Table 2.

Clinical studies on efficacy of exclusive enteral nutrition in pediatric CD. CREN = constant rate enteral nutrition, PF = polymeric formula, ED = elemental diet, PCDAI = Pediatric Crohn Disease Activity Index, PEN = partial enteral nutrition, EEN = exclusive enteral nutrition, IFX = infliximab, anti-TNF = anti-tumor necrosis factor, TGFβ2 = transforming growth factor beta 2.

Clinical Studies on Efficacy of Exclusive Enteral Nutrition
Author/Year	Study Type	Population	Method	Main Findings
Navarro et al. 1982 [17]	Clinical trial	Children with active CD (n = 17)	Exclusive constant rate enteral nutrition (CREN) using a combination of elemental diet and continuous alimentation for 2–7 months, subsequently CREN used to supplement oral alimentation from 12 to 22 months.	After 7 months of exclusive CREN: all children’s symptoms improved; 100% of children presented moderate disease (Lloyd Still and Green scoring >50).
Fell et al. 2000 [23]	Clinical trial	Children with active CD (n = 29)	EEN with TGFβ2 enriched PF for 8 weeks.	- After 8 weeks 79% (23/29) of children were in clinical remission. - PCDAI declined with treatment. Median PCDAI at baseline 30 (range 12.5–72.5) declined with treatment by a median of 15 at 2 weeks and 25 at 8 weeks (p < 0.00001). - Macroscopic and histological healing in the terminal ileum and colon was associated with a decline in ileal and colonic interleukin-1β. (pre-treatment to post-treatment ratio 0.008 and 0.06: p = 0.001, p = 0.006).
Afzal et al. 2004 [24]	Clinical trial	Children and adolescents with active CD (n = 26), mean age 14 years	EEN with PF for 8 weeks.	88.6% achieved clinical remission.
Bannerjee et al. 2004 [25]	Clinical trial	Children with active CD (n = 12)	EEN with PF for 6 weeks.	Significant improvements in inflammatory markers by day 3 (p < 0.05) and in clinical activity index PCDAI by day 7.
Gavin et al. 2005 [26]	Retrospective cohort study	Children and adolescents with new onset CD (n = 40), aged 6–16 years	EEN with PF for 8 weeks.	All patients improved symptomatically and gained weight after 8 weeks of EEN.
Afzal et al. 2005 [27]	Prospective cohort study	Children and adolescents with active CD (n = 65), aged 8–17 years. Disease localization: ileal (n = 12), ileocolonic (n = 39), colonic (n = 14).	EEN with PF for 8 weeks.	77% remission rate. Remission rates: Colonic group: 50% (7/14), ileocolon group 82.1% (32/39), ileum group 91.7% (11/12), (χ2 test, p = 0.021)). The colonic disease group showed the least fall in PCDAI scores at completion of treatment with EEN (p = 0.03), with the lowest remission rate (50%).
Knight et al. 2005 [28]	Retrospective cohort study	Children with CD (n = 44)	Treatment with EEN as primary treatment for 6–8 weeks.	90% (40/44) of patients responded to EEN with a median time to remission of 6 weeks. Crohn’s disease activity index (CDAI) decreased from pre-EEN to post-EEN, mean values of CDAI not available.
Day et al. 2006 [29]	Retrospective cohort study	Children with newly diagnosed CD (group 1, n = 15) and with active known long-standing CD (group 2, n = 12), mean age 11.8 years	- Group 1: EEN with PF for 6–8 weeks as sole initial therapy - Group 2: EEN with PF for 6–8 weeks in addition to any current medical therapy.	Twenty-four (89%) of 27 children completed their prescribed course of EEN. Nineteen (79%) of 24 children entered clinical remission (80% (12/15) in group 1 and 58% (7/12) in group 2). There was no clear relationship between disease location and response to treatment: 75% (3/4) with isolated small bowel, 72.5% (10/14) with ileocolonic and 67% (6/9) with pancolic disease attained remission (p > 0.05). In group 1 successful response to EEN was associated with positive weight gains (average weight gain 4.7 ± 3.5 kg) with mean PCDAI decreasing from 37.1 ± 10.8 to 6.7 ± 5.1 after 8 weeks (p < 0.0001). Also in group 2, despite a minor rate of remission, the overall average PCDAI scores significantly fell at 8 weeks (p < 0.0001) with an improvement of body weight and in at least one markers of inflammation.
De Bie et al. 2013 [30]	Retrospective cohort study	Children with newly diagnosed CD (n = 77), median age 13.9 years	Patients received EEN (as either hyperosmolar sip feeds or PF by nasogastric tube) for 6 weeks as remission induction therapy, combined with azathioprine maintenance treatment in 92%.	In patients completing a 6-week course of EEN (58) complete remission was achieved in 71% of patients, partial remission in 26%, and no response in 3%. Complete remission rates were higher in children presenting with isolated ileal/ileocaecal disease and malnutrition.
Grover et al. 2016 [31]	Clinical trial	Children with newly diagnosed predominantly luminal CD (n = 54), median age 12.4 years	EEN for 6–8 weeks in association with early thiopurine treatment (<3 months from diagnosis). Median duration between pre and post EEN assessments was 60.5 days (IQR 56–69.5)	Post EEN: remission rate (PCDAI < 10) 83% (45/54), biochemical remission (CRP < 5 mg/dL) 72% (39/54), complete mucosal healing 33% (18/54). Sustained remission was superior in those with complete mucosal healing vs. endoscopic disease 72% (13/18) vs. 28% (10/36), p = 0.003 at 1 year, 50% (8/16) vs. 8% (3/24), p = 0.008 at 2 years and 50% (8/16) vs. 6% (1/19), p = 0.005 at 3 years.