndrome in Children: Prevalenceat Diagnosis and at Follow-Up

Eleonora Giannetti, MD1, Gianluigi deAngelis, MD2, Rossella Turco, MD1, Angelo Campanozzi, MD3, Licia Pensabene, MD4,

Silvia Salvatore, MD5, Federica de Seta, MD1, and Annamaria Staiano, MD1

subtypes in childhood at diagnosis and

according to Rome III criteria, were enrolled over a 1-year period. Parents recorded weekly stool frequency andconsistency and gastrointest tency was scored accordingto the Bristol Stool Form Scale. Children were evaluated after 2, 3, 6, and 12 months.FGID Functional gastrointestinal disorderResults We enrolled 100 children with IBS (median age 9.9 years, range 4.2-16.7 years, 52 girls and 48 boys). Attime of enrollment, constipation-IBS was the prevalent subtype (45%), with a prevalence of girls at 62% (P < .005);diarrhea-IBS was reported in 26% of children, with a prevalence of boys at 69% (P < .005); and alternating-IBS wasdescribed in 29% of children, without a difference between sexes. During the follow-up, 10% of patients changedtheir IBS subtypes at 2 months, 9% at 3 months, 7% at 6 months, and 6.3% at 12 months. Twenty-four percent ofpatients changed IBS subtype between the time of enrollment and 12 months.ConclusionsConstipation-IBS is theprevalent subtype inchildren,withahigher frequency ingirls. Inboys,diarrhea-IBS is themost common subtype. It is important to acquire knowledge about IBS subtypes to design clinical trials thatmay eventually shed new light on suptype-specific approaches to this condition. (J Pediatr 2014;164:1099-103).

Irritable bowel syndrome (IBS), as described by using the Rome criteria, includes symptoms of abdominal pain or discomfortaccompanied by changes in bowel patterns.1,2 Studies have estimated the prevalence of IBS to range between 6% and 14% inchildren and between 22.0% and 35.5% in adolescents.3,4 A confident diagnosis, confirmation, and explanation of pain expe-

rience and reassurance can by itself be therapeutic.5 Specific goals of therapy includemodifying severity and developing strategiesfor dealing with symptoms.1 In adults, the Rome III committee recommends a subclassification into different subtypes based onthe predominant bowel habit (constipation-IBS [C-IBS] or diarrhea-IBS [D-IBS]).6 Different authors7 consider that patientswith symptoms of both constipation and diarrhea should constitute an alternating-IBS (A-IBS) or a mixed-IBS subtype.A systematic review showed that the clinical course of IBS is highly heterogeneous because IBS clinical subtype distribution

differs depending on the population evaluated, the geographical location, and the criteria used to define IBS and bowel habitsubtypes. In most cases, clinical course is characterized by the presence of mild-to-moderate symptoms appearing sequentially.8

A recent study in adults showed that the distribution of IBS subtypes is stable over time in most of the patients, although30%-40% of patients with IBS changed intestinal pattern at least once during a 2-week period.9

As reported in guidelines and review articles, drug therapy in IBS should be chosen on the basis of the predominant bowelsymptom.10-13 Only 1 study performed in pediatric patients in Sri Lanka showed an equal distribution of IBS subtypes.14

The aims of the present study were to establish the predominant IBS subtypes in children at diagnosis and to observe thechanges over time of IBS subtypes.

Methods

Patients eligible for the study were children aged 5-17 years who were referred for abdominal pain and subsequently received adiagnosis of IBS at 1 of 5 different Italian pediatric clinicsUniversity of Naples Federico II, University of Foggia, Hospital-University of Parma, University Magna Graecia of Catanzaro, and Universityof Insubria, Varesebetween January 2010 and January 2012. IBS was diagnosed

From the 1Department of Translational Medical Science,Section of Pediatrics, University of Naples Federico II,Naples, Italy; 2GastroenterologyUnit, Hospital-Universityof Parma, Parma, Italy; 3Department of Pediatrics,University of Foggia, Foggia, Italy; 4Department ofPediatrics, University Magna Graecia of Catanzaro,Catanzaro, Italy; and 5Department of Pediatrics,University of Insubria, Varese, Italy

The authors declare no conflicts of interest.

5-HT 5-hydroxytryptamine

A-IBS Alternating-irritable bowel syndrome

C-IBS Constipation-irritable bowel syndrome

D-IBS Diarrhea-irritable bowel syndromeIBS Irritable bowel syndromeinal and extraintestinal symptoms in a diary. Stool consistheir changes over 1 year.Study design This is an observational, prospective, multicenter study. Consecutive pediatric patients with IBS,Objectives To assess the prevalence of irritable bowel syndrome (IBS)0022-3476/$ - see front matter. Copyright 2014 Elsevier Inc.All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.12.043

1099

Statistical AnalysisStatistical analysis was carried out using SPSS statisticalsoftware package for Windows (13.0; SPSS Inc, Chicago,Illinois). A value of P < .05 was considered as significant.Fisher exact test was used to assess the prevalence of symp-toms in the 3 groups.

Results

Of 113 patients eligible for the study, 11 (9.7%) declinedparticipation. Two children (1.8%) were excluded from thestudy because they improved after the 2-week lactose-freediet trial. In all subjects, laboratory findings were unremark-able. No children changed from IBS to another FGID duringthe study period.We enrolled 100 children with diagnosis of IBS (48 boys

and 52 girls, median age 9.9 years, range 4.2-16.7 years).Median time between onset of symptoms and diagnosis

THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 164, No. 5using the Rome III criteria for pediatric functional gastroin-testinal disorders (FGIDs).1 Exclusion criteria were: (1)FGIDs other than IBS; (2) any underlying chronic disorders;(3) cerebral palsy; (4) delayed psychomotor development;and (5) children who had received drugs that modify bowelhabits, such as probiotics, laxatives, and antidiarrheals, dur-ing the previous month.An informed consent was obtained at enrollment from

parents of all children younger than 10 years and fromboth parents and children if older than 10 years. The studywas approved by the independent ethics committees of allparticipant centers.The study had a multicenter, observational, prospective

design. At the first visit (T0 [enrollment]), a medical historywas collected and all patients underwent clinical evaluation,laboratory tests (full blood cell count, inflammatory markers,antitransglutaminase and antiendomysial antibodies, fecalcalprotectin), and a trial with a lactose-free diet for 2 weeks,to exclude lactose intolerance. Information regardingabdominal pain characteristics, bowel habits, and associatedsymptoms were recorded using a previously validated self-administered questionnaire. The questionnaire was devel-oped according to the Rome III diagnostic questionnairefor pediatric FGIDs.15 Parents received a diary in which torecord weekly stool frequency and consistency, the presenceof specific behaviors during the evacuation such as retentiveposturing or excessive volitional stool retention, and thepresence of gastrointestinal symptoms. A score of the stoolconsistency was subsequently attributed according to theBristol Stool Form Scale.16 Patients were subclassified indifferent subtypes of IBS based on the adult Rome III classi-fication, due to the lack of a classification in the pediatricage.6 Children were prospectively evaluated at 2 (T1), 3(T2), 6 (T3), and 12 (T4) months after enrollment. At eachvisit, the interim history was assessed, weekly diaries werereviewed and discussed, a physical evaluation was performed,and the children and/or their parents were asked to againcomplete the IBS symptoms questionnaire. If a child didnot return for a planned follow-up visit, follow-up datawere obtained through a telephone call by the authors.After inclusion in the study, all children were treated with

reassurance and with lifestyle changes provided by means oforal and written instructions; in particular, families were ex-plained that IBS is a functional bowel disorder in the absenceof any organic cause and were educated to face episodes ofabdominal pain by attempting to reduce the patients anxietyandworries. Furthermore, childrenwere invited to play sportsand encouraged to practice outdoor activities,17 theywere rec-ommended to eliminate excess of fructose and spices from thediet,18-20 and they were encouraged to consume a regular fiberdiet (age in years plus 5 g/day)21,22 bymeans of written recom-mendations (Appendix; available at www.jpeds.com). Nodrug treatment was started during the follow-up period.Compliance with these recommendations and failure to

take other forms of therapy were assessed at each follow-upvisit by examination of the diary completed by patientsand/or their parents.1100was 6.2 months (range 2-10 months).At the time of enrollment (T0), C-IBS was the prevalent

subtype, present in 45 of 100 children (45%), with a preva-lence of 62% in girls (28/45; P < .05); D-IBS was reportedin 26 of 100 (26%) children, with a prevalence of 69% inboys (18/26; P < .05); and A-IBS was described in 29 of 100children (29%), with no significant difference in prevalencebetween sexes. The prevalence of the different subtypes atdiagnosis is shown in Figure 1.At diagnosis, 41% of patients had difficulty falling asleep,

53% of patients reported recurrent absences from schooland/or interruption of their activities, 32% of patients hadjoint pain, and 43% had headache. Difficulty falling asleep,absences from school and/or interruption of activities, andthe other reported extraintestinal symptoms were not signif-icantly related to IBS subtype (Table I).At 2-month follow-up (T1), 10 of 100 (10%) patients pre-

sented changes in IBS subtypes: 3 from C-IBS to D-IBS, 3from A-IBS to C-IBS, and 4 from A-IBS to D-IBS. At3-month follow-up (T2), 9 of 100 (9%) patients presented

Figure 1. Prevalence of the different IBS subtypes and dis-tribution according to sex at diagnosis.Giannetti et al

changes in IBS subtypes: 1 from A-IBS to C-IBS, 1 fromD-IBS to A-IBS, 1 from D-IBS to C-IBS, 2 from C-IBS toD-IBS, 2 from C-IBS to A-IBS, and 2 from A-IBS to D-IBS.At 6-month follow-up (T3), 7 of 100 patients (7%) presentedchanges in IBS subtypes: 3 from C-IBS to A-IBS, 2 fromA-IBS to D-IBS, 1 C-IBS to D-IBS, and 1 from D-IBS toA-IBS.After 1 year, in 53 of 95 children (55.7%), change in bowel

habit and abdominal pain disappeared, and 5 children were

to D-IBS. Figure 2 shows the distribution of subtypes duringthe 1-year study period.Overall, 23 of 95 patients (24.2%) changed IBS subtype

only once between T0 and T4, and the most frequent changeswere observed from A-IBS to C-IBS or D-IBS. Nine patientschanged IBS subtype more than once during the studyperiod. Changes of IBS subtypes throughout the study areshown in Table II (available at www.jpeds.com).

Discussion

The major findings of our study were that: (1) C-IBS was theprevalent subtype, with a significantly higher frequency ingirls, and D-IBS was more frequent in boys; (2) the prevalentsubtype did not change during the 12-month follow-upperiod; (3) there was a variation in bowel pattern in 24%of children during the follow-up period; and (4) among theintestinal and extraintestinal symptoms considered, nonewas related to IBS subtypes.In our study, distribution of IBS subtypes showed that C-

IBS was the most frequent subtype. A previous pediatricstudy assessing IBS subtypes in Sri Lankan children and ado-

Table I. Correlation between IBS subtypes andextraintestinal symptoms

IBS subtypes, n (%)

Total,100 P

C-IBS,45 (45)

D-IBS,26 (26)

A-IBS,29 (29)

Difficulty falling asleep,No. (%)

19 (42.2) 8 (30.7) 14 (48.3) 41 (41) .41

Absences fromschool/interruptionof activities, No. (%)

25 (55.5) 12 (46.1) 16 (55.2) 53 (53) .72

Joint pain, No. (%) 14 (31.1) 5 (19.2) 13 (44.8) 32 (32) .12Headache, No. (%) 22 (48.9) 9 (34.6) 12 (41.4) 42 (42) .49

May 2014 ORIGINAL ARTICLESlost at follow-up3 dropped out because drug prescriptionswere requested, whereas 2 discontinued the follow-up visits.In the remaining 42 children, C-IBS was still the most frequentsubtype, detected in 21of 42 children (50%;P= .01);C-IBSwaspresent in 12 of 21 girls and 9 of 21 boys (57%and 43%, respec-tively; P = .35). D-IBS was present in 12 of 42 patients (29%)and it was still more frequent in boys, with a prevalence of 2of 12 girls and of 10 of 12 boys (17% and 83%, respectively;P = .02). A-IBS was present in 9 of 42 (21%) patients withno difference between sexes (P = .4).From T3 to T4, changes of subtypes were observed in 6 of

95 children (6.3%): 3 from A-IBS to C-IBS and 3 from A-IBSFigure 2. Distribution of IBS subtypes at diagnosis and at the 4

Subtypes of Irritable Bowel Syndrome in Children: Prevalence atlescents, reported that C-IBS, D-IBS, and A-IBS were almostequally distributed.14 In a systematic review, Guilera et al8

found that, in adults, US studies showed a similar distribu-tion between C-IBS, D-IBS, and A-IBS and that Europeanstudies reported that both C-IBS and D-IBS subtypes werethe most commonly detected. Similarly, Engsbro et al9 founda tendency toward C-IBS and D-IBS being the most stablesubtypes. This pattern was also found by Dorn et al,23

whereas Penny et al24 and Halder et al25 described C-IBS asthe least stable subtype. Most of the available studies reportedA-IBS to be the most common subgroup,26 especially whenthe investigation is primary care office based.8 Ersryd and

timepoints during follow-up.Diagnosis and at Follow-Up 1101

potential to ameliorate the smooth muscle spasm, abdom-

THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 164, No. 5others have demonstrated that the presence of diarrhea is anexplanation for referral from primary care to gastroenterolo-gists,27-29 which might explain a higher proportion of D-IBSin some studies from gastroenterology outpatient clinics.30,31

According to most of the authors, A-IBS was the most com-mon Rome II subtype, whereas according to Rome IIIcriteria, C-IBS and D-IBS were the most common subtypes.In our population, female sex was more frequently associ-

ated with constipation and male sex with diarrhea, similar towhat was previously reported by Rajindrajith and Devanar-ayana in a pediatric cohort14 and by other authors in adultpopulations31-34 but not with the findings from another adultstudy that, using Rome III criteria, found no sex difference inthe prevalence of subtypes.27

Identification of IBS subtypes would be important in bothclinical practice and research, because pharmacological man-agement of IBS is becoming more specific and new therapiesare being developed that target specific IBS subtypes. Ourfindings showed that the point prevalence of subtypes is fairlystable over time, although 24% of patients changed subtypeduring a 1-year period. Our stability rate (76%) is higherthan that found in some adult studies. Engsbro et al9 foundthat, in a 10-week follow-up, about 60% of patients remainedwithin the same subtype from one period to the next, whereas30%-40% of patients changed subtype. Dorn et al23 found astability rate of Rome II subtypes of 15% and of Rome IIIsubtypes of 23% based on six 2-week periods over a total of15 months, and Drossman et al35 found 24% to be stable,when evaluating Rome II subtypes 6 times for 2 weeks during15 months. In contrast, Williams et al36 showed that amongthe whole survey sample, 30% of subjects remained in thesame IBS subtype in the 2001 and 2004 surveys and 18%changed IBS subtype, and the remaining 52% of subjectsno longer met the criteria for IBS during the follow-up.Mearin et al37 found that 61% of their patients were stablewhen evaluating them twice during 4 weeks with an intervalof 1 month.The discrepancy among these results could be related to

the different population and criteria used to define the sub-types of IBS and to a shorter follow-up compared with ourstudy. At present, there are no pediatric data on the vari-ability of IBS subtypes over time.It is interesting to note that in our population, similarly to

Garrigues et al,7 most changes occurred from A-IBS to C-IBSor D-IBS (21%); changes from C-IBS to D-IBS, or vice versa,occurred in a minority of patients (8%), and it was not com-mon to change from C-IBS or D-IBS to A-IBSdirect shiftsbetween these subtypes were rarely seen.Changes in symptoms and in bowel habit subtype may

depend on different factors besides the natural history ofthe disease, such as the effect of treatment or of the reassur-ance derived by a physician visit. In the present study, all chil-dren received the same behavioral and dietary advice to avoida treatment bias in the assessment of subtype changes.The interest in subtyping patients with IBS has grown

stronger as new drugs have been introduced on the market.As reported in several guidelines and review articles,10-131102inal pain, and change in bowel habit that patients with IBSexperience. A recent review by Camilleri and Di Lorenzo38

showed that the treatment of constipation or diarrhea alsoimproves abdominal pain, which is the most importantsymptom in IBS. In particular, treatment with lubiprostonewas associated with significant improvement in bowelmovement frequency as well as symptoms of abdominaldiscomfort/pain and bloating.39 A systematic review andmeta-analysis found that 5-HT3 antagonists improveabdominal pain and discomfort and global IBS symptomsin men and women with nonconstipated and diarrhea-predominant IBS.40

Our study has some limitations. First, as the study wasconducted at a tertiary care center, our population wasselected and patients had no comorbidities and no otherFGIDs and, during the follow-up period considered, didnot receive any pharmacological treatment. We cannotexclude that all these potentially confounding factors mayaffect the changes in IBS subtypes in a less pure population.Furthermore, we cannot rule out that the recommendationfor all children to follow the same diet plan, despite being es-tablished to not influence the course of the syndrome, couldhaveminimally affected the evolution of IBS subtypes. On theother hand, dietary recommendations were provided to thewhole population and represented an intervention that likelydetermined a trivial effect on the natural history of IBS.Finally, another potential drawback of our analysis is thatwe did not assess the impact of pharmacological therapy onIBS symptoms. However, this was beyond the aims of ourresearch and should be investigated in further studies.In conclusion, in our population, C-IBS is the most prev-

alent subtype overall at the timepoints considered, with a sig-nificant higher frequency in girls. A variation of bowelpattern is reported during the follow-up in25% of childrenwith IBS. It is important to acquire knowledge about IBS sub-types to design clinical trials that may eventually shed newlight on subtype-specific approaches to this condition. n

Submitted for publication Aug 6, 2013; last revision received Dec 11, 2013;

accepted Dec 19, 2013.

Reprint requests: Annamaria Staiano, MD, Department of Translational

Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini,

5, 80131 Naples, Italy. E-mail: staiano@unina.it

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Table II. Changes in IBS subtype throughout the study

Type of changes n (%)

No changes 63 (66.3)C-IBS 34 (36.9)D-IBS 23 (24.2)A-IBS 11 (11.6)C-IBS/ A-IBS or D-IBS 11 (11.6)

C-IBS/ A-IBS 5 (5.2)C-IBS/ D-IBS 6 (6.3)

D-IBS/ A-IBS or C-IBS 3 (3.1)D-IBS/ A-IBS 2 (2.1)D-IBS/ C-IBS 1 (1)

A-IBS/ C-IBS or D-IBS 18 (18.9)A-IBS/ C-IBS 7 (7.4)A-IBS/ D-IBS 11 (11.6)

Appendix. Irritable Bowl Syndrome Informative Sheet for Parents.

THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 164, No. 5

1103.e1 Giannetti et al

Subtypes of Irritable Bowel Syndrome in Children: Prevalence at Diagnosis and at Follow-UpMethodsStatistical Analysis

ResultsDiscussionReferences