Tack et al. BMC Gastroenterology (2019) 19:69 https://doi.org/10.1186/s12876-019-0985-1 RESEARCH ARTICLE Open Access Economic burden of moderate to severe irritable bowel syndrome with constipation in six European countries Jan Tack1,10* , Vincenzo Stanghellini2, Fermín Mearin3, Yan Yiannakou4, Peter Layer5, Benoit Coffin6, Magnus Simren7, Jonathan Mackinnon8, Gwen Wiseman9, Anne Marciniak9 and on behalf of the IBIS-C Study group Abstract Background: Irritable bowel syndrome with predominant constipation (IBS-C) is a complex disorder with gastrointestinal and nervous system components. The study aim was to assess the economic burden of moderate to severe IBS-C in six European countries (France, Germany, Italy, Spain, Sweden and the UK). Methods: An observational, one year retrospective-prospective (6 months each) study of patients diagnosed in the last five years with IBS-C (Rome III criteria) and moderate to severe disease at inclusion (IBS Symptom Severity Scale score ≥ 175). The primary objective was to assess the direct cost to European healthcare systems. Results: Five hundred twenty-five patients were included, 60% (range: 43.1–78.8%) suffered from severe IBS-C. During follow-up 11.1–24.0% of patients had a hospitalisation/emergency room (ER) visit, median stay range: 1.5–12.0 days and 41.1–90.4% took prescription drugs for IBS-C. 21.4–50.8% of employed patients took sick leave (mean: 11.6–64.1 days). The mean annual direct cost to the healthcare systems was €937.1- €2108.0. The total direct cost (combined costs to healthcare systems and patient) for IBS-C was €1421.7–€2487.1. Conclusions: IBS-C is not a life-threatening condition; however, it has large impact on healthcare systems and society. Direct and indirect costs for moderate to severe IBS-C were high with the largest direct cost driver being hospitalisations/ER visits. Keywords: IBS, IBS-C, Economic analysis, Healthcare resource utilisation, Europe Background predominant constipation (IBS-C), IBS with mixed bowel Irritable bowel syndrome (IBS) is a chronic functional habits (IBS-M), and IBS unclassified (IBS-U) [3]. Never- bowel disorder (FBD) characterised by symptoms of theless, the clinical continuum of symptoms has been recurrent abdominal pain accompanied by altered bowel shown to result in short-term subtype instability with function [1]. The prevalence of IBS varies between region around 40% of patients alternating between subtypes on a and country, however pooled prevalence estimates IBS to monthly basis [4, 5]. occur in 5–20% of the global population [2]. The Rome Influence by the nervous system adds to the clinical criteria [3] are the global standards developed by experts complexity of this FBD as it results in fluctuating symp- in functional bowel disorders which enable physicians to toms, both temporally (waxing and waning cycle of high identify and diagnose disorders such as IBS. Rome charac- disease activity and remission) and by severity [6, 7]. Yet terises IBS into subtypes based on the predominant bowel despite severity fluctuations, moderate-severe IBS is esti- habit: IBS with predominant diarrhoea (IBS-D), IBS with mated to account for around 60% of all IBS cases and has been shown to impose a considerable burden on patients * Correspondence: jan.tack@kuleuven.be [8]. This burden is manifested into a health economic bur- 1 University Hospital Gasthuisberg, Leuven, Belgium den through direct medical costs to healthcare systems 10 University of Leuven, Herestraat 49, 3000 Leuven, Belgium (HS) and indirect costs related to work absenteeism or Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tack et al. BMC Gastroenterology (2019) 19:69 Page 2 of 13 work impairment. Studies suggest that the burden of moderate to severe IBS-C at inclusion: defined as an Irrit- illness for IBS is quite substantial with all IBS sub- able Bowel Syndrome Symptom Severity Scale (IBS-SSS) types requiring similar levels of healthcare resource score ≥ 175 (moderate severity: ≥175–300; severe: > 300) utilisation [9–14]. [22]. Patients were excluded if they had participated in a Continued research and re-evaluation of diagnostic cri- clinical trial involving an experimental IBS-C treatment in teria have greatly improved physicians’ ability to differen- the six months prior to starting the observational period, tiate IBS from other FBDs and enhance the accuracy of or they had any condition that, in the investigator’s opin- subtype classification [3, 15]. For example, IBS-C and ion, would impact the patient’s ability to complete the chronic constipation are often confused due to their simi- study. This study was conducted in accordance with the larity in defecation patterns, despite IBS-C symptoma- Declaration of Helsinki as well as in compliance with ICH tology being dominated by abdominal pain [1, 16]. It is good clinical practices guidelines. The following ethics estimated that IBS-C accounts for around 30% of IBS committees approved the trial protocol and its amend- cases [17]. Treatment revolves around the use of therapies ments: Comité Consultatif sur le Traitement de l’Informa- which are not specifically approved for treating IBS-C, tion en matière de Recherche dans le domaine de la Santé such as laxatives, antispasmodics, prokinetics, and bulking (Paris, France), Israelitisches Krankenhaus (Hamburg, agents (e.g. dietary fibres). Although useful for treating Germany), University of Bologna (Bologna, Italy), constipation, in some patients these therapies show poor Humanitas Hospital IRCS (Milano, Italy), Floraspe efficacy, tolerability and are unable to treat all key IBS-C Renzetti Hospital (Lanciano, Italy), Agostino Gemelli symptoms when used individually [18, 19]. In Europe, the University Hospital (Rome, Italy), University of Parma guanylate cyclase-C agonist linaclotide is the only pharma- (Parma, Italy), University of Pisa (Pisa, Italy), University cological treatment approved for the treatment of IBS-C of Pescara (Pescara, Italy), Careggi University (Firence, and has been shown to be cost-effective compared to anti- Italy), University of Napoli Federico II (Napoli, Italy), depressants [20, 21]. University of L’Aquila (L’Aquila, Italy), University of Given the symptom and severity complexities of IBS-C Messina (Messina, Italy), University of Genoa (Genoa, there is a notable paucity of information related to health Italy). Ospedale S. Maria di Ca′ Foncello (Treviso, economic burden and resource utilisation, especially in suf- Italy), Fondazione IRCCS Policlinico San Matteo (Pavia, ferers at the more severe end of the severity spectrum. Italy), Centro médico Teknon (Barcelona, Spain), Hospital Newer agents approved to treat IBS-C may potentially Clínico San Carlos (Madrid, Spain), Hospital Universitario decrease the need for frequent visits to physicians and mul- 12 de Octubre (Madrid, Spain), Hospital Germans Trias I tiple medications, possibly translating into lower healthcare Pujol (Badalona, Spain), Hospital de Bellvitge (Barcelona, utilisation and drug-related costs. Therefore, this study Spain), Consorci Sanitari del Maresme (Mataró, aimed to learn more about the burden of the disease in a Spain), Hospital Universitario Virgen de la Macarena real-world population of moderate to severe patients with (Sevilla, Spain), Hospital Universitari Doctor Josep IBS-C across six European countries. Trueta (Girona, Spain), Hospital Universitari Sant Joan de Reus (Reus, Spain), National Institute for Methods Health Research (London, UK). The IBIS-C study was an observational, 12 month The study design is shown in Fig. 1. Baseline and retrospective-prospective (6 months each) multicentre 6-month retrospective data from included patients were study conducted in six European countries: France, obtained from patient medical records and patient inter- Germany, Italy, Spain, Sweden, and the UK. The first views. Demographic and clinical data were collected at patient was included in April 2012 and the last patient baseline. Symptom severity (IBS-SSS) was collected at last visit was in January 2014. Patients were recruited baseline and 6 months. Healthcare resource utilisation from primary or specialist care. directly related to IBS-C (general and specialist medical Screening was performed using retrospective data consultations, hospitalisations, diagnostic tests, thera- from patient records. Patients who met the eligibility pies, management of adverse reactions) was collected via criteria were included. Patients were included in the study a questionnaire that specified whether the costs were if they were ≥ 18 years of age, diagnosed with IBS-C in the public or private. Healthcare resource data were collected last 5 years using the Rome III criteria (recurrent IBS pain at baseline for up to 6 months for direct costs retrospec- or discomfort present for at least three days per month in tively and 3 months for indirect costs. Three-month the last three months; ≥ 2 of the following: improvement indirect costs were multiplied by two to provide a with defecation, onset associated with a change in stool retrospective 6-month estimate of indirect costs associ- frequency, or a change in stool form; ≥25% of bowel ated with IBS-C. Prospective healthcare resource uti- movements being hard or lumpy stools; < 25% of bowel lisation data were collected during routine follow-up at movements being loose or watery stools), and had 3 months (± 0.5 months) and 6 months (± 1 month) / early Tack et al. BMC Gastroenterology (2019) 19:69 Page 3 of 13 Fig. 1 Study design termination. All healthcare resource utilisation data were using descriptive statistics based on non-missing observa- calculated for patients that used the resource. tions. Costs were calculated as a mean with 95% confi- Direct costs were calculated both from a country dence interval (95% CI; calculated using 1000 bootstrap healthcare system’s perspective and the patient’s perspec- samples). Swedish krona (SEK) and Pound Sterling (GBP) tive using unit costs for each country. Hospitalisation were converted post hoc into Euro (EUR) using exchange costs were estimated from national diagnosis related rates of 1 SEK = 0.1134 EUR and 1 GBP = 1.2025 EUR, group (DRG) databases. For the patient’s perspective, respectively. only the sum of non-prescription medication, comple- A sample size of 90 patients per country was calculated mentary therapies and HS-related medications, consul- to produce a 95% CI equal to the sample mean ± ≤ 20% of tations, hospitalisations, and diagnostic procedures that the standard deviation of the direct costs associated with were paid for by the patient were taken into account; IBS-C [12]. For each country the retrospective, prospec- private consultation and private diagnostic procedure tive, and combined data periods were analysed separately. costs were not included. The separate analyses were then compared to determine Productivity losses in the week prior to baseline and at whether there was any statistical difference. An analysis of the 6-month visit were collected using the work produc- the combined data is presented for patient demographics tivity and activity impairment questionnaire for IBS-C and baseline characteristics; healthcare resource utili- (WPAI:IBS-C): a four component score for absenteeism, sation, work productivity and activity impairment, and all presenteeism (reduced productivity while at work), overall costs are presented by country. work impairment, and daily activity impairment (impair- ment in activities performed outside of work) [23]. Absen- Results teeism, presenteeism, and overall work impairment were A total of 525 patients across all countries were included recorded for employed patients and daily activity impair- in the study (France: N = 59; Germany: N = 102; Italy: N = ment for all patients. Indirect costs were calculated using 112; Spain: N = 112; Sweden: N = 36; UK: N = 104) questions about sick leave and work productivity impair- between April 2012 and January 2014. Over follow-up ment. The indirect costs were: cost of productivity for sick there were 62 (11.8%) discontinuations; 36 (6.9%) lost to leave (total number of days lost * 1 days’ salary), cost for follow-up, 19 (3.6%) with data missing, 5 (1.0%) with- work impairment (total number of work hours lost * 1 h’ drawals at the patients’ personal request, and 2 (0.4%) salary). In the event that the salary value was missing withdrawals due to illness. the mean value of the salary reported by employed patients was converted to gross income and used to Demographic, clinical and lifestyle characteristics at estimate indirect costs. baseline Exploratory analyses were performed and no confirma- Table 1 shows the main characteristics of this study co- tory statistical tests were performed. Demographics, hort. In summary, 459 (87.4%) of patients were included baseline characteristics, healthcare resource utilisation from specialist care with France, Italy and UK including characteristics and productivity losses were summarised 100% of patients from specialist care (range: 60.8–100%). Tack et al. BMC Gastroenterology (2019) 19:69 Page 4 of 13 Table 1 Patient Demographics FRANCE GERMANY ITALY SPAIN SWEDEN UK TOTAL N 59 102 112 112 36 104 525 Study centre recruitment, n (%) Primary Care 0 (0.0) 40 (39.2) 0 (0.0) 25 (22.3) 1 (2.8) 0 (0.0) 66 (12.6) Specialist Care 59 (100.0) 62 (60.8) 112 (100.0) 87(77.7) 35 (97.2) 104 (100.0) 459 (87.4) Age (years), mean (SD) 47.7 (15.7) 47.6 (18.1) 41.7 (17.0) 46.8 (13.7) 41.4 (12.7) 45.5 (14.6) 45.3 (15.8) Female, n (%) 49 (83.1) 85 (83.3) 96 (85.7) 96 (85.7) 33 (91.7) 97 (93.3) 456 (86.9) Higher education (university or similar), n (%) 16 (27.1) 42 (41.2) 50 (44.6) 30 (26.8) 15 (41.7) 31 (29.8) 184 (35.0) Employment status, n (%) Unemployed 12 (20.3) 9 (8.8) 15 (13.4) 31 (27.7) 4 (11.1) 25 (24.0) 96 (18.3) Student 1 (1.7) 10 (9.8) 15 (13.4) 3 (2.7) 2 (5.6) 1 (1.0) 32 (6.1) Part time (≤20 h/ week) 2 (3.4) 12 (11.8) 8 (7.1) 10 (8.9) 3 (8.3) 18 (17.3) 53 (10.1) Full time (> 20 h/ week) 29 (49.2) 44 (43.1) 62 (55.4) 49 (43.8) 24 (66.7) 47 (45.2) 255 (48.6) Retired 14 (23.7) 27 (26.5) 12 (10.7) 19 (17.0) 3 (8.3) 13 (12.5) 88 (16.8) Employed patients with salary above 11 (19.0) 19 (18.6) 23 (20.5) 42 (37.5) 20 (55.6) 38 (36.5) 153 (29.2) the national averagea, n (%) Level of physical exerciseb, n (%) Low 38 (64.4) 44 (43.1) 68 (60.7) 67 (59.8) 11 (30.6) 53 (51.0) 281 (53.5) Intermediate 15 (25.4) 47 (46.1) 34 (30.4) 33 (29.5) 14 (38.9) 38 (36.5) 181 (34.5) High 2 (3.4) 11 (10.8) 10 (8.9) 12 (10.7) 11 (30.6) 13 (12.5) 59 (11.2) Consumes alcohol, n (%) 6 (10.2) 31 (30.4) 25 (22.3) 22 (19.6) 27 (75.0) 61 (58.7) 172 (32.8) Current smoker, n (%) 8 (13.6) 15 (14.7) 22 (19.6) 26 (23.2) 7 (19.4) 22 (21.2) 100 (19.0) Patients who follow a diet, n (%) 12 (20.3) 21 (20.6) 50 (44.6) 48 (42.9) 15 (41.7) 43 (41.3) 189 (36.0) Type of diet, n (%) Hypocaloric 2 (3.4) 2 (2.0) 7 (6.3) 10 (8.9) 0 (0.0) 3 (2.9) 24 (4.6) Low sodium 1 (1.7) 1 (1.0) 2 (1.8) 9 (8.0) 1 (2.8) 1 (1.0) 15 (2.9) Low carbohydrate 1 (1.7) 1 (1.0) 2 (1.8) 7 (6.3) 4 (11.1) 5 (4.8) 20 (3.8) High-fibre 4 (6.8) 4 (3.9) 24 (21.4) 27 (24.1) 4 (11.1) 9 (8.7) 72 (13.7) Low-fibre 0 (0.0) 2 (2.0) 6 (5.4) 4 (3.6) 1 (2.8) 12 (11.5) 25 (4.8) Other 5 (8.5) 13 (12.7) 14 (12.5) 6 (5.4) 7 (19.4) 18 (17.3) 63 (12.0) Previous GI surgery, n (%) Appendectomy/cholecystectomy 23 (39.0) 31 (30.4) 25 (22.3) 20 (17.9) 6 (16.7) 30 (28.8) 135 (25.7) Bariatric surgery or surgery to remove a 2 (3.4) 3 (2.9) 0 (0.0) 0 (0.0) 1 (2.8) 1 (1.0) 7 (1.3) GI tract segment Other surgeries of the abdomen, pelvis, 17 (28.8) 19 (18.6) 16 (14.3) 27 (24.1) 11 (30.6) 37 (35.6) 127 (24.2) or retroperitoneal structures Time since IBS-C diagnosis (years), mean (SD) 2.6 (6.3) 4.6 (8.4) 2.9 (3.8) 2.3 (2.8) 2.3 (3.4) 2.6 (4.0) 3.0 (5.2) Symptom duration (years), mean (SD) 13.5 (13.5)1 15.0 (16.9) 10.4 (9.1) 9.6 (9.9) 15.6 (12.2) 15.3 (14.9) 12.8 (13.1) a Average gross income (€/year): France: 35,511; Germany: 42,633; Italy: 26,040; Spain: 27,674; Sweden: 40,568; UK: 39,303. bLow level: Sports activities 0–1 times a week/ walk less than 0.5 h per day; Medium level: Sports activities 2–3 times per week/ walk at least 0.5 h per day; High level: sports activities at least 4 times per week. 1N = 51 SD Standard deviation; GI gastrointestinal Patients were predominantly female (86.9%), with a (24.2%) patients (range: 14.3–35.6%) had another type of mean ± standard deviation (SD) age of 45.3 ± 15.8 years surgery of the abdomen, pelvis, or retroperitoneal struc- old. A total of 135 (25.7%) patients (range: 16.7–39.0%) tures. IBS-C symptoms were present for a mean duration had a prior appendectomy/cholecystectomy; seven (1.3%) of 12.8 ± 13.1 years (range: 9.6–15.6 years). Patients were patients (range: 1.0–3.4%) had bariatric surgery or surgery diagnosed with IBS-C for on average 3.0 ± 5.2 years (range: to remove a gastrointestinal (GI) tract segment; and 127 2.3–4.6 years) prior to study inclusion. Tack et al. BMC Gastroenterology (2019) 19:69 Page 5 of 13 In this cohort of moderate to severe IBS-C patients, on The proportion of patients requiring hospitalisation or average 60.0% had severe IBS-C at baseline (range: 43.1– emergency room visit for IBS-C showed variability 78.8%), 38.5% had moderate IBS-C (range: 20.2–56.9%), across Europe, with the lowest reported in Sweden and 1.5% had missing data (Table 2). Using the IBS-SSS (11.1%) and the highest in the UK (24.0%). The median questionnaire, current abdominal pain and distention were number of days hospitalised ranged from 1.5 days in reported for 95.8% (range: 89.8–98.1%) and 92.8% (range: Spain to 12.0 days in Sweden. The most frequently re- 88.1–96.2%) of patients, respectively. Furthermore, abdo- ported diagnostic related group related to hospitalisation minal pain was reported to occur for 6.0 ± 2.9 out of every was “gastroenteritis and/or abdominal pain”. 10 days on average (range: 5.4–7.0) and the most severe IBS Diagnostic tests related to IBS-C were performed on symptoms were a dissatisfaction with bowel habits 51.9% (UK) to 74.1% (Italy) of patients. On average, the and interference with life in general which had mean most common diagnostics test were blood tests (both scores of 76.6 ± 22.0 (range: 69.0–82.9) and 70.7 ± 21.8 haematology [37.9%] and clinical chemistry [33.0%]), (range: 59.6–79.5) respectively. abdominal ultrasounds (21.7%), and colonoscopies (17.5%) (Table 4). On average, prescription and non-prescription Healthcare resource utilisation related to IBS-C drugs used to treat IBS-C was similar; 41.1% (Italy) to During the 12-month retrospective- prospective study 90.4% (UK) took prescription drugs and 56.3% (Spain) to the majority of patients visited a General Practitioner 82.1% (Italy) took non-prescription drugs. The most com- (GP) (73.5%; range: 58.9–88.4%) and/or a specialist monly prescribed drugs across countries were: macrogol (92.2%; range: 79.4–100.0%) (Table 3). The mean num- plus electrolytes (21.2%); prucalopride (16.4%); Plantago ber of visits to physicians under the healthcare systems ovata (11.5% [not prescribed in Italy]); and mebeverine was higher for GPs (range: 2.1–6.4) than gastroentero- (10.2% [not prescribed in Sweden]). logists (range: 1.7–4.0). Overall Sweden had the lowest mean (95% CI) number of GP and gastroenterologist visits, 2.1 (1.4, 2.7) and 1.7 (1.4, 2.0) respectively, in Work productivity and activity impairment comparison to Italy which had the highest mean number During the 6 month prospective follow-up, at least one of visits 6.4 (4.0, 8.7) and 4.0 (3.1, 5.0) respectively. By period of sick leave was taken by 21.4% (Italy) to 50.8% contrast, private consultations were less frequent, yet (UK) of patients. Whilst on sick leave, the mean number maintained a similar GP: gastroenterologist ratio of of days on leave varied substantially across countries; from visits. In the UK, the proportion of patients seeking 11.6 days in Italy to 64.1 days in France. Over the course private consultation visits to either GPs or gastroente- of the year, patients had 3.3 separate episodes of leave in rologists was very low in comparison to Germany, France to 6.9 episodes in Italy. For those who reported France and Spain. work impairment while working, wide variability was seen Table 2 IBS-C symptoms at baseline FRANCE GERMANY ITALY SPAIN SWEDEN UK TOTAL N 59 102 112 112 36 104 525 IBS-SSS categorical items, n (%) Current abdominal pain 53 (89.8) 99 (97.1) 108 (96.4) 107 (95.5) 34 (94.4) 102 (98.1) 503 (95.8) Current abdominal distention 52 (88.1) 91 (89.2) 106 (94.6) 104 (92.9) 34 (94.4) 100 (96.2) 487 (92.8) IBS-SSS score (SD) Severity of abdominal paina 57.5 (25.3) 49.3 (23.8) 59.8 (19.8) 56.5 (21.4)3 56.6 (21.0)4 71.7 (20.6) 59.1 (22.9) b 5 Number of days with abdominal pain 7.0 (2.9) 5.4 (2.8) 5.4 (2.8) 5.7 (2.8) 6.8 (3.0) 6.9 (3.0) 6.0 (2.9) Severity of abdominal distentiona 66.5 (23.6)1 60.0 (21.4)2 64.8 (20.8) 65.0 (23.6) 66.6 (19.8) 75.2 (19.5) 66.4 (22.0) Dissatisfaction with bowel habitsa 71.6 (23.3) 69.0 (23.7) 78.9 (20.2) 77.9 (19.6) 75.8 (23.6) 82.9 (20.9) 76.6 (22.0) Interference with life in generala 79.5 (15.9) 68.2 (19.0) 59.6 (25.5) 71.4 (21.0) 70.9 (16.0) 79.4 (19.9) 70.7 (21.8) c IBS-SSS overall score 338.9 (78.6) 288.3 (78.8) 311.1 (75.1) 315.4 (82.2) 317.3 (81.8) 373.1 (82.5) 323.2 (84.3) Categorical severity of IBS-C, n (%) Mild (< 175) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Moderate (175 ≤ 300) 17 (28.8) 58 (56.9) 43 (38.4) 47 (42.0) 16 (44.4) 21 (20.2) 202 (38.5) Severe (> 300) 37 (62.7) 44 (43.1) 68 (60.7) 64 (57.1) 20 (55.6) 82 (78.8) 315 (60.0) a 0–100; best to worst. bin every10 days. c0–500; best to worst. 1N = 52. 2N = 91. 3N = 99. 4N = 30. 5N = 32 IBS-SSS Irritable Bowel Syndrome Symptom Severity Scale, SD Standard Deviation Tack et al. BMC Gastroenterology (2019) 19:69 Page 6 of 13 Table 3 Healthcare resource utilisation FRANCE GERMANY ITALY SPAIN SWEDEN UK N 59 102 112 112 36 104 Medical consultations (HS + Private), n (%) GP 45 (76.3) 80 (78.4) 66 (58.9) 99 (88.4) 22 (61.1) 74 (71.2) Specialists 59 (100.0) 81 (79.4) 112 (100.0) 94 (83.9) 34 (94.4) 104 (100.0) A) HS consultations Gastroenterologist, n (%) 59 (100.0) 51 (50.0) 112 (100.0) 67 (59.8) 23 (63.9) 104 (100.0) a Mean visits (95% CI) 2.2 (1.8, 2.6) 2.0 (1.5, 2.4) 4.0 (3.1, 5.0) 2.3 (1.9, 2.7) 1.7 (1.4, 2.0) 2.7 (2.3, 3.0) GP, n (%) 21 (35.6) 41 (40.2) 65 (58.0) 93 (83.0) 21 (58.3) 73 (70.2) a Mean visits (95% CI) 4.2 (2.4, 6.0) 4.3 (3.2, 5.5) 6.4 (4.0, 8.7) 3.8 (2.9, 4.7) 2.1 (1.4, 2.7) 6.2 (4.2, 8.3) B) Private consultations Gastroenterologist, n (%) 19 (32.2) 46 (45.1) 33 (29.5) 47 (42.0) 12 (33.3) 4 (3.8) Mean visits (95% CI)a 1.9 (1.1, 2.7) 2.7 (1.7, 3.7) 2.1 (1.6, 2.6) 2.2 (1.6, 2.8) 2.3 (1.4, 3.1) 2.0 (0.0, 4.3) GP, n (%) 29 (49.2) 68 (66.7) 4 (3.6) 17 (15.2) 2 (5.6) 2 (1.9) Mean visits (95% CI)a 3.9 (2.7, 5.0) 4.2 (3.2, 5.2) 3.1 (0.0, 6.4) 3.6 (2.3, 4.9) 1.5 (0.0, 7.9) 5.0 (0.0, 55.8) Hospitalisations or emergency room visits Any visit, n (%) 10 (16.9) 19 (18.6) 15 (13.4) 22 (19.6) 4 (11.1) 25 (24.0) b Number of hospitalisations, mean (95% CI) 1.5 (0.9, 2.0) 2.4 (1.3, 3.4) 1.8 (0.7, 2.9) 1.3 (1.0, 1.6) 2.5 (0.0, 5.3) 1.7 (1.2, 2.3) Median 1.0 1.0 1.0 1.0 2.1 1.0 b Number of days hospitalised, mean (95% CI) 5.7 (0.0, 12.2) 19.7 (3.2, 36.2) 17.9 (0.0, 41.6) 1.5 (0.6, 2.4) 10.7 (0.0,28.3) 11.8 (2.5, 21.1) Median 3.1 9.0 6.0 1.5 12.0 6.0 Diagnostic tests Any test n (%) 34 (57.6) 68 (66.7) 83 (74.1) 65 (58.0) 22 (61.1) 54 (51.9) b Number of tests, mean (95% CI) 3.4 (2.4, 4.3) 4.0 (3.4, 4.6) 4.5 (3.9, 5.2) 4.1 (3.4, 4.7) 3.5 (2.5, 4.6) 3.6 (2.9, 4.4) Median 2.5 3.5 4.0 4.0 3.0 3.0 Pharmacological therapies, n (%) Prescription drug 31 (52.5) 73 (71.6) 54 (48.2) 95 (84.8) 33 (91.7) 97 (93.3) Prescription drug for IBS-C 30 (50.8) 56 (54.9) 46 (41.1) 89 (79.5) 28 (77.8) 94 (90.4) Non-prescription drug for IBS-C 36 (61.0) 71 (69.6) 92 (82.1) 63 (56.3) 25 (69.4) 66 (63.5) Complementary therapies, n (%) 18 (30.5) 28 (27.5) 41 (36.6) 33 (29.5) 16 (44.4) 37 (35.6) Absenteeism and work impairment questionnaire for employed patients (over one year) Any sick leave taken, n (%) 12 (38.7) 19 (33.9) 15 (21.4) 14 (23.7) 12 (44.4) 33 (50.8) Number of times on sick leave, mean 3.3 (1.0, 5.6) 4.5 (3.0, 6.0) 6.9 (3.5, 10.2) 6.3 (1.9, 10.6) 5.7 (0.8, 10.6) 5.2 (3.8, 6.6) (95% CI)c Number of days on sick leave, mean (95% CI)c 64.1 (17.0, 29.5 (10.5, 48.5) 11.6 (4.1, 19.2) 52.4 (0.0, 51.3 (0.0, 113.6) 25.9 (12.7, 39.1) 111.2) 114.4) Any work impairment while working, n (%) 16 (51.6) 37 (66.1) 18 (25.7) 31 (52.5) 19 (70.4) 53 (81.5) Number of hours of work impairment, 69.1 (22.0, 140.4 (88.8, 83.2 (18.4, 54.8 (34.0, 280.3 (146.5, 161.9 (103.6, mean (95% CI)c 116.1) 192.0) 148.0) 75.7) 414.1) 220.2) a Number of visits (calculated in patients with at least 1 visit) b Calculated in patients with at least one hospitalisation/diagnostic test c In patients with at least one sick leave. 95% CI 95% Confidence Interval, GP General practitioner/family doctor, HS Healthcare system again with 25.7% of patients reporting impairment in Italy work productivity loss in employed patients was high; to 81.5% of patients in the UK. between 27.7% (Spain) and 51.5% (UK) (Table 5). In According to the WPAI:IBS-C questionnaire, in the addition, absenteeism and presenteeism for employed pa- week prior to inclusion in the study the percentage of tients varied from 3.1–18.5% and 27.6–47.9%, respectively. Tack et al. BMC Gastroenterology (2019) 19:69 Page 7 of 13 Table 4 Procedures, investigations or tests over 12 months due to IBS-C Procedures, investigations or tests due to IBS-C, n (%) FRANCE GERMANY ITALY SPAIN SWEDEN UK TOTAL N 59 102 112 112 36 104 525 Anascopy 3 (5.1) 3 (2.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 6 (1.1) Anorectal manometry 7 (11.9) 0 (0.0) 10 (8.9) 14 (12.5) 5 (13.9) 5 (4.8) 41 (7.8) Antibody test tissue 2 (3.4) 2 (2.0) 17 (15.2) 7 (6.3) 3 (8.3) 3 (2.9) 34 (6.5) Antibody testing endomysial 0 (0.0) 1 (1.0) 14 (12.5) 3 (2.7) 2 (5.6) 0 (0.0) 20 (3.8) Barium enema 0 (0.0) 0 (0.0) 0 (0.0) 5 (4.5) 0 (0.0) 5 (4.8) 10 (1.9) Blood tests, clinical chemistry 11 (18.6) 40 (39.2) 42 (37.5) 38 (33.9) 12 (33.3) 30 (28.8) 173 (33.0) Blood tests, haematology 14 (23.7) 45 (44.1) 58 (51.8) 42 (37.5) 10 (27.8) 30 (28.8) 199 (37.9) Colonoscopy 12 (20.3) 22 (21.6) 23 (20.5) 18 (16.1) 4 (11.1) 13 (12.5) 92 (17.5) Computed tomography, abdominal 5 (8.5) 1 (1.0) 4 (3.6) 6 (5.4) 2 (5.6) 8 (7.7) 26 (5.0) C-reactive protein (CRP) 8 (13.6) 22 (21.6) 13 (11.6) 6 (5.4) 8 (22.2) 8 (7.7) 65 (12.4) Endoscopy, Small intestine 0 (0.0) 2 (2.0) 0 (0.0) 0 (0.0) 2 (5.6) 1 (1.0) 5 (1.0) Endoscopy, Upper GI 6 (10.2) 8 (7.8) 7 (6.3) 6 (5.4) 1 (2.8) 5 (4.8) 33 (6.3) Erythrocyte sedimentation test 5 (8.5) 5 (4.9) 16 (14.3) 14 (12.5) 2 (5.6) 4 (3.8) 46 (8.8) Esophagoscopy 3 (5.1) 7 (6.9) 6 (5.4) 5 (4.5) 2 (5.6) 1 (1.0) 24 (4.6) Faecal occult blood 0 (0.0) 4 (3.9) 5 (4.5) 4 (3.6) 3 (8.3) 0 (0.0) 16 (3.0) Faecal ova and parasite test 0 (0.0) 1 (1.0) 12 (10.7) 4 (3.6) 0 (0.0) 2 (1.9) 19 (3.6) Fistulogram 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.0) 1 (0.2) Hydrogen breath test 5 (8.5) 6 (5.9) 10 (8.9) 8 (7.1) 0 (0.0) 0 (0.0) 29 (5.5) Magnetic resonance imaging 7 (11.9) 6 (5.9) 4 (3.6) 4 (3.6) 2 (5.6) 3 (2.9) 26 (5.0) Microbiological tests 1 (1.7) 4 (3.9) 4 (3.6) 1 (0.9) 0 (0.0) 1 (1.0) 11 (2.1) Radiology, Abdominal 2 (3.4) 2 (2.0) 13 (11.6) 8 (7.1) 0 (0.0) 9 (8.7) 34 (6.5) Radiology, Upper GI 0 (0.0) 0 (0.0) 4 (3.6) 1 (0.9) 0 (0.0) 2 (1.9) 7 (1.3) Sigmoidoscopy/proctosigmoidoscopy 0 (0.0) 4 (3.9) 1 (0.9) 2 (1.8) 2 (5.6) 6 (5.8) 15 (2.9) Small bowel aspiration 0 (0.0) 1 (1.0) 1 (0.9) 0 (0.0) 1 (2.8) 0 (0.0) 3 (0.6) Stool examination 3 (5.1) 15 (14.7) 14 (12.5) 5 (4.5) 2 (5.6) 1 (1.0) 40 (7.6) Thyroid function test 3 (5.1) 7 (6.9) 20 (17.9) 18 (16.1) 3 (8.3) 11 (10.6) 62 (11.8) Ultrasound, abdominal 8 (13.6) 36 (35.3) 46 (41.1) 16 (14.3) 1 (2.8) 7 (6.7) 114 (21.7) Urinalysis 1 (1.7) 22 (21.6) 23 (20.5) 18 (16.1) 4 (11.1) 9 (8.7) 77 (14.7) Other 9 (15.3) 6 (5.9) 6 (5.4) 10 (8.9) 7 (19.4) 19 (18.3) 57 (10.9) GI gastrointestinal The overall daily activity impairment varied from 36.3– consultations followed by medication costs (both prescrip- 56.8%. tion and non-prescription, and diagnostic tests (Fig. 2a). In the week prior to the 6-month visit, absenteeism The largest costs to the patient were medication costs and (0.9–7.0%) was found to have the greatest improvement, complementary therapy costs (Fig. 2b). whereas work productivity loss (26.1–39.6%) and pre- Overall, the UK had the highest the mean (95% CI) senteeism (25.4–43.3%) were found to slightly improve. direct cost to the healthcare system at € 2108.0 (€ 1504.1, There was no improvement in the daily activity impair- € 2775.5) while Italy had the lowest overall direct cost at € ment (33.0–51.4%). 937.1 (€ 524.8, € 1528.1). In terms of the direct costs to the patient, France reported the lowest patient costs at € Direct and indirect costs 236.8 (€ 161.7, € 332.9) and Spain reported the highest Costs related to the management of moderate to severe costs at € 567.6 (€ 333.1, € 840.7) (Table 6). Overall, total IBS-C varied greatly between countries. The largest cost mean (95% CI) direct costs ranged from € 1421.7 (€ 947.1, for all healthcare systems in the management of IBS-C € 2090.0) in Italy to € 2487.1 (€ 1848.2, € 3150.3) in the was hospitalisation (range: € 541.9 € 1183.1) [Fig. 2]. UK. Mean (95% CI) patient indirect cost had the largest The next largest cost for healthcare systems was medical variation in cost between countries; from €339.0 (€ 182.4, Tack et al. BMC Gastroenterology (2019) 19:69 Page 8 of 13 Table 5 Impairment in work productivity in employed patients (WPAI:IBS-C questionnaire) and daily activities in all patients with moderate to severe IBS-C at baseline and 6 months FRANCE GERMANY ITALY SPAIN SWEDEN UK Total 59 102 112 112 36 104 Presenteeism, % a N 27 52 66 45 24 58 Baseline 44.4 (32.9) 35.6 (28.2) 27.6 (27.7) 29.2 (27.5) 41.3 (22.1) 47.9 (28.7) N 15 49 65 49 20 41 6 Months 43.3 (27.7) 32.2 (24.9) 25.4 (21.4) 27.1 (23.9) 34.0 (21.4) 38.0 (28.0) Absenteeism, %a N 21 43 63 46 22 51 Baseline 18.5 (34.9) 14.7 (28.2) 3.1 (9.3) 6.1 (15.8) 6.9 (12.4) 8.4 (24.2) N 9 33 60 49 18 38 6 Months 0.9 (2.8) 3.2 (9.1) 0.9 (3.7) 2.9 (5.0) 2.7 (6.7) 7.0 (22.6) Overall work productivity loss, %a N 21 43 62 50 22 49 Baseline 46.3 (33.2) 44.1 (32.7) 27.7 (28.6) 32.3 (27.2) 44.4 (24.9) 51.5 (27.2) N 9 33 60 55 18 37 6 Months 39.6 (29.3) 32.0 (25.7) 26.1 (22.0) 29.8 (24.0) 32.4 (20.2) 39.1 (27.2) Daily activity impairment, % N 52 95 110 104 35 99 Baseline 48.1 (29.0) 36.3 (24.8) 41.1 (29.1) 39.6 (27.2) 48.0 (25.4) 56.8 (29.6) N 37 92 105 97 30 72 6 Months 50.5 (28.2) 38.0 (23.3) 33.0 (25.1) 37.9 (26.3) 43.0 (28.4) 51.4 (31.7) a Employed patients. All values are presented as mean (SD) € 517.1) in Italy to € 11,248.5 (€ 4580.2, € 20,192.6) in Nevertheless, as this study is focused on a more severe Sweden. patient subgroup, it is worth noting that within this moderate to severe population a higher incidence of Annual cost stratified by severity prior abdominal surgery was reported compared to IBS When stratified by baseline IBS-C severity, the mean patients in general [25]. annual cost to healthcare systems for patients with moder- Overall, patients in this cohort reported a high fre- ate IBS-C (range: € 314.4 - € 1308.4) was approximately a quency of symptoms that led to substantial direct and third of the cost to the healthcare systems compared to indirect costs for healthcare systems and society. Despite patients with severe IBS-C (range: € 961.0 - € 2883.3 differences in European healthcare system structures (Table 7). Direct costs to the patient were similar regard- direct costs were similar with hospitalisations/ER visits less of severity: moderate IBS-C range: € 204.8 - € 539.2; being the largest cost driver [26–28]. Costs attributable to severe IBS-C range: € 256.8 - € 887.3 per year. Overall dir- hospitalisations/ER visits in this study were higher than ect costs for IBS-C approximately doubled with increased that reported for IBS patients in general [13, 24, 29]. This severity: moderate IBS-C range: € 589.2 - € 1642.4; severe finding is related to the predominantly severe IBS-C IBS-C range: € 1217.8 - € 3770.7. Indirect costs showed population of this study and suggests that patients with lower costs for moderate IBS-C (range: € 297.7 - € 6710.9) more severe IBS-C may require more inpatient care. compared to severe IBS-C (range: € 370.2- € 14,878.4). Furthermore, as a consequence of this, the costs for medi- cations and consultations accounted for a smaller percen- Discussion tage of total costs than previously reported [12, 24]. It is Irritable bowel syndrome is a complex FBD that is char- highly likely that variability between countries included in acterised by a wide variety of symptoms. The increasing this study is due to differences in therapeutic management recognition of the disorder’s complexity highlights the and reimbursement policies. The somewhat unexpected importance of a more detailed understanding of the frequency and duration of hospitalisations/ER visits has impact that this disorder has on society. The aim of this not been previously reported in cross-sectional surveys study was to assess the economic impact to healthcare and combined with other health economic data suggests systems of moderate to severe IBS-C in patients from six that there is a proportion of IBS-C patients who have un- European countries. In terms of characteristics, the controlled illness associated with exceptionally high costs patients in this study had similar sociodemographic [30–32]. For all countries there was a clear asymmetric values to previous IBS studies [9, 11, 13, 14, 24]. distribution of cost that highlights a subset of patients Tack et al. BMC Gastroenterology (2019) 19:69 Page 9 of 13 a) b) Fig. 2 Mean healthcare resource utilisation costs for the (a) HS and (b) patient. * includes hospitalisations and adverse reactions within the included population who required substantial It is worth noting that like healthcare costs, the current medical attention, enough to make the overall economic management of the disease also exhibits asymmetry that cost resemble the US healthcare system costs for IBS-C can be attributed to the presence of a subgroup of “heavy [24, 31, 33]. resource users”. This reinforces the probability of treat- In terms of resource utilisation, the proportion of ment management being unable to adequately control patients who underwent diagnostic tests in this study symptoms over time. was comparable to that seen in primary care, signifying In relation to the direct cost of IBS-C, indirect costs that patients with more severe IBS-C were still undergo- were more substantial and more variable between ing a diagnosis of exclusion [34]. Yet, despite multiple countries. For example, Sweden had the highest in- tests, the lower overall prescription medication use direct costs at over € 11,000 per year due to Sweden (compared to IBS patients in general) and high non- having the highest percentage of employed patients prescription/ complementary therapy use suggested an whose income was above the national average in this overall dissatisfaction with current prescription medica- study, and one of the highest average gross incomes in tions [33, 35]. These current management practices Europe. The focus on work productivity and sick leave resulted in a degree of absenteeism that was two to three as an estimate of indirect cost is a limitation of this times greater than that reported for other IBS and IBS-C study as salaries and type of employment are variable studies [14, 36, 37]. between countries. As these variables were not adjusted Tack et al. BMC Gastroenterology (2019) 19:69 Page 10 of 13 Table 6 Direct and indirect annual costs per patient related to IBS-C FRANCE GERMANY ITALY SPAIN SWEDEN UK N 59 102 112 112 36 104 Direct cost to HS (€) Mean 1366.8 1422.6 937.1 1067.3 1276.9 2108.0 (95% CI) (504.1, 2565.4) (621.2, 2600.9) (524.8, 1528.1) (729.6, 1446.6) (491.5, 2368.6) (1504.1, 2775.5) Min, Max 19.0–24,079.0 0.0, 47,390.0 0.0, 25,363.0 0.0, 9680.0 0.0, 13,937.7 45.7, 16,773.7 Median 186.0 93.5 107.0 262.5 271.3 870.0 Direct cost to Patient (€) Mean 236.8 539.0 484.5 567.6 347.1 379.1 (95% CI) (161.7, 332.9) (313.4, 840.9) (371.6, 627.2) (333.1, 840.7) (243.7, 484.0) (221.6, 579.6) Min, Max 14.0, 2358.0 0.0, 11,506.0 17.0, 6179.0 0.0, 8092.0 0.0, 1716.0 0.0, 6500.7 Median 147.0 129.0 303.0 103.5 209.6 63.7 TOTAL DIRECT COST (€) Mean 1603.7 1961.6 1421.7 1635.0 1623.9 2487.1 (95% CI) (715.4, 2815.7) (1063.0, 3142.0) (947.1, 2090.0) (1226.0, 2061.4) (803.4, 2710.9) (1848.2, 3150.3) Min-Max 33.0, 24,097.0 0.0, 48,403.0 17.0, 28,355.0 0.0, 10,782.0 29.5, 14,100.0 57.7, 16,780.9 Median 342.0 340.0 489.0 518.5 634.8 1070.8 Indirect cost (€)1 Mean 2473.8 2619.0 339.0 1361.9 11,248.5 4097.2 (95% CI) (831.9, 4594.1) (1400.2, 4130.6) (182.4, 517.1) (312.5, 2866.4) (4580.2, 20,192.6) (2498.7, 5984.4) Min, Max 0.0, 37,753.0 0.0, 50,997.0 0.0, 5232.0 0.0, 59,630.0 0.0, 101,827.3 0.0, 45,271.7 Median 0.0 0.0 0.0 0.0 442.8 156.3 Currency conversion performed on 11th Feb 2014 (EUR/SEK = 8.8183; EUR/GBP = 0.8316). 1France N = 57 HS Healthcare system Bold data are summation of Direct costs to HS + Direct costs to patient for in the analyses total direct and indirect costs were care centres and thus benefitting from more dedicated not combined. management. This could have also introduced a referral Stratification by disease severity showed that the total bias in the sample studied. In addition, the exclusion of direct cost of IBS-C in patients with severe disease private consultation and diagnostic procedure costs may severity (60% of the sample) was approximately double further underestimate direct costs. Furthermore, the the cost of IBS-C for patients with moderate disease retrospective element of the study may be associated severity with some notable exceptions. Total direct costs with some recall bias, leading to some imprecision sur- in Germany showed the largest disparity with severe rounding estimates. Lastly, variation in the proportion of IBS-C mean costs approximately 6-fold greater than severe patients in each country may have translated into moderate IBS-C costs. By contrast, the greatest similarity increased variation between countries. in total direct costs was in Sweden, where both moder- ate and severe IBS-C patients have a direct cost of Conclusions around € 1600 per year. Mean indirect costs were sub- Although IBS-C is not a life-threatening condition, this stantially greater for patients with severe disease com- study has shown that moderate to severe IBS-C has a pared to patients with moderate disease, however, costs significant and costly impact on healthcare systems and were skewed by a subset of patients with high costs. As patients. The absence of a standard of care, combined moderate-severe IBS accounts for approximately two with an absence in the improvement of work impair- thirds of all IBS cases, this indicates a high economic ment, indicates that symptoms in patients with moderate cost to both healthcare systems and society [7, 17]. to severe IBS-C remain uncontrolled. These results The main limitations of this study were the incomplete highlight the need for a greater understanding of more assessment of indirect healthcare costs associated with severe IBS patients, moving away from a “one size fits work productivity and absenteeism, and the potential all” management approach to one that recognises the underestimation of healthcare resource utilisation due to individual complexity of this FBD and which focuses on the majority of patients being included from specialist treating the patients’ individual symptoms. Table 7 Annual costs related to moderate and severe IBS-C FRANCE GERMANY ITALY SPAIN SWEDEN UK MODERATE SEVERE MODERATE SEVERE MODERATE SEVERE MODERATE SEVERE MODERATE SEVERE MODERATE SEVERE N 17 37 58 44 43 68 47 64 16 20 21 82 Direct cost to HS (€) Tack et al. BMC Gastroenterology Mean 421.4 961.0 314.4 2883.3 507.0 1219.9 675.5 (387.1, 1371.8 (858.4, 1291.0 (185.5, 1264.9 (363.9, 1308.4 (594.4, 2325.0 (1604.3, (95% CI) (134.9, (206.7, (163.1, (1060.1, (187.4, (576.8, 1098.1) 1954.0) 3384.9) 2554.8) 2123.6) 3119.0) 947.3) 2162.6) 498.6) 5569.8) 902.9) 2143.1) Min, Max 19.0, 19.0, 0.0, 0.0, 0.0, 4.0, 0.0, 6601.0 0.0, 9680.0 0.0, 13,937.7 0.0, 11,657.4 45.7, 6984.1 45.7, 16,773.7 3956.0 16,761.0 3747.0 47,390.0 5316.0 25,363.0 (2019) 19:69 Median 157.0 201.0 46.0 236.5 64.0 160.5 199.0 357.5 156.7 271.4 590.4 898.9 Direct cost to Patient (€) Mean 204.8 256.8 274.7 887.3 289.2 612.8 539.2 (110.0, 596.0 (341.8, 351.3 (168.3, 343.5 (225.4, 481.8) 325.2 (93.3, 396.2 (212.6, (95% CI) (105.2, (157.1, (158.2, (417.6, (228.9, (438.1, 1033.3) 952.6) 616.6) 613.4) 642.0) 340.2) 410.7) 412.3) 1498.7) 348.6) 851.8) Min, Max 14.0, 14.0, 0.0, 0.0, 17.0, 37.0, 0.0, 8092.0 0.0, 7004.0 0.0, 1716.0 17.4, 883.4 0.0, 2409.8 0.0, 6500.7 1034.0 2358.0 2400.0 11,506.0 739.0 6179.0 Median 132.0 164.0 71.0 255.0 256.0 372.5 65.0 149.0 177.8 255.2 72.2 52.9 TOTAL DIRECT COST (€) Mean 626.2 1217.8 589.2 3770.7 796.3 1832.7 1214.7 (683.4, 1967.8 (1355.9, 1642.4 (493.7, 1608.4 (663.0, 1633.6 (850.4, 2721.3 (2003.0, (95% CI) (316.4, (405.5, (384.0, (1814.4, (439.3, (1115.4, 1783.1) 2651.8) 3637.4) 3153.5) 2508.7) 3545.2) 1124.0) 2446.1) 824.7) 6496.7) 1227.0) 2727.7) Min-Max 33.0, 33.0, 0.0, 0.0, 17.0, 44.0, 0.0, 8245.0 41.0, 10,782.0 29.5, 14,100.0 30.1, 12,175.6 57.7, 7221.0 57.7, 16,780.9 3978.0 17,017.0 3822.0 48,403.0 6055.0 28,355.0 Median 361.0 334.0 190.0 742.5 315.0 610.0 339.0 648.5 492.6 760.2 829.7 1111.1 Indirect cost (€) Mean 2514.1 2464.9 1279.6 4384.7 297.7 370.2 362.0 (146.6, 2117.6 (328.8, 6710.9 (453.4, 14,878.4 (4884.1, 1364.7 (608.3, 4845.1 (2869.9, (95% CI) (125.6, (586.7, (377.1, (2088.3, (39.7, (169.7, 689.7) 4725.8) 15,788.3) 29,930.1) 2286.3) 7296.5) 7733.3) 5157.7) 2499.4) 7495.6) 629.3) 597.6) Min, Max 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 5625.0 0.0, 59,630.0 0.0, 50,979.5 0.0, 101,826.8 0.0, 7015.4 0.0, 45,271.7 37,678.0 37,753.0 23,714.0 50,997.0 5232.0 4154.0 Median 0.0 0.0 0.0 64.0 0.0 0.0 0.0 0.0 41.3 2696.4 668.6 93.8 Currency conversion performed on 11th Feb 2014 (EUR/SEK = 8.8183; EUR/GBP = 0.8316) HS Healthcare system Bold data are summation of Direct costs to HS + Direct costs to patient Page 11 of 13 Tack et al. BMC Gastroenterology (2019) 19:69 Page 12 of 13 Abbreviations Authors’ contributions CI: Confidence interval; DRG: Diagnosis related group; ER: Emergency room; Guarantor of article: JT. Specific author contributions: JT was the lead EUR: Euro; FBD: Functional bowel disorder; GBP: Pound Sterling; coordinator of the study; VS (Italy), FM (Spain), YY (UK), PL (Germany), BC GI: Gastrointestinal; GP: General Practitioner; HS: Healthcare systems; (France), and MS (Sweden) were national coordinators from each IBS: Irritable bowel syndrome; IBS-C: Irritable bowel syndrome with participating country. JM managed the publication plan, helped analyse predominant constipation; IBS-D: Irritable bowel syndrome with predominant study data and wrote the manuscript. GW and AM provided funding support diarrhoea; IBS-M: Irritable bowel syndrome with mixed bowel habits; IBS- and critically reviewed the manuscript. All authors revised and approved the SSS: Irritable Bowel Syndrome Symptom Severity Scale; IBS-U: Irritable bowel final version of the manuscript. syndrome unclassified; SD: Standard deviation; SEK: Swedish krona; WPAI:IBS- C: Work productivity and activity impairment questionnaire for IBS-C Ethics approval and consent to participate The following ethics committees approved the trial protocol and its amendments: Comité Consultatif sur le Traitement de l’Information en Acknowledgements matière de Recherche dans le domaine de la Santé (Paris, France), The authors would like to thank the IBIS-C patients and the IBIS-C Study Israelitisches Krankenhaus (Hamburg, Germany), University of Bologna group for their participation in this study. The authors would also like to (Bologna, Italy), Humanitas Hospital IRCS (Milano, Italy), Floraspe Renzetti thank Neus Valveny and Jordan Bertsch from TFS Develop S.L. for respective Hospital (Lanciano, Italy), Agostino Gemelli University Hospital (Rome, Italy), medical writing and biostatistics support. The study was sponsored and University of Parma (Parma, Italy), University of Pisa (Pisa, Italy), University of funded by Almirall S.A and subsequent manuscript writing was financially Pescara (Pescara, Italy), Careggi University (Firence, Italy), University of Napoli supported by Allergan International. Federico II (Napoli, Italy), University of L’Aquila (L’Aquila, Italy), University of IBIS-C Study Group (alphabetical order by country): Messina (Messina, Italy), University of Genoa (Genoa, Italy). Ospedale S. Maria France: Dr. Bouchoucha, Hôpital Avicenne, Bobigny; Dr. Ducrotte, Hôpital di Ca′ Foncello (Treviso, Italy), Fondazione IRCCS Policlinico San Matteo Charles Nicolle, Rouen; Dr. Macaigne, Hôpital de Lagny, Lagny; Dr. Mion, (Pavia, Italy), Centro médico Teknon (Barcelona, Spain), Hospital Clínico San Hôpital Edouard Herriot, Lyon; Dr. Schneider, Strasbourg; Dr. Le Sidanier, Carlos (Madrid, Spain), Hospital Universitario 12 de Octubre (Madrid, Spain), Hôpital Dupuytren, Limoges; Dr. Tardy, Martigues; Dr. Zerbib, Hôpital Saint Hospital Germans Trias I Pujol (Badalona, Spain), Hospital de Bellvitge André, Bordeaux. Germany: Dr. Andresen, Israelitic Hospital, Hamburg; Prof. (Barcelona, Spain), Consorci Sanitari del Maresme (Mataró, Spain), Hospital Bischoff, Universtität Hohenheim, Stutgart; Dr. Jander, Arzt für Innere Medizin, Universitario Virgen de la Macarena (Sevilla, Spain), Hospital Universitari Neuötting; Dr. Jung, Praxis Dr. Thomas Jung, Deggingen; Prof. Krammer, Doctor Josep Trueta (Girona, Spain), Hospital Universitari Sant Joan de Reus Enddarmzentrum Mannheim, Mannheim; Dr. Langhorst, Kliniken Essen Mitte, (Reus, Spain), National Institute for Health Research (London, UK). Essen; Dr. Omankowsky, Praxis Dr. S. Omankowsky, Berlin; Prof. Schiefke, Eurogastro, Leipzig; Dr. Steuer, Praxis Dr. Steuer, Hemsbach; Prof. Van der Consent for publication Voort, Martin Luther Krankenhausbetrieb, Berlin; Dr. Von Arnim, Not applicable. Universitätsklinikum Magdeburg Klinik für Gastroenterologie und Hepatologie, Magdeburg. Italy: Dr. Annese, Careggi University, Florence; Prof. Competing interests Cuomo, University of Napoli Federico II, Naples; Prof. De Angelis, University JT receives grants and/or research support from Abbott, Novartis and Shire; of Parma, Parma; Prof. Di Mario, Ospedale S. Maria di Ca′ Foncello, Treviso; honoraria and/or consultancy fees from Almirall, AstraZeneca, Danone, GI Dr. Di Stefano, Policlinico S. Matteo, Pavia; Dr. Ferrini, F. Renzetti Hospital, Dyamics, GlaxoSmithKline, Ironwood, Janssen, Menarini, Novartis, Rhythm, Lanciano; Prof. Gasbarrini, Catholic University-Gemelli Hospital of Rome, Shire, Takeda, Theravance, Tsumura, Will Pharma and Zeria; and speaker fees Rome; Dr. Giaccobe, University of Messina, Messina; Prof. Marchi, University of from Abbott, Almirall, AstraZeneca, Janssen, Menarini, Novartis, Shire, Takeda Pisa, Pisa; Prof. Marzio, University of Pescara, Pescara; Dr. Repici, Humanitas and Zeria. Hospital IRCS, Milan; Prof. Savarino, University of Genova, Genova. Spain: Dr. VS receives grants and/or research support from Alfa Wassermann, Almirall, Angós, Clínica Universidad de Navarra, Pamplona; Dr. Berdier, CAP Vallcarca - Aptalis, Italchimici, Norgine, Shire, Takeda, Valeas; honoraria and/or Sant Gervasi, Barcelona; Dr. Brotons, CAP Sardenya, Barcelona; Dr. Caballero- consultancy fees from Abbott, Alfa Wasserman, Almirall, Angelini, Aptalis, Plasencia, Clinica Dr. Caballero, Granada; Dr. Clavé, Hospital Mataró, Mataró; CM&D Pharma, Farmaderma, Ironwood, Norgine, Shire, Takeda, Valeas, Dr. Fort, Hospital Dr. Josep Trueta, Girona; Dr. García, Hospital Universitario Vibrant and Zeria. del Tajo, Madrid; Dr. Gómez, Hospital USP Sagrado Corazón, Seville; Dr. FM receives speaker fees from Almirall. Martínez, Hospital Sant Joan de Reus, Reus; Dr. Perelló, Hospital de YY receives grants from Shire; Medtronic; and speaker fees from Almirall, Viladecans, Viladecans; Dr. Rey, Hospital Clínico San Carlos, Madrid; Dr. Shire, and Sucampo. Sánchez-Antolín, Hospital Universitario Río Hortega, Valladolid; Dr. Serra, PL receives financial support from Abbott / Solvay, Almirall, Aptalis / Axcan, Hospital Germans Trias i Pujol, Badalona; Dr. Tantinà, CAP Centelles, Centelles; Norgine, and Shire. Dr. Torán, CAP Mareseme, Mataró. Sweden: Dr. Ekesbo, Capio Citykliniken BC receives honoraria and/or consultancy fees from Almirall, Mundipharma, Malmö, Malmö; Prof. Hellström, Läkarhuset Hötorget City, Stockholm; Dr. Mayoly Spindler, and Menarini. Kjellström, Aleris Specialistvård Sabbatsberg, Stockholm; Dr. Lindberg, MS receives unrestricted research grants from Danone, and AstraZeneca; Karolinska Institute, Stockholm; Dr. Walter, Linköping University, Linköping. consultant and/or Advisory Board member fees from Danone, Nestlé, Chr UK: Dr. Arebi, St Mark’s Hospital, Middlesex; Dr. Bridger, Dorset County Hansen, Almirall, Albireo and Shire; participation fees for company-sponsored Hospital, Dorchester; Dr. Butt, South Tyneside NHS Foundation Trust, South speaker’s bureau from Almirall, Shire, Tillotts and Takeda. Shields; Dr. Emmanuel, University College Hospital, London; Prof. Eugenicos, JM is an employee of TFS Develop S.L, contracted by Almirall S.A to conduct Western General Hospital, Edinburgh; Dr. Kaushik, Royal Blackburn Hospital, the study. Blackburn; Dr. Millar, North Middlesex University Hospital NHS Trust, London; GW and AM are employees of Allergan International. Prof. Sanders, Royal Hallamshire Hospital, Sheffield; Prof. Whorwell, Wythenshawe Hospital, Manchester. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Funding This study and all data analyses were funded in full by Almirall, S.A. The Author details preparation of this paper was funded by Almirall, S.A and Allergan 1 University Hospital Gasthuisberg, Leuven, Belgium. 2University Hospital International. 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