Publications by authors named "Dan Turner"

230 Publications

Kidney transplant recipients vaccinated before transplantation maintain superior humoral response to SARS-CoV-2 vaccine.

Clin Transplant 2021 Sep 10:e14478. Epub 2021 Sep 10.

Organ transplantation unit, Tel-Aviv Medical Center Tel-Aviv, Israel and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Majority of transplant recipients did not develop an appreciable humoral response following SARS-CoV-2 vaccine, in contrast to dialysis patients and healthy individuals. We analyzed the serologic response to BNT162b2 (Pfizer-BioNTech) vaccine in a cohort of 19 kidney transplant recipients, vaccinated prior to transplantation, compare to 109 recipients vaccinated after transplantation, and to 39 healthcare workers, by determining the level of anti-spike antibodies after transplantation. All controls and 17 of 19 (90%) of recipients vaccinated before transplant were seropositive, while only 49 of 109 (45%) recipients vaccinated post-transplant had positive serology (p<0.001). Median anti-spike IgG in the group of kidney transplant recipients vaccinated after transplantation (10.7 AU/mL, (IQR 0-62.5)) was lower than the patients vaccinated before transplantation (66.2 AU/mL (21.6-138)), which was significantly lower than in the controls (156 AU/mL (99.7-215.5)). Negative humoral response was associated with vaccination post transplantation [odds ratio 22.4], older age [OR = 1.04], and longer time on dialysis [OR = 1.02], while higher lymphocyte count at time of vaccination was protective [OR = 0.52]. Our findings of sustained superior humoral response to SARS-CoV-2 vaccine in kidney transplant recipients vaccinated prior to transplantation strongly support the recommendations of SARS-CoV-2 vaccination of transplant candidates, especially those younger than 60 years. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/ctr.14478DOI Listing
September 2021

Seroprevalence of SARS-CoV-2 antibodies in patients with autoimmune inflammatory rheumatic diseases.

Clin Exp Rheumatol 2021 Sep 7. Epub 2021 Sep 7.

Rheumatology Department, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Israel.

Objectives: To assess the prevalence of anti-SARS-CoV-2 antibodies in autoimmune inflammatory rheumatic disease (AIIRD) patients, and to define clinical factors associated with seropositivity.

Methods: A cross sectional study was conducted at a tertiary rheumatology department in Israel. Consecutive patients completed a questionnaire and were tested for SARS-CoV-2 anti-nucleoprotein IgG (N-IgG). If this was positive, an anti-S1/S2 spike IgG (S-IgG) test was done. If both were positive, the patient was considered seropositive. Seropositive patients were retested after 3 months.

Results: The study included 572 AIIRD patients. Thirty patients were found seropositive, for a seroprevalence of 5.24%. The seropositive rate was significantly lower for patients treated with immunosuppressive medications (3.55%, p≤0.01), and specifically for patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) (2.7%, p≤0.05). These associations remained significant in the multivariate regressions adjusting for age, sex and exposure to a known COVID-19 patient. A second serology test 3 months later was collected in 21 of the 30 seropositive patients. In a mean±standard deviation (SD) of 166.63±40.76 days between PCR and second serology, 85% were still positive for N-IgG, and 100% were still positive for S-IgG, with a higher mean±SD titre compared to the first S-IgG (166.77±108.77 vs. 132.44±91.18, respectively, p≤0.05).

Conclusions: Humoral response to SARS-CoV-2 in AIIRD patients may be affected be immunosuppressive treatment, especially bDMARDs. In patients with AIIRD, titres of SARS-CoV-2 IgG antibodies, especially N-IgG antibodies, fade with time, while S-IgG antibodies persist.
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September 2021

Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.

Gastroenterology 2021 Jul 20. Epub 2021 Jul 20.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background And Aims: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development.

Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis.

Results: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.

Conclusions: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.
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http://dx.doi.org/10.1053/j.gastro.2021.07.009DOI Listing
July 2021

The pediatric ulcerative colitis activity index (PUCAI) predicts steroid-failure in adults with acute severe colitis.

Scand J Gastroenterol 2021 Sep 14;56(9):1049-1055. Epub 2021 Jul 14.

Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

Background: One-third of patients with acute severe ulcerative colitis (ASC) fail to respond to intravenous corticosteroids (IVCS) and require second-line therapy or colectomy. We aimed to explore the performance of the Pediatric Ulcerative Colitis Activity Index (PUCAI), for predicting response to IVCS in adults with ASC, and to base a two-step decision-making process for guiding the introduction of second-line therapy.

Methods: This was a retrospective multicenter cohort study of adult patients with ASC. PUCAI score, Oxford criteria, and Swedish index were determined at baseline, day three and five of hospitalization, and discharge when outcomes were ascertained.

Results: 153 patients were included (mean age 34.7 ± 14.6, median disease duration 7.8 years [IQR 0-17.4]), of whom 51 (33%) required second-line therapy, and 23 (15%) eventually underwent colectomy by discharge. At days three and five, the median PUCAI scores were higher in non-responders compared with responders (55 [45-69] 38 [25-55] at day 3, and 55 [36-65] 20 [5-30] at day 5; both  < .001). The negative and positive predictive values (NPV and PPV) of IVCS failure were 76/63% for the Oxford criteria, 83/52% for the Swedish index as determined on day 3, and 73/100% for PUCAI ≥ 65 points on day five. The corresponding figures for PUCAI ≥ 45 at day 3 were 83/54%.

Conclusion: The PUCAI is a highly predictive tool for IVCS failure. PUCAI ≥ 45 on day 3 has an excellent NPV for IVCS failure indicating preparation for second-line therapy, and PUCAI ≥ 65 on day 5 has a high PPV to initiate the therapy.
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http://dx.doi.org/10.1080/00365521.2021.1947368DOI Listing
September 2021

Which Diet for Crohn's Disease? Food for Thought on the Specific Carbohydrate Diet, Mediterranean Diet, and Beyond.

Gastroenterology 2021 Sep 30;161(3):798-800. Epub 2021 Jun 30.

Northwestern University Feinberg School of Medicine, Digestive Health Center, Northwestern Medicine, Chicago, Illinois. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.06.058DOI Listing
September 2021

Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study.

Lancet Gastroenterol Hepatol 2021 08 19;6(8):616-627. Epub 2021 Jun 19.

Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.

Background: Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis.

Methods: The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557.

Findings: 93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p<0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period.

Interpretation: Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis.

Funding: AbbVie.
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http://dx.doi.org/10.1016/S2468-1253(21)00142-4DOI Listing
August 2021

Development and Validation of a Pediatric MRI-Based Perianal Crohn Disease (PEMPAC) Index-A Report from the ImageKids Study.

Inflamm Bowel Dis 2021 Jun 21. Epub 2021 Jun 21.

Radiology Department, Shaare Zedek Medical Center, Jerusalem, Israel.

Background: As part of the prospective multicenter ImageKids study, we aimed to develop and validate the pediatric MRI-based perianal Crohn disease (PEMPAC) index.

Methods: Children with Crohn disease with any clinical perianal findings underwent pelvic magnetic resonance imaging at 21 sites globally. The site radiologist and 2 central radiologists provided a radiologist global assessment (RGA) on a 100 mm visual analog scale and scored the items selected by a Delphi group of 35 international radiologists and a review of the literature. Two weighted multivariable statistical models were constructed against the RGA.

Results: Eighty children underwent 95 pelvic magnetic resonance imaging scans; 64 were used for derivation and 31 for validation. The following items were included: fistula number, location, length and T2 hyperintensity; abscesses; rectal wall involvement; and fistula branching. The last 2 items had negative beta scores and thus were excluded in a contending basic model. In the validation cohort, the full and the basic models had the same strong correlation with the RGA (r = 0.75; P < 0.01) and with the adult Van Assche index (VAI; r = 0.93 and 0.92; P < 0.001). The correlation of the VAI with the RGA was similar (r = 0.77; P < 0.01). The 2 models and the VAI had a similar ability to differentiate remission from active disease (area under the receiver operating characteristic curve, 0.91-0.94). The PEMPAC index had good responsiveness to change (area under the receiver operating characteristic curve, 0.89; 95% confidence interval, 0.69-1.00).

Conclusions: Using a blended judgmental and mathematical approach, we developed and validated an index for quantifying the severity of perianal disease in children with CD. The adult VAI may also be used with confidence in children.
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http://dx.doi.org/10.1093/ibd/izab147DOI Listing
June 2021

Ustekinumab in Pediatric Patients with Moderately to Severely Active Crohn's Disease Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study.

J Crohns Colitis 2021 May 26. Epub 2021 May 26.

Connecticut Children's Medical Center, Hartford, CT, USA.

Background And Aims: The objective was to evaluate the pharmacokinetics, safety/tolerability, and efficacy of ustekinumab in children with moderately to severely active Crohn's disease.

Methods: In this Phase 1, multicentre, 16-week, double-blind induction dose-ranging study (NCT02968108), patients aged 2-<18 years (body weight ≥10 kg) were randomized (1:1) to one of 2 weight range-based intravenous induction doses: 130mg vs 390mg in patients ≥40kg and 3mg/kg vs 9mg/kg in patients <40kg. At week 8, all patients received a single subcutaneous ustekinumab maintenance dose of 90mg in patients ≥40kg or 2mg/kg in patients <40kg.

Results: Forty-four patients were randomized and treated with ustekinumab (n=23 lower dose; n=21 higher dose); median (interquartile range) age was 13.0 (12-16) years. Pharmacokinetics were similar to those in adults with Crohn's disease. However, serum ustekinumab concentrations were lower among those with body weight <40kg compared with patients ≥40kg and the reference Phase 3 adult population. Through week 16, 73% of patients reported ≥1 adverse event (82.6% lower vs 62% higher dose); 2 discontinued due to adverse events (1 in each group). Serious adverse events occurred in 16% (26% lower, 5% higher dose), with Crohn's disease exacerbation being the most frequent. At week 16, 22%/29% (lower/higher dose) achieved clinical remission (Pediatric Crohn's Disease Activity Index ≤10).

Conclusions: The pharmacokinetics/safety profiles were generally consistent with those observed in adults with Crohn's disease. These results suggest a different dosing regimen may be required for patients <40kg than that employed in this study; additional pharmacokinetic analyses may be needed in this population.
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http://dx.doi.org/10.1093/ecco-jcc/jjab089DOI Listing
May 2021

Human immunotypes impose selection on viral genotypes through viral epitope specificity.

J Infect Dis 2021 May 11. Epub 2021 May 11.

Centre for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV+ ART-naive clinical trial participants.

Methods: HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs) and imputed HLA alleles, using generalized linear models with Bonferroni correction.

Results: Human (388,501 SNPs) and HIV (3,010 variants) genetic data was available for 2,122 persons. Four HIV variants were associated with VL (p-values<1.66×10 -5). Twelve HIV variants were associated with a range of 1-512 human SNPs (p-value<4.28×10 -11). We found 46 associations between HLA alleles and HIV variants (p-values<1.29×10 -7). We found HIV variants and immunotypes when analyzed separately, were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding prediction showed HLA alleles to be weaker binders of associated HIV AA variants relative to alternative variants on the same position.

Conclusions: Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay puts emphasis that viral and human genetics should be studied in the context of each other.
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http://dx.doi.org/10.1093/infdis/jiab253DOI Listing
May 2021

Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients.

J Hepatol 2021 08 21;75(2):435-438. Epub 2021 Apr 21.

Organ Transplantation Unit, Division of Surgery, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Liver Unit, Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background & Aims: Two SARS-CoV-2 mRNA vaccines were approved to prevent COVID-19 infection, with reported vaccine efficacy of 95%. Liver transplant (LT) recipients are at risk of lower vaccine immunogenicity and were not included in the registration trials. We assessed vaccine immunogenicity and safety in this special population.

Methods: LT recipients followed at the Tel-Aviv Sourasky Medical Center and healthy volunteers were tested for SARS-CoV-2 IgG antibodies directed against the Spike-protein (S) and Nucleocapsid-protein (N) 10-20 days after receiving the second Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine dose. Information regarding vaccine side effects and clinical data was collected from patients and medical records.

Results: Eighty LT recipients were enrolled. Mean age was 60 years and 30% were female. Twenty-five healthy volunteer controls were younger (mean age 52.7 years, p = 0.013) and mostly female (68%, p = 0.002). All participants were negative for IgG N-protein serology, indicating immunity did not result from prior COVID-19 infection. All controls were positive for IgG S-protein serology. Immunogenicity among LT recipients was significantly lower with positive serology in only 47.5% (p <0.001). Antibody titer was also significantly lower in this group (mean 95.41 AU/ml vs. 200.5 AU/ml in controls, p <0.001). Predictors for negative response among LT recipients were older age, lower estimated glomerular filtration rate, and treatment with high dose steroids and mycophenolate mofetil. No serious adverse events were reported in either group.

Conclusion: LT recipients developed substantially lower immunological response to the Pfizer-BioNTech SARS-CoV-2 mRNA-based vaccine. Factors influencing serological antibody responses include age, renal function and immunosuppressive medications. The findings require re-evaluation of vaccine regimens in this population.

Lay Summary: The Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine elicited substantially inferior immunity in liver transplant recipients. Less than half of the patients developed sufficient levels of antibodies against the virus, and in those who were positive, average antibody levels were 2x less compared to healthy controls. Factors predicting non-response were older age, renal function and immunosuppressive medications.
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http://dx.doi.org/10.1016/j.jhep.2021.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058047PMC
August 2021

Exploring Popular Social Media Networks for Patients With Inflammatory Bowel Diseases: Insights for Better Care.

J Clin Gastroenterol 2021 Apr 21. Epub 2021 Apr 21.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv Division of Gastroenterology, IBD Center, Rabin Medical Center, Petah Tikva IBD Center, Sheba Medical Center, Tel Hashomer, Ramat Gan Coller School of Management, Tel Aviv University, el Aviv University, Ramat Aviv, Tel Aviv Shaare Zedek Medical Center Hadassah Medical School, The Hebrew University, Jerusalem, Israel.

Goal: The aim was to assess topics of interest and concerns among patients with inflammatory bowel diseases (IBD) who are active online.

Background: Social media (SM) networks are a major communication tool for patients with IBD and health care professionals.

Patients And Methods: We performed an anonymized investigation of SM networks for IBD patients; I-a thematic analysis of patients' posts, II-an online survey advertised through Facebook and other popular SM networks throughout November 2019.

Results: Analyzing 2133 posts (2014 to 2019) revealed 18 topics of interest. The online survey was completed by 534 respondents [63%-Crohn's disease, 56%-female, median age-38 years (interquartile range: 28.7 to 51.0)]. Most respondents (70%) were followed in referral centers, and 45% were receiving biological therapy. Respondents reported high satisfaction with IBD care and health care provider professionalism. The top 5 topics of interest were diet, lifestyle, complementary and alternative medicine, diagnostic test interpretation, and specialist referrals and reviews. Cluster analysis demonstrated that gender, income, and education level were associated with specific interest and concerns.

Conclusion: Patients' activity on SM is independent of their satisfaction with formal IBD care and rather reflects an ongoing need for information and support. These needs may be addressed both in clinical settings and through online tools.
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http://dx.doi.org/10.1097/MCG.0000000000001551DOI Listing
April 2021

Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus.

Am J Transplant 2021 08 7;21(8):2719-2726. Epub 2021 May 7.

Organ Transplantation Unit, Sackler Faculty of Medicine, Tel-Aviv Medical Center, Tel-Aviv University, Tel-Aviv, Israel.

COVID-19 is associated with increased morbidity and mortality in transplant recipients. There are no efficacy data available regarding these patients with any of the available SARS-CoV-2 vaccines. We analyzed the humoral response following full vaccination with the BNT162b2 (Pfizer-BioNTech) in 136 kidney transplant recipients, and compared it to 25 controls. In order to exclude prior exposure to the virus, only participants with negative serology to SARS-CoV-2 nucleocapsid protein were included. All controls developed a positive response to spike protein, while only 51 of 136 transplant recipients (37.5%) had positive serology (p < .001). Mean IgG anti-spike level was higher in the controls (31.05 [41.8] vs. 200.5 [65.1] AU/mL, study vs. control, respectively, p < .001). Variables associated with null humoral response were older age (odds ratio 1.66 [95% confidence interval 1.17-2.69]), high-dose corticosteroids in the last 12 months (1.3 [1.09-1.86]), maintenance with triple immunosuppression (1.43 [1.06-2.15]), and regimen that includes mycophenolate (1.47 [1.26-2.27]). There was a similar rate of side effects between controls and recipients, and no correlation was found between the presence of symptoms and seroconversion. Our findings suggest that most kidney transplant recipients remain at high risk for COVID-19 despite vaccination. Further studies regarding possible measures to increase recipient's response to vaccination are required.
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http://dx.doi.org/10.1111/ajt.16615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250589PMC
August 2021

Perianal Crohn's Disease Is Associated With Poor Disease Outcome: A Nationwide Study From the epiIIRN Cohort.

Clin Gastroenterol Hepatol 2021 Apr 9. Epub 2021 Apr 9.

Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address:

Background & Aims: Limited population-based data have explored perianal involvement in Crohn's disease (CD) and compared the disease course between severe and non-severe perianal CD (PCD). We aimed to explore the disease course of these phenotypes in a population-based study of CD.

Methods: Cases were identified from the epi-IIRN cohort and included 2 Israeli health maintenance organizations covering 78% of the population. We validated specific algorithms to identify fistulizing PCD and to differentiate severe from non-severe disease by medication utilization, International Classification of Disease, 9th Revision codes, and perianal procedures.

Results: A total of 12,904 CD patients were included in an inception cohort from 2005 (2186 pediatric-onset, 17%) providing 86,119 person-years of follow-up. Fistulizing PCD was diagnosed in 1530 patients (12%) (574 with severe PCD, 4%). The prevalence of PCD was 7.9%, 9.4%, 10.3%, and 11.6% at 1, 3, 5, and 10 years from CD diagnosis, respectively. At 5 years, PCD patients were more likely to be hospitalized (36% in non-PCD vs 64% in PCD; P < .001), undergo inflammatory bowel disease-related surgeries (9% vs 38%, respectively; P < .001), and develop anorectal cancer (1.2/10,000 person-years for non-PCD vs 4.2/10,000 for PCD; P = .01). Severe PCD was associated with poorer outcomes compared with non-severe PCD, as shown for hospitalizations (61% in non-severe PCD vs 73% in severe; P = .004) and surgeries (35% vs 43%; P = .001).

Conclusions: Despite higher utilization of immunomodulators and biologics, PCD is associated with poor disease outcomes, especially in severe PCD.
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http://dx.doi.org/10.1016/j.cgh.2021.04.007DOI Listing
April 2021

Monitoring Enables Progress: A Nationwide Quality Improvement Program in Children With Crohn Disease.

J Pediatr Gastroenterol Nutr 2021 Aug;73(2):236-241

Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center.

Objectives: In this quality improvement program, named quality in pediatric inflammatory bowel disease, we constructed a nation-wide platform that prospectively recorded clinically important quality indicators in pediatric inflammatory bowel diseases (PIBD), aiming at improving clinical management across the country.

Methods: Representatives of all 21 PIBD facilities in Israel formed a Delphi group to select quality indicators (process and outcomes), recorded prospectively over 2 years in children with Crohn's disease 2-18 years of age seen in the outpatient clinics. Monthly anonymized reports were distributed to all centers, allowing comparison and improvement. Trends were analyzed using the Mann-Kendall test, reporting τ (tau) values.

Results: The indicators of 3254 visits from 1709 patients were recorded from September 2017 to September 2019 (mean age 14.7 ± 3.1 years, median disease duration 1.8 years (interquartile range 0.69-4.02)). An increase in three of five process indicators was demonstrated: obtaining drug levels of anti-tumor necrosis factor (TNF) (τ = 0.4; P = 0.005), utilization of fecal calprotectin (τ = 0.38; P = 0.008) and bone density testing (τ = 0.45; P = 0.002). Among outcome indicators, three of nine improved as measured during the preceding year: calprotectin <300 μg/mg (τ = 0.35; P = 0.015), and "resolution of inflammation" defined as a composite of endoscopy, imaging and fecal calprotectin (τ = 0.39; P = 0.007). Endoscopic healing reached borderline significance (τ = 0.28; P = 0.055). An increase in the use of biologics throughout the study was observed (τ = 0.47; P = 0.001) with a concurrent decrease in the use of immunomodulators (τ = -0.47; P = 0.001).

Conclusions: Quality improvement nationwide programs can be implemented with limited resources while facilitating standardization of care, and may be associated with improvements in measured indicators.
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http://dx.doi.org/10.1097/MPG.0000000000003133DOI Listing
August 2021

Agreement on Symptoms Between Children With Ulcerative Colitis and Their Caregivers: Towards Developing the TUMMY-UC.

J Pediatr Gastroenterol Nutr 2021 Aug;73(2):e35-e38

Shaare Zedek Medical Center, Jerusalem, Israel.

Abstract: As part of the development of the TUMMY-UC, a patient-reported outcome (PRO) measure for pediatric ulcerative colitis (UC), we aimed to explore agreement on UC symptoms between children and their caregivers. We conducted 44 interviews with children ages 8-12 years, who completed the PRO version of the TUMMY-UC, and their caregivers, who completed the observer-reported outcome (obsRO) version. There was excellent agreement between the total TUMMY-UC PRO and obsRO scores (intra-class correlation coefficient = 0.92 [95% confidence interval 0.74-0.98]). The obsRO scores were always within the same disease-activity category as the corresponding PRO score (ie, remission, mild and moderate-severe disease). There was a strong correlation of the TUMMY-UC PRO and obsRO scores with physician global assessment of disease activity (r = 0.94 and r = 0.90, respectively, P < 0.001) and the pediatric UC activity index (r = 0.95 and r = 0.96; P < 0.001). These data support conceptual equivalence between the PRO and obsRO TUMMY-UC versions, and provide support for their incorporation into one score.
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http://dx.doi.org/10.1097/MPG.0000000000003120DOI Listing
August 2021

Pediatric-onset Inflammatory Bowel Disease Has Only a Modest Effect on Final Growth: A Report From the epi-IIRN.

J Pediatr Gastroenterol Nutr 2021 Aug;73(2):223-230

Pediatric Gastroenterology Unit, "Dana-Dwek" Children's Hospital, Tel-Aviv Sourasky Medical Center.

Objectives: The impact of pediatric-onset inflammatory bowel disease (IBD) on growth is debated. We aimed to investigate the effect of IBD on anthropometric measures at young adulthood.

Methods: Children diagnosed with Crohn disease (CD) or ulcerative colitis (UC) (2005-2019) were identified in a national database along with matched non-IBD controls.

Results: Overall, 2229 IBD cases (68% CD) were matched to 4338 controls. Only females with CD differed in final height from controls (z scores: -0.37 ± 1.09 vs -0.25 ± 1.06, respectively; P = 0.01), corresponding to a mean difference of 0.7 ± 0.2 cm (all females) and 1.2 ± 0.3 cm in females diagnosed <14 years (P = 0.02). Final height was reduced in both sexes according to adjusted mean height difference analysis (-0.43 cm, 95% confidence interval -0.85 to -0.02; P = 0.04). This difference increased in patients with CD who underwent abdominal surgery (-0.91 cm, 95% confidence interval -1.39 to -0.42; P = 0.01). The proportion of patients with CD achieving final height z scores of -1 and zero differed significantly from controls for both males (71.1% and 34.8% vs 79.1% and 43.0%, respectively; P < 0.001) and females (67.7% and 30.4% vs 79.6%, and 43.3%, respectively; P < 0.001). Patients treated with anti-tumor necrosis factor agents during growth potential had similar height improvement to other regimens. Predominantly, patients with CD were leaner, with a greater proportion of subjects with underweight, compared with controls.

Conclusions: In pediatric-onset IBD, absolute final height was modestly affected by females with CD. Nevertheless, greater proportions of both sexes with early diagnosis of CD failed to achieve normal final height, compared with controls.
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http://dx.doi.org/10.1097/MPG.0000000000003072DOI Listing
August 2021

The Effect of Nutritional Therapy on Bone Mineral Density and Bone Metabolism in Pediatric Crohn Disease.

J Pediatr Gastroenterol Nutr 2021 06;72(6):877-882

Juliet Keidan Institute of Pediatric Gastroenterology & Nutrition, Shaare Zedek Medical Center.

Objectives: Both the inflammatory burden of Crohn disease (CD) and corticosteroids have a negative effect on bone density. Exclusive enteral nutrition (EEN) avoids corticosteroids and promotes endoscopic healing. We aimed to explore the effect of nutritional therapy on bone health in pediatric CD.

Methods: This was a planned sub-study of a clinical trial enrolling children with new-onset mild-moderate CD. Children were randomized to either 6 weeks EEN followed by 6 weeks 25% partial enteral nutrition (PEN) or 6 weeks of 50% PEN with a CD exclusion diet followed by 6 weeks of 25% PEN with exclusion diet. Bone formation and resorption were measured at baseline, week 12 and week 24 by serum C-Propeptide of Type I Procollagen (CICP) and type I Collagen N-Telopeptide (NTX), respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) scan at baseline and week 24.

Results: Median CICP improved from 130 ng/mL (106-189) at baseline to 223 (143-258) at week 12 and 193 (143-252) at week 24 (P = 0.016 for both, n = 29 children). Median NTX remained unchanged (P = 0.45 and P = 0.45). Thirty-six children had DXA scans performed at diagnosis; 81% and 33% had z scores of <-1 and <-2, respectively. DXA z scores did not improve from baseline (adjusted total body less head [TBLH] BMD -1.62 ± 0.87) to week 24 (-1.76 ± 0.75; P = 0.30, n = 21 with both scans).

Conclusions: Low bone density is common in new-onset mild-moderate pediatric CD. CICP, a sensitive marker of bone formation, improved following dietary intervention but this was not associated with improved BMD.
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http://dx.doi.org/10.1097/MPG.0000000000003073DOI Listing
June 2021

Drop-out of medical follow-up among people living with HIV in Tel-Aviv area.

AIDS Care 2021 Feb 10:1-5. Epub 2021 Feb 10.

Crusaid Kobler AIDS Center, Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Access to HIV anti-retroviral treatment (ART) has significantly improved survival and the quality of life of people living with HIV (PLHIV). However, effective therapy necessitates high adherence to ART. The aim of this study was to identify the extent to which PLHIV in Israel were not retained in therapy and their obstacles to accessing care. The Department of Tuberculosis and AIDS (DTA) and the two existing HIV clinics in the Tel-Aviv metropolitan area performed a retrospective study for all PLHIV who were consulted at these clinics during 2008-2011, but were absent in 2012. From that population, 25% were randomly chosen for qualitative interviews. This study included 278 PLHIV not retained in care (13.4% of registered patients), of whom 194 (69.8%) were male, and 58.3% were Israeli citizens. Total number of clinic visits was 1959 (mean: 7.05 visits per patient; range: 1-39; SD: ±7.2) and the total person-years of follow-up for 267 PLHIV was 1,044 (mean: 3.9 py; 0-23; SD: ±4.4). Identified risk groups were: Originating from Generalized Epidemic countries (43.5%, 82.6% were non-Israelis); Men having Sex with Men (22.6%); Injecting Drug Users (12.9%) and Others (28.9%). Among Israelis, major reasons for clinic nonattendance included distance to the clinics and perceived lack of time. The major impediment to seeking care among undocumented migrants was lack of medical insurance. The DTA acted swiftly to make HIV-related services accessible to undocumented migrants. Barriers described by Israeli participants were generally more individual in nature, and should be addressed at the clinic level.
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http://dx.doi.org/10.1080/09540121.2021.1883516DOI Listing
February 2021

Identifying Health Economic Considerations to Include in the Research Protocol of a Randomized Controlled Trial (the REDUCE-RISK Trial): Systematic Literature Review and Assessment.

JMIR Form Res 2021 Jan 25;5(1):e13888. Epub 2021 Jan 25.

Pediatric Gastroenterology and Nutrition, Vrije Universiteit Brussel, University Hospital Brussels, Brussels, Belgium.

Background: The REDUCE-RISK trial was set up to compare the effectiveness of weekly subcutaneously administered methotrexate with daily oral azathioprine or 6-mercaptopurine in low-risk Crohn disease (CD) or subcutaneously administered adalimumab (ADA) in high-risk CD in a pediatric population (age 6-17 years).

Objective: The aim of this study is to perform a systematic review to provide input into the research protocol to gather the necessary information to improve the performance of an evidence-based economic evaluation when the trial is finished.

Methods: The Centre for Reviews and Dissemination (CRD) Health Technology Assessment (HTA) database, websites of HTA institutes, CRD's National Health Service Economic Evaluation Database, MEDLINE (OVID), and Embase databases were consulted to retrieve (reviews of) relevant economic evaluations. Studies were eligible if they included a pediatric or adult population with inflammatory bowel diseases (CD and ulcerative colitis [UC]) treated with ADA (Humira). There were no restrictions on the comparator. Only economic evaluations expressing outcomes in life years gained or quality-adjusted life years gained were selected.

Results: A total of 12 primary studies were identified. None of these studies included a pediatric population because of a lack of supporting trials. The economic evaluations identified in our systematic review indicate that ADA is an appropriate intervention for inclusion in such a trial. From a health economic point of view, it is important to make an incremental analysis comparing such an intervention with standard care and not immediately versus another (expensive) biological treatment. Information on the impact of children's school attendance and parents' productivity is currently lacking in economic evaluations, and none of the underlying trials measured quality of life (QoL) using a generic utility instrument.

Conclusions: The review of the economic literature on ADA for the treatment of patients with CD supports the performance of a trial with biologicals in pediatric patients, including making a distinction according to disease severity. Conducting an economic literature review enabled us to decide which variables should be added to the research protocol from an economic point of view. Measurements for children's and parents' QoL (EuroQol 5-Dimension questionnaires), children's school attendance, and parents' productivity (WPAI-CD-CG questionnaire) were added to the research protocol. This will provide support for the calculation of the cost-effectiveness of the interventions evaluated in the REDUCE-RISK trial.

Trial Registration: ClinicalTrials.gov NCT02852694; https://clinicaltrials.gov/ct2/show/NCT02852694.
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http://dx.doi.org/10.2196/13888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870354PMC
January 2021

Epidemiology of Inflammatory Bowel Diseases in Israel: A Nationwide Epi-Israeli IBD Research Nucleus Study.

Inflamm Bowel Dis 2021 Jan 13. Epub 2021 Jan 13.

The Juliet Keiden Institute of Pediatric Gastroenterology and Nutrition Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.

Background: There are currently no nationwide data on the epidemiology of inflammatory bowel diseases (IBD) in Israel. We aimed to determine the population-based epidemiological trends of IBD in the diverse Israeli population.

Methods: Health-administrative data were retrieved from all 4 Israeli health maintenance organizations, insuring 98% of the population, using validated identification algorithms. National trends were determined using Joinpoint regression analysis calculating annual percent change and average annual percent change (AAPC).

Results: By 2019, there were 46,074 patients with IBD in Israel, corresponding to a national prevalence of 519/100,000 (0.52%), of whom 54.1% had Crohn disease (CD) and 45.9% had ulcerative colitis (UC). The number of Jewish patients doubled from 18,701 in 2005 (354/100,000) to 38,950 (589/100,000) in 2018 (AAPC, +4.0%; P < 0.05), and the number of Arab patients increased 3-fold from 1096 (102.1/100,000) to 3534 (240.7/100,000; AAPC, +6.8%; P < 0.05) during the same years. However, the increase rate has gradually decelerated over time (annual percent change during 2005-2008, 2009-2014, and 2005-2018 was +6.7%, +4.2%, and +2.3%, respectively; P < 0.05). Pediatric prevalence increased from 37.4 to 52.2/100,000, with CD predominating in both Jews and Arabs. The incidence of CD remained stable (from 15.9/100,000 to 14.9/100,000) and the incidence of UC decreased (15.4/100,000 to 10.5/100,000 (AAPC, -3.2%; P < 0.001)). In contrast, pediatric incidence of CD increased from 7.3/100,000 to 8.3/100,000 (AAPC, +1.9%; P < 0.05) and that of UC increased from 2.6 to 4.4/100,000 (AAPC, +5.8%; P < 0.05).

Conclusions: The IBD prevalence rate in Israel is still increasing but gradually decelerating, probably due to the decreasing overall IBD incidence. Nonetheless, incidence rate in children is still increasing. Ongoing narrowing in the rates between Jews and Arabs over time may indicate shared environmental factors.
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http://dx.doi.org/10.1093/ibd/izaa341DOI Listing
January 2021

STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD.

Gastroenterology 2021 04 19;160(5):1570-1583. Epub 2021 Feb 19.

Department of Medicine I, Agaplesion Markus Hospital, Goethe University, Frankfurt/Main, Germany. Electronic address:

Background: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD.

Methods: Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale.

Results: In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn's disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth.

Conclusions: STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.
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http://dx.doi.org/10.1053/j.gastro.2020.12.031DOI Listing
April 2021

Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

J Pediatr Gastroenterol Nutr 2021 03;72(3):456-473

Child Life and Health, University of Edinburgh, Department of Paediatric Gastroenterology, The Royal Hospital for Sick Children, Edinburgh.

Background: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups.

Methods: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists).

Results: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries.

Conclusions: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.
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http://dx.doi.org/10.1097/MPG.0000000000003017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221730PMC
March 2021

Associations of NOD2 polymorphisms with Erysipelotrichaceae in stool of in healthy first degree relatives of Crohn's disease subjects.

BMC Med Genet 2020 10 15;21(1):204. Epub 2020 Oct 15.

Department of Medicine, University of Toronto, Toronto, ON, Canada.

Background: Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn's disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset.

Methods: Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15-40-fold increased risk of developing CD in homozygous or compound heterozygous individuals.

Results: Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae.

Conclusions: This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.
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http://dx.doi.org/10.1186/s12881-020-01115-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566148PMC
October 2020

Benign Evolution of SARS-Cov2 Infections in Children With Inflammatory Bowel Disease: Results From Two International Databases.

Clin Gastroenterol Hepatol 2021 02 12;19(2):394-396.e5. Epub 2020 Oct 12.

Hôpital Necker Enfants Malades, APHP, Université de Paris, Paris, France.

The coronavirus disease 2019 (COVID-19) pandemic caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents most often with mild clinical symptoms, but the severe forms are of major concern. SARS-CoV-2 enters human cells via the angiotensin-converting enzyme 2 receptor, expressed on epithelial and endothelial cells. Because the highest angiotensin-converting enzyme 2 expression is in the terminal ileum and colon, and up-regulated further during inflammation, and many COVID-19 patients experience gastrointestinal symptoms, longitudinal data are necessary to determine whether inflammatory bowel disease (IBD) patients are at risk for severe or complicated COVID-19. A recent analysis in IBD patients from the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry showed older age, steroid medication, and comorbidities as risk factors for severe evolution, and the same study showed that the 29 IBD patients younger than age 20 had only mild disease courses. This report describes the disease course of COVID-19 in an expanded sample of pediatric IBD patients from 2 international databases.
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http://dx.doi.org/10.1016/j.cgh.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550063PMC
February 2021

The Medical Management of Paediatric Crohn's Disease: an ECCO-ESPGHAN Guideline Update.

J Crohns Colitis 2020 Oct 7. Epub 2020 Oct 7.

Assistance Publique- Hôpitaux de Paris, Hôpital Necker Enfants Malades, Pediatric Gastroenterology, Paris, France.

Objective: We aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease [CD].

Methods: We formed 10 working groups and formulated 17 PICO-structured clinical questions [Patients, Intervention, Comparator, and Outcome]. A systematic literature search from January 1, 1991 to March 19, 2019 was conducted by a medical librarian using MEDLINE, EMBASE, and Cochrane Central databases. A shortlist of 30 provisional statements were further refined during a consensus meeting in Barcelona in October 2019 and subjected to a vote. In total 22 statements reached ≥ 80% agreement and were retained.

Results: We established that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity, to reduce bowel damage. Patients with perianal disease, stricturing or penetrating behaviour, or severe growth retardation should be considered for up-front anti-tumour necrosis factor [TNF] agents in combination with an immunomodulator. Therapeutic drug monitoring to guide treatment changes is recommended over empirically escalating anti-TNF dose or switching therapies. Patients with low-risk luminal CD should be induced with exclusive enteral nutrition [EEN], or with corticosteroids when EEN is not an option, and require immunomodulator-based maintenance therapy. Favourable outcomes rely on close monitoring of treatment response, with timely adjustments in therapy when treatment targets are not met. Serial faecal calprotectin measurements or small bowel imaging [ultrasound or magnetic resonance enterography] are more reliable markers of treatment response than clinical scores alone.

Conclusions: We present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa161DOI Listing
October 2020

Predicting Outcomes in Pediatric Crohn's Disease for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

Gastroenterology 2021 01 23;160(1):403-436.e26. Epub 2020 Sep 23.

IBD Centre, SickKids Hospital, University of Toronto, Toronto, Canada. Electronic address:

Background & Aims: A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management.

Methods: A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence.

Results: Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density.

Conclusions: These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.
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http://dx.doi.org/10.1053/j.gastro.2020.07.065DOI Listing
January 2021

Predicting Outcomes in Pediatric Ulcerative Colitis for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

Gastroenterology 2021 01 23;160(1):378-402.e22. Epub 2020 Sep 23.

Institute of Pediatric Gastroenterology, Shaare Zedek Medical Center, the Hebrew University of Jerusalem, Israel. Electronic address:

Background & Aims: A better understanding of prognostic factors in ulcerative colitis (UC) could improve patient management and reduce complications. We aimed to identify evidence-based predictors for outcomes in pediatric UC, which may be used to optimize treatment algorithms.

Methods: Potential outcomes worthy of prediction in UC were determined by surveying 202 experts in pediatric UC. A systematic review of the literature, with selected meta-analysis, was performed to identify studies that investigated predictors for these outcomes. Multiple national and international meetings were held to reach consensus on evidence-based statements.

Results: Consensus was reached on 31 statements regarding predictors of colectomy, acute severe colitis (ASC), chronically active pediatric UC, cancer and mortality. At diagnosis, disease extent (6 studies, N = 627; P = .035), Pediatric Ulcerative Colitis Activity Index score (4 studies, n = 318; P < .001), hemoglobin, hematocrit, and albumin may predict colectomy. In addition, family history of UC (2 studies, n = 557; P = .0004), extraintestinal manifestations (4 studies, n = 526; P = .048), and disease extension over time may predict colectomy, whereas primary sclerosing cholangitis (PSC) may be protective. Acute severe colitis may be predicted by disease severity at onset and hypoalbuminemia. Higher Pediatric Ulcerative Colitis Activity Index score and C-reactive protein on days 3 and 5 of hospital admission predict failure of intravenous steroids. Risk factors for malignancy included concomitant diagnosis of primary sclerosing cholangitis, longstanding colitis (>10 years), male sex, and younger age at diagnosis.

Conclusions: These evidence-based consensus statements offer predictions to be considered for a personalized medicine approach in treating pediatric UC.
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http://dx.doi.org/10.1053/j.gastro.2020.07.066DOI Listing
January 2021

Clinical Criteria Can Identify Children With Osteopenia in Newly Diagnosed Crohn Disease.

J Pediatr Gastroenterol Nutr 2021 02;72(2):270-275

Juliet Keidan Department of Paediatric Gastroenterology, Shaare Zedek Medical Center.

Objectives: Chronic inflammation of Crohn disease (CD) is associated with reduced bone mineral density (BMD). As bone mass is almost exclusively accrued during childhood, early recognition of osteopenia is especially important in pediatric CD. We aimed to identify variables associated with osteopenia to guide dual-energy X-ray absorptiometry (DXA) scan screening to those who most need it.

Methods: This was a retrospective inception cohort study of children newly diagnosed with CD, and routinely referred to DXA scans. Demographic and explicit clinical data were recorded along with whole-body less head BMD, adjusted for age, sex, and height by z-scores.

Results: Of the 116 included children (mean age 13 ± 3.1 years, 67 [58%] boys, mean body mass index [BMI] 16.7 ± 2.6), 63 (54%) had normal BMD (z-score > -1) or borderline osteopenia (-1 ≥ z-score > -2) and 53 (46%) had osteopenia (z-score ≤ -2). Osteopenia was associated with lower BMI z-score (-0.8 ± 1.2 vs -1.8 ± 1.1, P < 0.001) and higher PCDAI (33.7 ± 15.2 vs 25.7 ± 16.5; P = 0.009) than those with BMD z-score >-2. In total, 59% of children with BMI z-score <-0.5 had moderate-severe osteopenia and only 18% of those with higher z-scores. Multivariate logistic regression identified BMI z-score as the sole risk factor (OR 1.28 [95% CI 1.08-1.52], P = 0.005). BMI z-score ≥-0.5 excludes osteopenia with a sensitivity 87%, specificity 49%, NPV 82%, and PPV 59%.

Conclusions: Osteopenia was found in nearly half of children with newly onset CD. BMI z-score <-0.5 should prompt referral to DXA screening.
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http://dx.doi.org/10.1097/MPG.0000000000002911DOI Listing
February 2021
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