Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the digestive tract(Reference Pittayanon, Lau and Leontiadis1,Reference Ventham, Kennedy and Nimmo2) . As a type of IBD, Crohn’s disease (CD) has no proven cure and can impact proper digestion and absorption, which can result in malnutrition in children(Reference Pittayanon, Lau and Leontiadis1–Reference van Rheenen, Aloi and Assa3). Exclusive enteral nutrition (EEN) and corticosteroids (CS) are both proven to be effective therapies for the induction of remission in paediatric CD(Reference Hart, Farbod and Szamosi4–Reference Ruemmele, Veres and Kolho6). The use of CS has raised concerns due to possible side effects, including reduced bone density and growth delay(Reference Narula, Dhillon and Zhang7). Given the safety concerns, there has been an increasing interest in the use of EEN to induce remission of active CD. EEN may have a profound impact on microbiota diversity and inflammation marker levels(Reference Pigneur, Lepage and Mondot8–Reference Schwerd, Frivolt and Clavel10). However, conflicting results exist in previous studies(Reference Leach, Mitchell and Eng11–Reference Tang, Huang and Shi13). Furthermore, the implementation of EEN is challenging as it commonly requires the use of a nasogastric feeding tube for 6–8 weeks along with avoidance of other food intake, which may reduce the compliance of the child and family(Reference Levine, Wine and Assa14,Reference Lawley, Wu and Navas-López15) . To improve adherence, more studies have focused on partial enteral nutrition (PEN), which allows children to take some whole food alongside an enteral formula(Reference Urlep, Benedik and Brecelj16). Recent studies in adults and children reported that PEN could be as effective as EEN in inducing clinical and endoscopic remission in children with active CD, and PEN was better tolerated by paediatric patients(Reference Levine, Wine and Assa14,Reference Urlep, Benedik and Brecelj16–Reference Sigall Boneh, Sarbagili Shabat and Yanai19) .
The mechanism underlying the clinical effectiveness of EEN and PEN in paediatric IBD patients remains unclear. One hypothesis is that EEN and PEN may induce changes in the faecal microbiome and this could promote remission(Reference Levine, Wine and Assa14). Recent data in humans illustrate that dysbiosis plays an important role in the development of IBD(Reference Pittayanon, Lau and Leontiadis1), and enteral nutrition may have a profound impact on the microbiota diversity(Reference Pigneur, Lepage and Mondot8–Reference Schwerd, Frivolt and Clavel10). A previous systematic review compared the effectiveness of EEN and PEN v. CS, but the authors mostly focused on the clinical remission of CD(Reference Narula, Dhillon and Zhang7). In addition to intestinal microbiota, more recently, mucosal healing is an outcome that is gaining acceptance as a recommended measure of disease activity in CD(Reference Ruemmele, Veres and Kolho6,Reference Turner, Ricciuto and Lewis20) . Two systematic reviews assessed mucosal healing between EEN and CS in the paediatric population but did not consider the effect of EEN or PEN on intestinal microbiota(Reference Yu, Chen and Chen21,Reference Swaminath, Feathers and Ananthakrishnan22) .
We conducted a systematic review and meta-analysis to determine the impact of both EEN and PEN v. CS in children with active luminal CD on intestinal microbiota, mucosal healing, clinical remission, relapse of active disease, post-treatment weight, faecal calprotectin (FC), health-related quality of life (HRQL), adherence to the assigned intervention and adverse events up to 12 months following initial treatment.
Materials and methods
Study selection and patient population (inclusion and exclusion criteria)
Our study protocol was registered on PROSPERO (CRD42021254082). We considered both randomised controlled trials (RCT) and cohort studies in children (≤18 years of age) with newly diagnosed or active luminal CD according to the Pediatric Crohn’s Disease Activity Index (PCDAI), defined as a score >10, or alternatively, other clearly defined definitions of newly diagnosed or active CD by investigators. Studies that compared the administration of any type of enteral nutrition (i.e. elemental, semi-elemental or polymeric) to CS (e.g. methylprednisolone, prednisone or hydrocortisone) were considered for inclusion. Randomised trials and cohort studies were analysed separately. We excluded the following types of studies: trials allowing oral intake other than clear liquids in EEN treatment, trials allowing co-interventions with antibiotics and having outcomes of microbiota analysis and trials not defining CD activity and remission.
Data sources and search strategy
We searched the following five databases from inception until 3 February 2021: Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL) and Clinicaltrials.gov. The references of eligible studies and review articles were searched to identify additional studies. Abstracts or posters without published full-text articles were excluded as the preliminary results often differ from final published reports(Reference Toma, McAlister and Bialy23). For our target outcomes, authors were contacted for additional unpublished results, including missing outcome data. Our review had no language restrictions. Google Translate tool was used to translate articles written in non-English languages. If further clarification was required, we considered contacting translators/authors.
Outcome measures
Our primary outcomes included intestinal microbiome signatures (e.g. sequencing with 16S ribosomal RNA gene) and mucosal healing rate (endoscopy score)(Reference Hart, Farbod and Szamosi4,Reference Pigneur, Lepage and Mondot8–Reference Tang, Huang and Shi13) . Data on α-diversity metrics (e.g. relative abundance and Shannon diversity index) and β-diversity metrics (e.g. Bray–Curtis index to visualise clustering) were also collected for our outcome of microbiome signatures(Reference Finotello, Mastrorilli and Di Camillo24). Shannon diversity index, clustering and relative abundance of bacterial genera if available were described as continuous variables. Mucosal healing was defined as complete endoscopic remission using the Simple Endoscopic Score for Crohn Disease (SES-CD) of 0(Reference Daperno, D’Haens and Van Assche25). When SES-CD scores were not reported, other clear definitions for mucosal healing were also considered (e.g. the Crohn’s Disease Endoscopic Index of Severity less than 3 points or a drop of >70 % at follow-up endoscopy)(Reference Pigneur, Lepage and Mondot8,Reference Cellier, Sahmoud and Froguel26) . Our primary outcomes were assessed at 4–12 weeks after therapy initiation.
Our secondary outcomes included clinical remission (4–12 weeks after induction therapy) and clinical relapse rate (at a 6–12-month time-point). Remission and relapse were measured using the PCDAI score (remission was defined as <15 points, or <7·5 points without the height component of the index) or using other clearly defined author definitions (e.g. short PCDAI, abbreviated PCDAI and Lloyd-Still disease activity index)(Reference Turner, Griffiths and Walters27–Reference Azcue, Rashid and Griffiths30). Clinical relapse was defined as the occurrence or worsening of symptoms accompanied by a PCDAI score > 10 points in a patient who had previously reached clinical remission(Reference Scarpato, Strisciuglio and Martinelli31). Other secondary outcomes included nutritional status (i.e. weight in both kg and Z-score measurements), FC level (i.e. a biochemical marker of inflammation to implicate disease activity), adherence (i.e. withdrawal rates), adverse events and HRQL (e.g. IMPACT I–III questionnaire or other validated health status measurements) at 4–12 weeks after induction therapy(Reference Narula, Dhillon and Zhang7,Reference Griffiths, Nicholas and Smith32–Reference Otley, Smith and Nicholas37) .
Data screening (eligibility assessment) and data extraction
Titles and abstracts were independently screened by two reviewers. If inclusion criteria were met, publications were exported, screened and carried onto independent full-text screening. Discrepancies between reviewers on inclusion and exclusion decisions were resolved among themselves, and a third reviewer was involved if consensus was not reached. A piloted data collection form was used to independently extract data and assess the risk of bias (RoB) in duplicate. Data were extracted for study population characteristics, study design details, information on administration or exposure to EEN/PEN and CS, and eligible outcomes.
Quality assessment
Two reviewers independently appraised the RoB using the Cochrane RoB tool for randomised trials (RoB 2.0)(Reference Sterne, Savovic and Page38), while the RoB for non-randomised studies of interventions (ROBINS-I) tool was used to assess cohort studies(Reference Sterne, Hernan and Reeves39). Overall ratings of ‘low’, ‘some concerns’ or ‘high’ were determined for each domain within the RoB 2.0 tool. Ratings of ‘low’, ‘moderate’, ‘serious’ or ‘critical’ were determined for each domain within the ROBINS-I tool. We resolved any discrepancies through discussion between the two reviewers and, when necessary, through consultation with a third senior methodologist.
Data synthesis
We analysed aggregated data through quantitative synthesis. A random effects meta-analysis was performed due to potential heterogeneity between studies. The I 2 statistic and inconsistency between studies using forest plots were used to assess heterogeneity(Reference Higgins, Thompson and Deeks40).
Data permitting, for cohort studies, we planned to pool adjusted and unadjusted effect sizes separately. For dichotomous outcomes, pooled risk ratios (RR) and 95 % CI were calculated (e.g. mucosal healing, clinical remission, relapse, adherence and adverse events). For continuous outcomes (e.g. microbiota diversity, bacterial abundance, FC level, HRQL score and weight), we pooled mean difference (MD) with a standard deviation or standardised mean differences (SMD) with corresponding 95 % CI. Cohen’s D scores, were used to determine the effect of SMD estimates(Reference Cohen41).
As an a priori decision, subgroup analyses were planned for the effect of: (1) EEN v. CS and PEN v. CS separately, (2) mild to moderate CD v. severe CD and (3) newly diagnosed CD v. all active CD (including previously diagnosed patients) as outcomes may differ based on previous studies(Reference Hart, Farbod and Szamosi4,Reference Pigneur, Lepage and Mondot8,Reference Levine, Wine and Assa14,Reference Borrelli, Cordischi and Cirulli42,Reference Hojsak, Pavic and Misak43) . Sensitivity analyses removing studies that are high RoB studies for each outcome were also considered. Publication bias was considered using funnel plots if there were >10 included studies for an outcome(Reference Sterne, Sutton and Ioannidis44,Reference Egger, Davey Smith and Schneider45) . All analyses were performed using Review Manager (RevMan) Version 5.3 and Stata 16.0.
Assessment of certainty of evidence
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to assess the certainty of evidence for the included outcomes(Reference Schünemann, Brożek and Guyatt46). Two review authors independently assessed the certainty of evidence as high, moderate, low or very low using the GRADE approach, which included assessments of RoB, inconsistency, imprecision, indirectness and publication bias.
Results
Characteristics and risk of bias of included studies
Our search (online Supplementary Table 1) retrieved a total of 3272 articles (Fig. 1). After excluding duplicates, we screened 2420 titles and abstracts and reviewed seventy-seven full-text articles for potential eligibility (Fig. 1). Details on important excluded studies are available in online Supplementary Table 2. A total of nineteen studies on patients with CD were included in our systematic review (Table 1). Three studies were RCT (n 76) that assigned participants to receive EN or CS, while the remaining sixteen studies (n 1104) were cohort studies that observed the effect of EN v. CS (five of these were prospective while eleven were retrospective) (Table 1). All nineteen studies considered the use of EEN, while CS type and dosage varied (Table 1). None of nineteen studies reported on PEN v. CS.
Flow diagram of the study selection process.
Characteristics of included studies
CD, Crohn’s disease; EEN, exclusive enteral nutrition; CS, corticosteroids; PCDAI, Pediatric Crohn’s Disease Activity Index; RCT, randomised controlled trial; CDEIS, Crohn’s disease index of severity; HBI, Harvey–Bradshaw Index.
Using the Cochrane RoB 2.0 tool for RCT, three studies had ‘some concerns’ or ‘high RoB’ for each outcome when comparing EEN v. CS, particularly with respect to bias in the randomisation process and bias in measurement of outcomes (Fig. 2). Similarly, sixteen cohort studies were at serious RoB for each of the outcomes due to a lack of measurement/control of important confounders (Fig. 3).
Risk of bias summary of included randomised controlled trials.
Risk of bias summary of included cohort studies.
With regard to subgroup analysis, no studies reported on the use of PEN v. CS, or mild to moderate CD v. severe CD, so a priori subgroup analyses were not completed. Two RCT enrolled patients with newly diagnosed CD only(Reference Pigneur, Lepage and Mondot8,Reference Borrelli, Cordischi and Cirulli42) , while one RCT enrolled all active CD(Reference Terrin, Berni Canani and Ambrosini47). Furthermore, ten cohort studies included patients with newly diagnosed CD only, while the remaining six cohort studies included patients with all active CD (Table 1). Sensitivity analyses based on the RoB were not conducted based on a priori decision in the protocol as no studies had a low RoB.
Effects of interventions
Microbial signatures
One RCT (n 19, 19 CD) and one cohort study (n 30, 20 CD, 10 UC) assessing EEN v. CS reported on stool microbial diversity and bacterial abundance(Reference Hart, Farbod and Szamosi4,Reference Pigneur, Lepage and Mondot8) . In the RCT (n 19), Shannon diversity index, which was assessed in four patients in each group, suggested that microbial α-diversity tended to increase after EEN therapy (from 3·82 to 5·0), whereas the change was minimal on steroid therapy (from 5·39 to 5·75)(Reference Pigneur, Lepage and Mondot8). The RCT also reported on β-diversity index based on principal components analysis of dominant microbiota composition, indicating a significant clustering before treatment and during CS or EEN treatment. Concerning bacterial abundance at genus and species levels measured at 8 weeks, both EEN (n 4) and CS (n 4) groups caused significant changes in the microbiota composition after treatment (Table 2).
The results of the microbiota outcome before and after treatment in EEN and CS groups
RCT, randomised controlled trial; EEN, exclusive enteral nutrition; CS, corticosteroids.
Another cohort study with twenty CD patients reported microbiota Shannon diversity index, clustering and relative abundance but did not provide specific values for each group(Reference Hart, Farbod and Szamosi4). The study noted a significant increase in Shannon diversity over time after treatment (P = 0·006) in both EEN and CS treatments, but the increase did not differ between the groups. Based on the principal coordinates analysis for bacterial abundance, tighter clustering was observed at the end of treatment when compared with stool microbiota at baseline, independent of treatment type. Patients treated with EEN (n 16) showed a marked depletion in the Fusobacterium, Escherichia/Shigella and Veillonella genera, while patients treated with CS (n 4) showed reductions in the Alistipes, Veillonella and Fusobacterium genera.
Meta-analysis and forest plots were not generated for the two microbiome signature studies due to limited available data.
Mucosal healing
Two RCT with fifty-six participants provided data on mucosal healing(Reference Pigneur, Lepage and Mondot8,Reference Borrelli, Cordischi and Cirulli42) . We found an RR of 2·36 (95 % CI (1·22, 4·57); I 2 = 0 %) (Table 3, Fig. 4). In absolute effects, forty more children had mucosal healing per 100 children receiving EEN (95 % CI, from 6 more to 100 more) (Table 3), a moderate effect size based on low certainty of evidence. Subgroup analysis could not be completed as both studies were from the newly diagnosed CD group.
Summary of findings (95 % confidence intervals)
EEN, exclusive enteral nutrition; CS, corticosteroids; RCT, randomised controlled trial; RR, risk ratio; SMD, standardised mean difference.
* Serious concerns around the randomisation process (particularly with lack of allocation concealment) and issues around blinding of the outcome assessors in studies with more weight suggest some serious risk of bias.
† With a small number of sample size or total events, fragility exists within the results. Furthermore, the optimal information size threshold is not met, and the effect estimate overlaps the GRADE recommended threshold for appreciable benefit, suggesting imprecision.
‡ When considering the included study/studies bias due to confounding, which is an important domain in the risk of bias tool, was not fully addressed. At least one important baseline confounder (e.g. disease severity, disease location, co-morbidities, concomitant medications, anthropometric measurements) was not measured or controlled for studies that hold more weight within the meta-analyses.
§ With a small number of sample size or total events, fragility exists within the results. Furthermore, CI include the possibility of a small or no effect and important benefit or harm, suggesting imprecision.
‖ There is a significant level of heterogeneity that subgroup analyses cannot explain. This suggests some serious inconsistencies exist between studies.
¶ Begg’s plot was suggestive of publication bias (P = 0·005).
** Serious concerns around the randomisation process (particularly with lack of allocation concealment) suggest some serious risk of bias.
†† With a small number of sample size and total events, fragility exists within the results.
‡‡ There is unexplained heterogeneity that exists. Subgroup analyses were not feasible due to a limited number of studies.
Forest plots for comparison of outcomes between enteral nutrition v. corticosteroids in children with Crohn’s disease (CD).
Only one retrospective cohort study with forty-seven participants reported on mucosal healing(Reference Berni Canani, Terrin and Borrelli48). From this study, based on very low certainty of evidence, we found a RR of 1·76 (95 % CI (0·80, 3·86)) and a corresponding risk difference indicating that thirty more children will experience mucosal healing per 100 children receiving EEN (95 % CI from 8 fewer to 100 more) (Table 3, Fig. 4).
Clinical remission
Remission was assessed in three RCT(Reference Pigneur, Lepage and Mondot8,Reference Borrelli, Cordischi and Cirulli42,Reference Terrin, Berni Canani and Ambrosini47) and thirteen cohort studies(Reference Hart, Farbod and Szamosi4,Reference Papadopoulou, Rawashdeh and Brown28,Reference Scarpato, Strisciuglio and Martinelli31,Reference Hojsak, Pavic and Misak43,Reference Berni Canani, Terrin and Borrelli48–Reference Soo, Malik and Turner56) . When considering RCT evidence, seventy-six participants provided data. From the pooled analysis, we calculated a RR of 1·28 (95 % CI (0·99, 1·67); I 2 = 0 %, very low certainty of evidence), which in absolute effects means eighteen more children had remission per 100 children receiving EEN (from 1 fewer to 43 more) (Table 3, Fig. 4).
When considering cohort studies, based on thirteen studies, a total of 958 participants were included in the pooled analysis. We calculated a RR of 1·18 (95 % CI (1·02, 1·38); I 2 = 73 %, very low certainty of evidence), which in absolute effects means twelve more children will experience remission per 100 children receiving EEN (from 1 more to 24 more) (Table 3). However, there was substantial heterogeneity present for this outcome (I 2 = 73 %). The test of interaction for the subgroup analysis based on newly diagnosed CD v. all active CD was not significant in cohort studies (P = 0·59), and heterogeneity remained within the newly diagnosed CD group, suggesting the heterogeneity was not well explained by this subgroup analysis (Fig. 4). Furthermore, there were concerns regarding publication bias (P = 0·005) (Fig. 5).
Funnel plot for cohort studies of clinical remission.
Relapse
For relapse at 12 months, we found six cohort studies(Reference Lambert, Lemberg and Leach29,Reference Scarpato, Strisciuglio and Martinelli31,Reference Hojsak, Pavic and Misak43,Reference Berni Canani, Terrin and Borrelli48,Reference Lafferty, Tuohy and Carey53,Reference Soo, Malik and Turner56) with 395 children that found an overall RR of 0·76 (95 % CI (0·56, 1·03); I 2 = 56 %, very low certainty of evidence) (Fig. 4). As compared with CS, there were twelve fewer (22 fewer to 2 more) relapse events per 100 patients followed in the EEN intervention group (Table 3). Subgroup analysis for newly diagnosed v. all active CD found no statistically significant effect (P = 0·23) between the two groups. Substantial heterogeneity was still present in the newly diagnosed CD group, and significant heterogeneity for the overall effect (I 2 = 56 %) was not well explained (Fig. 4). No RCT evidence was available for this outcome.
Nutritional status
One RCT reported on post-treatment weight for thirty-two children(Reference Borrelli, Cordischi and Cirulli42). The SMD in post-treatment weight was 0·74 sd units lower in the EEN group (SMD -0·74, 95 % CI (-1·46, -0·02), very low certainty of evidence) than the CS group (Fig. 4). When the MD was described as a weighted MD, the EEN group achieved a 2·40 kg lower post-treatment weight compared with the CS group (MD -2·40, 95 % CI (-4·59, -0·21)). Among the four cohort studies with 183 children reporting on post-treatment weight(Reference Azcue, Rashid and Griffiths30,Reference Kierkuś, Szymańska and Szczepański52,Reference Lafferty, Tuohy and Carey53,Reference Hradsky, Copova and Zarubova57) , we found a lower SMD of 0·26 sd units in the EEN group compared with the CS group (SMD -0·26, 95 % CI (-0·54, 0·04); I 2 = 1 %, very low certainty of evidence) (Table 3). When the MD was described as a weighted MD in two cohort studies (n 62)(Reference Azcue, Rashid and Griffiths30,Reference Kierkuś, Szymańska and Szczepański52) , the EEN group achieved a 5·20 kg lower post-treatment weight compared with CS group (MD -5·20, 95 % CI (-14·11, 3·71)). When the MD was described as a weighted MD for Z-score in another two cohort studies (n 121)(Reference Lafferty, Tuohy and Carey53,Reference Hradsky, Copova and Zarubova57) , the EEN group achieved 0·22 lower post-treatment weight compared with CS group (MD -0·22, 95 % CI (-0·74, 0·31)).
Faecal calprotectin
Two cohort studies considered our outcome measuring FC levels(Reference Scarpato, Strisciuglio and Martinelli31,Reference Levine, Turner and Pfeffer Gik54) . Meta-analyses were not feasible as data were available as medians accompanied by a range. Both studies simply reported non-significant differences in FC values at week 8 since diagnosis of CD (Levine et al., (1736 (617–2000) µg/g in EEN group and 558 (162–1848) µg/g in CS group)(Reference Levine, Turner and Pfeffer Gik54); Scarpato et al., 291·5 (15–1470) µg/g in EEN group and 435 (20–610) µg/g in CS group(Reference Scarpato, Strisciuglio and Martinelli31)). No forest plots were generated from the FC studies due to limited data.
Adherence (withdrawal rate)
The outcome of adherence to the intervention was reported in two RCT with fifty-seven participants(Reference Borrelli, Cordischi and Cirulli42,Reference Terrin, Berni Canani and Ambrosini47) and two cohort studies with 168 participants(Reference Lambert, Lemberg and Leach29,Reference Connors, Basseri and Grant50) . In two RCT, we calculated a RR of 0·95 (95 % CI (0·15, 6·03), very low certainty of evidence), which in absolute effects means no more (0) children had withdrawal per 100 children receiving EEN (from 6 fewer to 36 more) (Table 3). In two cohort studies, we calculated a RR of 3·06 (95 % CI (0·36, 26·23), very low certainty of evidence), which in absolute effects means no more (0) children will have withdrawal per 100 children receiving EEN as there were no events in the control group (Table 3). No significant heterogeneity was present for this outcome (I 2 = 0 %). The reasons for withdrawal in EEN group were inability to introduce the formula, intolerance of the nasogastric tube feeding and development of an enterovesical fistula. The reason for two withdrawal events in the steroid therapy group was the worsening of disease activity.
Adverse events
We found two RCT (n 52)(Reference Borrelli, Cordischi and Cirulli42,Reference Terrin, Berni Canani and Ambrosini47) and two cohort studies (n 75) reported on this outcome(Reference Berni Canani, Terrin and Borrelli48,Reference Luo, Yu and Zhao58) . When considering RCT evidence, we found a RR of 0·32 (95 % CI (0·13, 0·80), low certainty of evidence) (Table 3). In absolute effects, when compared with CS, there were thirty fewer (38 fewer to 9 fewer) patients with adverse events per 100 patients in the EEN group (Table 3). When considering cohort studies, as compared with CS, there was a RR of 0·19 (95 % CI (0·02, 2·26), very low certainty of evidence), which means sixty-four fewer (77 fewer to 99 more) patients with adverse events per 100 patients in the EEN group (Table 3). Significant heterogeneity for the overall effect (I 2 = 71 %) was not explained, and subgroup analyses were not feasible due to a limited number of studies (Fig. 4).
Adverse events described in the EEN group are abdominal pain/discomfort, nausea, vomiting, flatulence, diarrhoea and insomnia, whereas, in the CS group, adverse events described include abdominal pain, nausea and/or vomiting, flatulence, insomnia, cushingoid appearance, acne, skin striae, hirsutism, myopathy/muscle weakness, headache, depression, hyperglycaemia and osteoporosis. No serious adverse event was reported.
Health-related quality of life
No studies that met our eligibility criteria reported on the HRQL outcome, and no forest plots were generated due to limited data. A list of important excluded studies (e.g. abstract only) can be found in online Supplementary Table 2. Based on the published abstracts, one prospective cohort study of thirty-one children reported a small but significant difference in generic HRQL (KIDSCREEN-10 index) between the children on CS (higher HRQL) v. those on EEN (MD 2·24 points, 95 % CI (0·34, 4·15))(Reference Hart, Farbod and Halgren59). The MD and 95 % CI in the abstract were lower than the minimal important difference estimate of 4·53 obtained from parental ratings of KIDSCREEN-10 index(Reference Hirschfeld, von Brachel and Thiele60). Another prospective cohort study (n 64) did not find a significant difference in the disease-specific HRQL score between children receiving either EEN or CS(Reference Humphrey, Grant and Walters61).
Discussion
Summary of main results and certainty of evidence
Our systematic review found three RCT and sixteen cohort studies having evaluated enteral nutrition in children with CD. Among two RCT (n 56)(Reference Pigneur, Lepage and Mondot8,Reference Borrelli, Cordischi and Cirulli42) based on low certainty of evidence, at 4–12 weeks after induction EEN may result in an increase in mucosal healing in 40 per 100 children followed (from 6 more to 100 more) when compared with CS. Based on three RCT (n 76)(Reference Pigneur, Lepage and Mondot8,Reference Borrelli, Cordischi and Cirulli42,Reference Terrin, Berni Canani and Ambrosini47) , eighteen more children had clinical remission per 100 children receiving EEN (from 1 fewer to 43 more), based on very low certainty of evidence. In one RCT (n 32)(Reference Borrelli, Cordischi and Cirulli42), we found that children on EEN experienced 2·40 kg lower post-treatment weight as compared with CS alone (4·59 lower to 0·21 lower), based on very low certainty evidence. Among two RCT (n 52) on EEN therapy(Reference Borrelli, Cordischi and Cirulli42,Reference Terrin, Berni Canani and Ambrosini47) , thirty fewer children per 100 followed (38 fewer to 9 fewer) were likely to experience adverse events based on low certainty evidence. On the basis of very low certainty of evidence, no significant effect on adherence outcome was detected(Reference Borrelli, Cordischi and Cirulli42,Reference Terrin, Berni Canani and Ambrosini47) . With respect to intestinal microbial signatures described in one RCT(Reference Pigneur, Lepage and Mondot8), a narrative synthesis was completed due to limited available data. Although the effect on the Shannon diversity seems to indicate a trend towards EEN, it is not possible to conclude the efficacy of treatment based on the very limited sample size.
When reviewing cohort studies (n 1104 participants), twelve more children had clinical remission per 100 children receiving EEN (from 1 more to 24 more), but the certainty of evidence is very low(Reference Hart, Farbod and Szamosi4,Reference Papadopoulou, Rawashdeh and Brown28,Reference Scarpato, Strisciuglio and Martinelli31,Reference Hojsak, Pavic and Misak43,Reference Berni Canani, Terrin and Borrelli48–Reference Soo, Malik and Turner56) . In addition, the evidence is very uncertain for the effect of EEN on mucosal healing(Reference Berni Canani, Terrin and Borrelli48), relapse at 12 months(Reference Lambert, Lemberg and Leach29,Reference Scarpato, Strisciuglio and Martinelli31,Reference Hojsak, Pavic and Misak43,Reference Berni Canani, Terrin and Borrelli48,Reference Lafferty, Tuohy and Carey53,Reference Soo, Malik and Turner56) , post-treatment weight(Reference Azcue, Rashid and Griffiths30,Reference Kierkuś, Szymańska and Szczepański52,Reference Lafferty, Tuohy and Carey53,Reference Hradsky, Copova and Zarubova57) , and adherence(Reference Pigneur, Lepage and Mondot8,Reference Connors, Basseri and Grant50) , and adverse events(Reference Berni Canani, Terrin and Borrelli48,Reference Luo, Yu and Zhao58) . With regard to intestinal microbial signatures, HRQL and FC(Reference Hart, Farbod and Szamosi4,Reference Scarpato, Strisciuglio and Martinelli31,Reference Levine, Turner and Pfeffer Gik54) , a narrative synthesis was completed due to a lack of available data, and the potential effects were unclear.
Strengths and limitations
Strengths of our systematic review included a comprehensive search of five databases as well as the use of internationally recognised tools to assess RoB and certainty of evidence(Reference Sterne, Savovic and Page38,Reference Sterne, Hernan and Reeves39) . We also considered two study designs and nine outcomes to provide a more comprehensive understanding of the literature on enteral nutrition therapy in paediatric CD. This is the first systematic review to compare stool microbiome and HRQL between enteral nutrition and CS in paediatric CD. However, limitations to the data presented are important to consider. First, for most included studies with limited sample size, especially observational studies, important baseline confounding factors such as disease severity, concomitant medications and anthropometric measurements are important to consider(Reference Scarpato, Strisciuglio and Martinelli31,Reference Hojsak, Pavic and Misak43,Reference Levine, Turner and Pfeffer Gik54,Reference Hradsky, Copova and Zarubova57,Reference Piovani, Pansieri and Peyrin-Biroulet62) . Sixteen cohort studies were at serious risk due to a lack of measurement/control of these important confounders. Therefore, the results from the cohort studies should be interpreted with caution, although underpowered and small studies should still be used as the best available evidence(Reference Guyatt, Mills and Elbourne63). Second, our review did not address the cost-effectiveness analysis of EEN v. CS in patients with CD, which may have important clinical considerations when assigning patients to the induction therapy(Reference Tsertsvadze, Gurung and Court64). Finally, although the authors were contacted, we were not able to obtain complete information on microbiota signatures from two studies, which may have provided additional data for our quality assessment and meta-analysis.
Meaning of the study and relation to previous studies
Treatments for induction of remission in children with active CD include enteral nutrition, CS and biologic agents(Reference van Rheenen, Aloi and Assa3). Recently, enteral nutrition has been recommended as primary therapy in children with active CD due to the remission induction efficacy(Reference van Rheenen, Aloi and Assa3,Reference Ruemmele, Veres and Kolho6) . Similar to our study’s conclusions from RCT evidence, three previous systematic reviews determined no significant differences between EEN and CS in clinical remission in the paediatric population(Reference Narula, Dhillon and Zhang7,Reference Yu, Chen and Chen21,Reference Swaminath, Feathers and Ananthakrishnan22) . However, our conclusion based on cohort studies is different and suggests that EEN seems to be beneficial in clinical remission, but the evidence is uncertain. Similar to another systematic review, the evidence on 1-year relapse rates between EEN and CS remains uncertain but trends towards lower relapse rates in the EEN group(Reference Yu, Chen and Chen21). In addition to clinical symptoms, therapeutic goals have changed with a recent focus on targeting objective improvement, including mucosal/histological healing(Reference Ruemmele, Veres and Kolho6,Reference Turner, Ricciuto and Lewis20) . Although patients treated with CS may achieve similar clinical remission and HRQL outcomes, they may fail to induce mucosal healing(Reference Narula, Dhillon and Zhang7,Reference Hart, Farbod and Halgren59,Reference Humphrey, Grant and Walters61,Reference Neurath and Travis65) . Similar to recent systematic reviews(Reference Narula, Dhillon and Zhang7,Reference Yu, Chen and Chen21,Reference Swaminath, Feathers and Ananthakrishnan22) , outcomes of mucosal healing based on two RCT in our review showed that children on EEN were more likely to achieve endoscopic verified mucosal healing than children administered CS. Despite low certainty of evidence, the potential advantage of enteral nutrition over CS treatment may be clinically appealing when weighing the therapeutic options for treating paediatric CD. Furthermore, recent studies indicated that EEN might have a therapeutic impact on the microbiota diversity and inflammation marker levels, although conflicting results exist among paediatric and adult studies(Reference Pigneur, Lepage and Mondot8–Reference Schwerd, Frivolt and Clavel10). From two related studies, we found only one RCT that reported on microbial diversity values as measured through the Shannon index in just four children in each group(Reference Pigneur, Lepage and Mondot8). In another cohort study of twenty patients with CD, there were incomplete microbiota values with respect to microbiota diversity and bacterial abundance(Reference Hart, Farbod and Szamosi4). Regarding microbiota indices, sparse data and heterogeneity exist between the two studies, although the effect on the Shannon diversity index seems to indicate a trend in favour of EEN in the RCT (Table 2).
With regard to the weight changes after treatment, a previous systematic review showed that weight gain in the EEN group was higher than the CS group but was not statistically significant(Reference Yu, Chen and Chen21). One RCT in our review reported that the post-treatment weight was lower in the EEN group v. the CS group(Reference Borrelli, Cordischi and Cirulli42). However, weight and BMI may provide an inaccurate and misleading assessment of body composition analysis which divides the body into fat-free mass (lean mass) and fat mass. CS may lead to an increase in fat mass and a decrease in lean mass, so the misinterpretation of clinical parameters of nutrition may mask potential deficits in lean mass and malnutrition after steroid treatment(Reference Bryant, Trott and Bartholomeusz66–Reference Sylvester, Leopold and Lincoln69). For HRQL, unfortunately, no RCT or cohort studies met our eligibility criteria. While authors of the related studies were contacted for more information based on the published conference abstracts, the full-text articles with additional data were not successfully obtained to conduct a meta-analysis and generate forest plots. However, one prospective cohort study in Canada (abstract only) reported a higher generic HRQL score in the CS group compared with the EEN group and indicated a trend towards CS. To interpret the magnitude of the HRQL effect, the anchor-based minimal important difference estimate was used according to available data and published evidence(Reference Norman, Sloan and Wyrwich70–Reference Carrasco-Labra, Devji and Qasim72). Although the result was statistically significant, the MD did not meet the minimal important difference estimate(Reference Hart, Farbod and Halgren59). Another prospective cohort Canadian study (abstract only) found that for children receiving either EEN or steroids for induction therapy, disease-specific HRQL scores were similar over time(Reference Humphrey, Grant and Walters61). Regarding FC, there is no single standard cut-off value to implicate the presence of mucosal inflammation(Reference Jukic, Bakiri and Wagner73). Due to this potential controversy, we did not use the dichotomous FC data for meta-analysis(Reference Levine, Turner and Pfeffer Gik54). Similar to the previous systematic reviews(Reference Narula, Dhillon and Zhang7,Reference Yu, Chen and Chen21) , our review indicated that children on EEN were less likely to experience adverse events when compared with steroid therapy in paediatric IBD, although the withdrawal rates do not differ between two groups. The findings may be clinically useful when assessing the risks and benefits of EEN and CS.
Implications for practice and research
The study results may help inform clinical practices and provide guidance for the design of future research. Our findings may be useful when assessing the clinical risks and benefits of EEN and CS in children with active CD, especially for mucosal healing, clinical remission, relapse, adherence and adverse events. However, meta-analyses and determining the certainty of evidence were not feasible for the following outcomes: microbiota signatures, HRQL and FC. Our systematic review may provide valuable inferences and implications for future research areas in paediatric IBD treatment. Further RCT and cohort studies are required to better understand the applicability of EEN when considering these outcomes, especially microbiota diversity, growth parameters and FC. Crohn’s specific HRQL is also an important patient-centred metric to be evaluated and compared with anchor-based minimal important differences. Moreover, further RCT and cohort studies regarding PEN v. CS may expand the available literature and provide important insight into the management of paediatric IBD.
Conclusions
Our study suggests that based on low certainty of evidence, EEN may be more beneficial than CS for mucosal healing at 4–12 weeks after induction therapy with fewer adverse events. However, the impact on clinical remission, relapse at 12 months post-induction therapy, post-treatment weight and adherence is uncertain based on very low certainty of evidence. Furthermore, the evidence on the effect of EEN compared with CS on microbiota signatures, FC and HRQL remains unclear due to limited available data, although there seems to be a trend in favour of EEN regarding gut microbiota. Additional sufficiently powered RCT are required to better assess the impact of enteral nutrition v. CS on paediatric CD.
Acknowledgements
The authors would like to extend sincere thanks to Denise Smith, MLIS, Health Sciences Library, McMaster University, for assistance in developing the search strategies.
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
M. Z., B. C. J., M. S. and P. M. contributed to the study idea, study design, study supervision, data interpretation and critical review of the manuscript. Z. D. and K. N. contributed to literature search, study design, data collection, data analysis, data interpretation and manuscript writing. All authors have approved the final version of the manuscript and the authorship list.
The authors declare no conflicts of interest.
Supplementary material
For supplementary material referred to in this article, please visit https://doi.org/10.1017/S0007114523000405
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