ORIGINAL ARTICLE pISSN 1598-9100 • eISSN 2288-1956 https://doi.org/10.5217/ir.2019.00073 Intest Res 2020;18(3):289-296 Presentation and outcomes among inflammatory bowel disease patients with concurrent intestinalis: a case series and systematic review

Youran Gao1, Meka Uffenheimer2, Michael Ashamallah3, Gregory Grimaldi4, Arun Swaminath5, Keith Sultan1 1Division of Gastroenterology, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY; 2Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Departments of 3Medicine and 4Radiology, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY; 5Division of Gastroenterology, Lenox Hill Hospital, New York, NY, USA

Background/Aims: Inflammatory bowel disease (IBD) involves chronic inflammation of the colon with ulcerative (UC), and the colon and/or with Crohn’s disease (CD). Pneumatosis intestinalis (PI), characterized by compromise of the intestinal wall with gas-filled , has rarely been reported with IBD. The presentation, best management and outcomes of PI with IBD are poorly defined. Methods: We conducted a search for PI in all abdominal computed tomography (CT) reports at 2 large tertiary care hospitals from January 1, 2010 to December 31, 2017, cross referenced to ICD codes for IBD. CT and chart review was performed to confirm PI and IBD respectively. A systematic review excluding case reports was performed for PI with IBD for comparison. Results: Of 5,990 patients with a CT report mentioning PI, we identified 11 cases of PI with IBD, 4 UC, 6 CD, and 1 indeterminate colitis. PI was limited to the small bowel in 5 patients, the right colon in 5, and small bowel and colonic in 1. All 3 mortalities had CD, small intestinal PI and portal/mesenteric venous gas. The systematic literature search identified 9 articles describing 58 patients with IBD and PI. These cases were mostly included in larger cohorts of PI patients without extractable data on presentation or outcomes in the IBD subpopulation. Conclusions: Ours appears to be the first reporting of presentations and outcomes, outside of case reports, for those with PI and IBD. The high mortality for those with CD and PI of the small bowel appears to define a group requiring more than supportive medical care. (Intest Res 2020;18:289- 296)

Key Words: Computed tomography; Inflammatory bowel disease; Intestinal disease; Pneumatosis cystoides intestinalis; Syste­ matic review

INTRODUCTION 100,000 persons for UC.1,2 CD can affect any portion of the GI tract, but most commonly affects the terminal and/or Inflammatory bowel disease (IBD) is a chronic inflammatory proximal colon. CD is characterized by discontinuous, often disorder mainly including CD and UC. Overall, IBD affects transmural inflammation that typically spares the . about 1.4 million Americans with prevalence rates ranging Conversely, UC classically involves the rectum in a pattern of from 25 to 300 per 100,000 persons for CD and 35 to 250 per continuous inflammation which tracks proximally toward the cecum, affecting mainly the mucosa.3 The pathogenesis of IBD has yet to be fully elucidated. Nonetheless, evidence suggests Received January 11, 2019. Revised August 28, 2019. Accepted August 29, 2019. that an inappropriate inflammatory response in genetically Correspondence to Youran Gao, Division of Gastroenterology, North Shore predisposed individuals is caused by dysregulation between University Hospital and Long Island Jewish Medical Center, 300 Community Drive, Manhasset, NY 11030, USA. Tel: +1-516-3873990, Fax: +1-516- the commensal microbiota, intestinal epithelial cells, and im- 3873930, E-mail: [email protected] mune cells within these tissues.4 The inflammatory response

© Copyright 2020. Korean Association for the Study of Intestinal Diseases. All rights reserved. 289 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Silvio Danese, et al. • iSTART consensus recommendations

Youran Gao, et al. • IBD with pneumatosis intestinalis

results in a compromised mucosal barrier, which may allow 2017. Informed consent was waived for the study. All result luminal, immunogenic bacteria into the lamina propria, po- documents/reports underwent a natural language search with tentially perpetuating inflammation.5 mPower (Nuance Communications, Burlington, MA, USA) for Pneumatosis intestinalis (PI), a relatively rare disorder, is the terms “pneumatosis” or “pneumatosis intestinalis” or defined by multiple gas-filled cysts within the submucosa “pneumatosis coli.” Only those with ICD-9 or ICD-10 diagno- and/or subserosa of the intestine. Though palpation of an ab- sis of IBD were included for further review to confirm that PI dominal mass on physical exam may be appreciated,6 it is was present. That is, patients whose CT report excluded PI most commonly identified by CT imaging. There are 2 main (e.g., “no evidence of pneumatosis”) were excluded from anal- theories as to how PI develops: mechanical and bacterial.6 The ysis. Images were reviewed by North Shore University Hospi- mechanical theory postulates that intraluminal gas is forced tal’s chief of abdominal imaging (G.G.). Individual charts were into a defect or potential defect of the intestinal mucosa (i.e., then reviewed for demographics, IBD type/history, treatment from direct trauma or colitis) when the bowel wall is placed both prior to and following PI diagnosis, and outcomes data under pressure.7 Gas may also be introduced to the bowel wall including length of stay and mortality. from the lungs, with the air first tracking through the mediasti- num.8 The bacterial theory states that cystic gas collections re- 2. Systematic Review sult from hydrogen producing bacteria within the bowel wall, A systematic review was performed according to the Preferred and is supported by the presence of hydrogen in some cysts Reporting Items for Systematic Reviews and Meta-Analysis without an obvious connection between the mucosa.6 Labora- checklist (PRISMA) guidelines. Institutional review board ap- tory evidence both supporting and refuting this theory exists proval was not required. with the ultimate cause of PI still a matter of debate.9 Some non-GI conditions that have been correlated with the 3. Search Strategy appearance of PI include emphysema, AIDS (acquired im- An online search for relevant publications was performed us- mune deficiency syndrome), organ transplantation, glucocor- ing PubMed/Medline, EMBASE, Cochrane Central Register of ticoid use, chemotherapy use, and collagen vascular diseases. Controlled Trials (CENTRAL), and Web of Science databases. In about one-fifth of patients, PI is considered primary, in that For PubMed, the search conducted was: ((((((((((ulcerative there is no other associated illness. Not surprisingly, PI has colitis) OR Crohn’s disease) OR inflammatory bowel disease) also been observed in patients with IBD. Most descriptions of OR ) OR “Enteritis”[Mesh]) AND “intestinal emphyse- PI occurring in the setting of IBD are to be found in case re- ma”) OR pseudolipomatosis) OR (pneumatosis[All Fields] ports, which are inadequate to provide data on the prevalence AND intestinalis[All Fields])) OR pneumatosis intestinalis) and significance of PI in the setting of IBD. Given the limited OR “Pneumatosis Cystoides Intestinalis”[Mesh]) OR lympho- available information, we sought to comprehensively review pneumatosis. For the other databases, key search terms were for all cases or PI and IBD encountered in our health system, used. For EMBASE, the terms used were “‘pneumatosis intes- examine clinical presentations, treatment and outcomes. Ad- tinalis’/exp” and “‘inflammatory bowel disease’/exp.” For CEN- ditionally, we conducted a systematic review of the literature TRAL and Web of Science, the key words were “pneumatosis” of PI in the setting of IBD to better understand whether our ex- and “inflammatory bowel disease.” Only papers published in perience was typical of this patient population. English and between the dates January 1, 1972 to August 20, 2018 were included. The year 1972 was chosen as the cutoff METHODS date as this was the year CT scanners started being manufac- tured.10 All titles were initially screened, and appropriate ab- 1. Case Series stracts were reviewed. Articles identified on PubMed with ap- Following IRB approval (IRB No. 18-0019), a retrospective case propriate titles also had their MeSH terms reviewed. series was conducted of all patients over 18 years of age who underwent an emergency room or inpatient CT of the abdo- 4. Inclusion Criteria men for any indication at 2 of Northwell Health’s Tertiary Care To be included in this review, studies had to meet the follow- Hospitals, North Shore University Hospital and Long Island ing publication criteria: they reported on more than 3 patients Jewish Medical Center from January 1, 2010 to December 31, with PI and the diagnostic tool used was CT.

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https://doi.org/10.5217/ir.2019.00073 • Intest Res 2020;18(3):289-296 No No No No No No No No Yes Yes Yes Mortality 6 5 7 5 8 6 7 3 6 8 5 (day) length of stay Hospital Surgery resection of necrotic bowel None None Laparotomy with None Ileocolic resection None None None None None None Treatment metronidazole tazobactam metronidazole vancomycin, meropenem Meropenem Ertapenem Ciprofloxacin, Piperacillin, Prednisone None Ciprofloxacin, Ertapenem, Prednisone Prednisone, infliximab Adalimumab CT finding Portal and/ Portal or mesenteric venous gas in Yes No Yes Yes No No No No No Yes No Location of PI on CT colon thickening and stricture Small bowel and transverse Cecum Ileum Small bowel ileum with small bowel Terminal Small bowel with thickening Proximal transverse colon Right colon Cecum Right colon and pancolitis Small bowel for CT pain pain pain pain Indication Fever Abdominal Septic shock Sepsis Abdominal UC flare A  bdominal Abdominal Diarrhea UC flare obstruction diarrhea pain admission Reason for Renal failure CD Sepsis Sepsis bowel Partial CD Bloody UC flare Abdominal UC flare PI IBD prior to admission medication None None None None Prednisone Azathioprine None None Mesalamine Adalimumab None 5 7 3 3 4 9 22 23 12 16 30 (yr) Disease duration CD CD CD CD CD CD UC UC UC UC type minate Indeter Disease Sex Patient Clinical Characteristics, Treatment, and Outcome Treatment, Clinical Characteristics, Patient Male Female Female Male Female Male Female Female Male Female Female Age (yr) 69 69 76 96 62 20 68 77 77 22 61 PI, pneumatosis intestinalis. Table 1. Table www.irjournal.org 291 Silvio Danese, et al. • iSTART consensus recommendations

Youran Gao, et al. • IBD with pneumatosis intestinalis

5. Exclusion Criteria RESULTS Studies were excluded from analysis if (1) the article was a let- ter, editorial, or comment; (2) they reported on pediatric pa- 1. Case Series tients; and (3) no IBD patients were included. The 5,990 patients had a CT abdomen report mentioning PI, of which 411 patients had IBD. After excluding those reports spec- 6. Data Extraction ifying an absence of PI, 11 confirmed cases of PI with IBD re- Two reviewers (K.S. and M.U.) independently reviewed the lit- mained. The mean age was 63.4±22 years (range, 19–96 years) erature according to the above, predefined guidelines. Each of which 7 were females, 4 had UC, 6 had CD and 1 had inde- reviewer read the identified papers to ensure that all the pre- terminate colitis (Table 1). No patient had a prior CT scan dem- defined qualities were met. The title and study details (first au- onstrating PI during the study period. PI was limited to the thor, journal, year) were recorded. Within each article, the small bowel in 5 patients, to the right colon in 5, with one case number of patients with IBD and PI were identified. Of these of both small bowel and colonic PI. The only patient to under- patients, presence of portal venous gas, type of IBD (CD, UC, go an endoscopic procedure during their admission was a 22- IBD undefined), method of PI diagnosis, treatment (medical year-old female with UC. Incomplete colonoscopy 5 days fol- and/or surgical) and outcomes (mortality) were recorded. lowing her CT revealed active disease with deep ulceration to Where information was unavailable, unknown was recorded. the extent of examination in the sigmoid colon. Pre-admission All data were independently recorded by both reviewers in medications included one case each of adalimumab, predni- separate databases and only compared at the end of the data sone, azathioprine, and mesalamine. extraction process to limit selection bias. In case of disagree- During hospitalization 1 patient received adalimumab, 1 in- ments, the categorization created by K.S. was honored. Dupli- fliximab and corticosteroid, 2 corticosteroids, and 6 patients cates were removed, and any disparities were clarified. received broad spectrum antibiotics. Patients receiving bio-

PubMed EMBASE CENTRAL Web of Science

2,014 Articles 103 Articles 32 Articles 118 Articles 699 Articles 19 Articles excluded 31 Articles excluded 106 Articles excluded excluded based on based on date and after title screen since available on date and language language PubMed 1,315 Articles 84 Articles 1 Article 12 Articles 1,025 Articles 3 Articles excluded 1 Article excluded 2 Articles excluded excluded after title since only available since repeat from based on language screen on PubMed PubMed 290 Articles 81 Articles 0 Article 10 Articles 260 Excluded after abstract screen: 60 Articles excluded ∙ <3 patients: 203 7 Articles excluded after after title screen ∙ Comment, letter, or editorial: 27 title screen ∙ Literature review: 15 ∙ Diagnostic tool other than CT was used: 16 21 Articles 3 Articles ∙ No patient had both IBD and PI: 22 20 Excluded after abstract screen: 3 Articles excluded after ∙ Pediatric population: 4 ∙ <3 patients: 15 abstract review: ∙ Experimental trial: 2 ∙ Literature review: 1 ∙ <3 patients: 1 ∙ Non-human subjects: 3 ∙ No patient had both IBD and PI: 1 ∙ Poster abstract: 1 30 Articles ∙ Not available in English: 1 1 Article ∙ Pediatric population: 1 0 Article ∙ Repeat article: 1 ∙ Not available in English: 1 ∙ Repeat article: 4

21 Excluded after full-text screen: ∙ <3 patients: 3 ∙ Letter: 1 ∙ No patient had both IBD and PI: 16 ∙ No CT use: 7 ∙ Poster abstract: 2 ∙ Underlying diseases were not documented: 2

10 Articles

Fig. 1. Systematic review methodology. PI, pneumatosis intestinalis.

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https://doi.org/10.5217/ir.2019.00073 • Intest Res 2020;18(3):289-296 IBD and PI patients specific information with PI and history of CD being managed on steroids. He had conservative treatment and an uneventful recovery. were male and 4 female. They had a mean age of 33.5 years old. At the time of presentation, their current medications were (6), steroids (2), sulfasalazine azathioprine (1). Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded male presenting 49-Year-old Not recorded Of the patients with PI, 2 Not recorded 0 0 0 0 Mortality reported of IBD+PI (%) Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded patients with 22 42 18 24 17 30 18 20 33 of entire Mortality sample (%) Not recorded rate reported rate 1 5 treatment PI patients for IBD and Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded Conservative >1 1 treatment Surgery as PI patients for IBD and Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded 0 0 Patients Patients PI, and IBD with HPVG, Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded Not recorded PI & >1 3 8 0 0 1 0 0 record record No. of UC patients Not Not PI & >1 10 2 1 1 0 6 0 No. of CD recorded recorded patients Not Not PI 6 2 1 1 2 6 1 & 10 27 >2 No. of IBD patients 102 217 88 40 50 27 127 149 123 500 Total no. Total in article discussed of patients paper Type of Type within PI population within PI population within PI population within PI population within PI population within PI population within PI population within PI population within IBD population within PI population IBD patients IBD patients IBD patients IBD patients IBD patients IBD patients IBD patients IBD patients PI patients IBD patients Year 2010 2010 2007 2017 2017 2016 2014 2013 1992 1990 13 19 16 20 Systematic Review Included Articles 15 18 14 12 11 17 author First Ferrada Treyaud Umapathi Lee DuBose Lassandro Wayne Greenstein John Knechtle Table 2. Table PI, pneumatosis intestinalis; HPVG, hepatic venous pressure gradient. www.irjournal.org 293 Silvio Danese, et al. • iSTART consensus recommendations

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logic and/or corticosteroid were managed for IBD exacerba- tients with both PI and IBD. The limited extractable data spe- tion. For those patients receiving antibiotics alone, there was cific to IBD patients in the studies precluded meta-analysis. either clinical uncertainty regarding IBD exacerbation or the primary management was directed towards suspected infec- DISCUSSION tion or sepsis. Only 1 patient, a 20-year-old male with CD, had no additional medical treatment during hospitalization. He In our case series we have observed that a CT finding of PI in a continued on his pre-admission azathioprine, was given intra- hospitalized IBD patient is a rare event, with mortality limited venous fluids and low residue diet and was discharged with- to those CD patients with small bowel PI and CT evidence of out complication after 6 days. Two patients, both with CD, had portal/mesenteric venous gas. As only a minority of patients surgery. One patient needed emergent exploratory laparoto- identified were treated with corticosteroids and/or biologic my for and the other had ileocolic resec- therapy suggesting an IBD exacerbation, it remains unclear tion for stricture and obstruction. whether a finding of PI is related to IBD severity in this popu- There were 3 mortalities (27%) all with CD; 2 with isolated lation. As expected for a rarely observed entity, the systematic small bowel PI and one with both small bowel and colonic PI review confirmed that there is minimal data available on the and all with evidence of portal and/or mesenteric venous gas. prevalence, management and outcomes of PI in the setting of The first, a 69-year-old male was admitted for acute kidney IBD. Only one of the studies, by John et al.11 provided a preva- failure and fevers prior to recognition of PI. His cause of death lence of PI in a group of patients with CD, finding PI in 6 out of was attributed to worsening renal failure. The 2 other patients 50 patients (12%) undergoing CT abdomen. We suspect that died from sepsis. One, a 76-year-old female died immediately this high prevalence may reflect the selection of a sicker group following an exploratory laparotomy and resection of exten- of patients for CT evaluation, as access to CT was more limited sive small bowel necrosis. The other, a 96-year-old male ex- during the study time period. Management, both medical and pired during supportive comfort care, with elimination of surgical, was also rarely reported across the included studies. blood draws and with an emphasis on pain management. All Though the pooled results of the systematic review noted a 3 had received antibiotics, without corticosteroid or biologic similar mortality rate of 22% among all PI patients, mortality therapy. The remaining 8 patients made a full recovery and among IBD patients was not specifically addressed and as were discharged from the hospital. such cannot be compared to our own center’s experience. Limitations to our findings are those common among retro- 2. Systematic Review spective studies. Despite access to the admission medical re- Ten studies met inclusion criteria (Fig. 1) of which 9 articles cord, and high reliability of tracking treatment during hospital- primarily described patients with PI, including some with IBD, ization, we cannot be sure of the accuracy of historical data while 1 described the prevalence of PI from a population of such as medication use in the days and months prior to hospi- CD patients (Table 2).11-20 There were no differences in data -ex talization. Also, though one might suspect that a population traction noted between the 2 reviewers. In total, 58 IBD pa- with worsening IBD would have undergone invasive testing tients with PI were identified. IBD disease type was defined in such as a sigmoidoscopy or colonoscopy in the near term pri- 7 of the 10 studies including 21 with CD and 13 with UC. A or to admission, no such procedures were recorded. In such mean age of 33.5 years was available in the article reporting on cases, it would be plausible that PI was not merely the result of PI within a CD population and in another article, a single pa- worsening disease activity, but perhaps related to procedural tient was 49 years.11,12 Data on medical management was avail- trauma. Additionally, since no commonly employed objective able on 6 patients across 2 studies.11,12 One patient was treated clinical disease activity scores where obtained during the pa- through observation and had an uneventful recovery.12 There tients’ admission it remains unclear whether there was a rela- were no outcomes data on the remaining 5 patients.11 Utiliza- tionship between IBD severity and the finding of PI. As such tion of surgery was noted in 2 articles, identifying 2 patients we cannot draw a direct link between IBD disease activity and who underwent surgery.11,13 No outcomes were reported. Nine outcomes in this group. Also, given the small number of cases, articles reported on mortality.12-20 Pooling the data results yield- and the lack of established treatment protocols, little can be ed an overall mortality rate of 22% for patients with PI, but there concluded regarding the relationship between treatment and was no specific data available on mortality in the subset of pa- outcomes. Additionally, though our methodology is depen-

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https://doi.org/10.5217/ir.2019.00073 • Intest Res 2020;18(3):289-296 dent upon the radiologist to report PI when observed, it’s un- Ashamallah M. Conceptualization: Grimaldi G, Swaminath A. likely that such a rare and significant finding would be left out Review and editing: Swaminath A., Sultan K. Approval of final of the final CT report. Conversely, important benefits to the manuscript: all authors. methodology of patient identification are also worth mention- ing. Rather than relying solely upon diagnosis coding to iden- ORCID tify those with PI and IBD, our ability to first identify PI by a di- rect search of all CT abdomen reports decreases the possibili- Grimaldi G https://orcid.org/0000-0002-2530-7514 ty of missing cases of PI. Though the subsequent identification Swaminath A https://orcid.org/0000-0003-3495-012X of IBD in this group involved cross referencing with IBD diag- Sultan K https://orcid.org/0000-0002-7619-2024 nosis codes, the final small number of cases identified allowed for direct chart review in these individuals to confirm their REFERENCES IBD diagnosis. In conclusion, a systematic search of all CT scan reports 1. Loftus EV Jr. Clinical epidemiology of inflammatory bowel from emergency room and inpatient encounters at 2 large ter- disease: incidence, prevalence, and environmental influences. tiary care hospitals during the study period revealed only 11 Gastroenterology 2004;126:1504-1517. cases of PI occurring in the setting of IBD. As demonstrated by 2. Malik TA. Inflammatory bowel disease: historical perspective, the results of the systematic review, this appears to be the first epidemiology, and risk factors. Surg Clin North Am 2015;95: reporting of its kind in a broad inpatient IBD population. Also, 1105-1122. this would appear to be the first reporting outside of case re- 3. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J ports describing in detail the disease distribution of PI with Med 2009;361:2066-2078. IBD and its associated outcomes. The small numbers unfortu- 4. Friedman S, Blumberg RS. Inflammatory bowel disease. In: nately do not allow conclusions as to the best management Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J, practices, whether medical or surgical, when PI is found to eds. Harrison’s principles of internal medicine. New York: Mc- complicate IBD. Despite the limited numbers, the high mortal- Graw-Hill, 2014:351-353. ity rate observed in those with PI small intestinal involvement, 5. Wedlake L, Slack N, Andreyev HJ, Whelan K. Fiber in the treat- and portal/mesenteric venous gas appears to identify a high- ment and maintenance of inflammatory bowel disease: a sys- risk patient appropriate for early intensive care unit care and tematic review of randomized controlled trials. Inflamm Bow- surgical consultation. Conversely, those without these features el Dis 2014;20:576-586. appear to do well with supportive medical care alone. Further 6. Wald A. Pneumatosis coli (pneumatosis cystoides intestinalis). studies, both retrospective and prospective will be needed to In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and define best practices for patient management of this rare but Fordtran’s gastrointestinal and disease. Philadelphia: complicated disease presentation. Saunders Elsevier, 2016:2306-2308. 7. Galandiuk S, Fazio VW, Petras RE. Pneumatosis cystoides in- FINANCIAL SUPPORT testinalis in Crohn’s disease: report of two cases. Dis Colon Rectum 1985;28:951-956. The authors received no financial support for the research, au- 8. Ho LM, Paulson EK, Thompson WM. Pneumatosis intestina- thorship, and/or publication of this article. lis in the adult: benign to life-threatening causes. AJR Am J Roentgenol 2007;188:1604-1613. CONFLICT OF INTEREST 9. Yale CE, Balish E, Wu JP. The bacterial etiology of pneumatosis cystoides intestinalis. Arch Surg 1974;109:89-94. No potential conflict of interest relevant to this article was re- 10. Maizlin ZV, Vos PM. Do we really need to thank the Beatles ported. for the financing of the development of the computed tomog- raphy scanner? J Comput Assist Tomogr 2012;36:161-164. AUTHOR CONTRIBUTION 11. John A, Dickey K, Fenwick J, Sussman B, Beeken W. Pneuma- tosis intestinalis in patients with Crohn’s disease. Dig Dis Sci Original draft: Gao Y. Formal analysis: Gao Y, Uffenheimer M., 1992;37:813-817. www.irjournal.org 295 Silvio Danese, et al. • iSTART consensus recommendations

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