Case Report: Morphologic and Functional Characteristics of Intestinal Mucosa in a Child With Short Bowel Syndrome After Treatment With Teduglutide: Evidence in Favor of GLP-2 Analog Safety.

Teduglutide is a glucagon-like peptide-2 (GLP-2) analog employed in patients with short bowel syndrome (SBS) to reduce the need of parenteral nutrition in these patients, by virtue of its effects on enteric function. The experimental studies reported that the stimulating action of GLP-2 on epithelial turnover implies the potential development of dysplastic and neoplastic lesion. However, the clinical trials could not detect preneoplastic lesions on histologic material, and in a recent pilot study the occurrence of polyps was similar before and after treatment and included only low-grade dysplastic lesions. Another clue in GLP-2 function in stimulating mucosal restore is its enhancement through cooperation with epidermal growth factor (EGF). In this study, we analyzed gastroscopy and colonoscopy samplings from a child successfully weaned off parenteral nutrition with teduglutide. Villous and crypt structure was regular both in duodenal and in colonic samplings; in properly oriented villi, villus/crypt ratio was regular. The absorptive epithelium demonstrated a regular morphology. No atypia was detected in enterocytes, along epithelial structures. At the ultrastructural analysis, only a few enterocytes with vacuolized cytoplasm were observed. An S-phase marker Ki67 stained nuclei in the transitional amplifying zone, while nuclei stained by the cell cycle regulatory proteins p21 and p27 were placed in the differentiated epithelium of the duodenal villi and colonic crypts, as in the control cases. The counts of enterocytes immunostained with the same antisera, evaluated with image analysis software, were in the range of control cases. The ratio of the number of epidermal growth factor receptor (EGFR) signals/the number of centromere probe of chromosome 7 (CEP7) signals was less than 2. The findings available from this single patient are consistent with good preservation of functional capability of intestinal epithelium after treatment with GLP-2, given the histologic and ultrastructural features of enterocytes. In addition, the findings from cell cycle regulatory proteins immunolocalization and quantitative analysis show that cell renewal machinery in our case is comparable to control cases. The gene of the receptor EGFR is regularly expressed in enteric epithelium of our case. Morphologic and functional data from our patient improve evidence in favor of the safety of GLP-2 employ in SBS.

Intestinal ultrasonography in pediatric population.

Bowel ultrasound (US) is a low cost, non-invasive, bed side practice and a reproducible procedure that represents a high yield tool in clinical practice and in the diagnostic workup of a consistent group of acute and chronic gastrointestinal (GI) tract disease. Moreover, in case of GI diseases of neonatal and pediatric age, it allows an easier evaluation due to the small body size and scarce presence of fat tissue in the abdominal wall and peritoneal cavity and gas content. No particular preparation of the patient is needed, nevertheless a 3 to 5 hour fasting state improves the quality of the examination. The exam focuses on wall thickness and stratification, lumen content, distensibility and compressibility, presence of peristalsis of explorable segment of the GI tract and includes the investigation of mesentery, perivisceral tissues and nodes features. Color doppler flowmetry admits a qualitative evaluation of GI wall and mesentery vascularization. Healthy GI wall appears at a US evaluation as a multilayered structure in which hyperechoic and hypoechoic layers alternate sequentially. In this article we provide a quickly available overview on findings, signs and applications of US in major GI pediatric diseases.

Overexpression of endogenous retroviruses in children with celiac disease.

Human endogenous retroviruses (HERVs) represent 8% of our genome. Although no longer infectious, they can regulate transcription of adjacent cellular genes, produce retroviral RNAs, and encode viral proteins that can modulate both innate and adaptive immune responses. Based on this, HERVs have been studied and proposed as contributing factors in various autoimmune disorders. Celiac disease (CD) is considered an autoimmune disease, but HERV expression has not been studied in celiac patients. The aim of this study is to assess the transcription levels of pol genes of HERV-H, -K, and -W and of their TRIM28 repressor in WBCs from celiac children and age-matched control subjects. A PCR real-time TaqMan amplification assay was used to evaluate HERV and TRIM28 transcripts with normalization of the results to glyceraldehyde-3-phosphate dehydrogenase. The RNA levels of pol genes of the three HERV families were significantly higher in WBCs from 38 celiac patients than from 51 control subjects. TRIM28 transcription was comparable between the two study populations.Conclusion: Present results show, for the first time, that pol genes of HERV-H, -K, and -W are overexpressed in patients with CD. Given their proinflammatory and autoimmune properties, this suggests that HERVs may contribute to the development of CD in susceptible individuals. What is Known: • Based on this, HERVs have been studied and proposed as contributing factors in various autoimmune disorders. What is New: • Present results show, for the first time, that pol genes of HERV-H, -K, and -W are overexpressed in patients with CD.

Predictivity of early and late assessment for post-surgical recurrence of Crohn's disease: Data from a single-center retrospective series.

BACKGROUND AND AIMS: Post-surgical recurrence of Crohn's disease (CD) after ileocolonic resection is common. Early identification of features associated with recurrence is a standard procedure of postoperative management, but the prognostic role of such features when detected at later time points is unclear. We compared the predictivity for Crohn's disease recurrence of common clinical-instrumental variables when assessed early (<12 months) or late (>36 months) after surgery. METHODS: This retrospective study considered CD patients who had ileocolonic resection and were followed for a median of 7.6 years. Clinical characteristics, post-surgical therapy, endoscopy recurrence (Rutgeerts' score ≥i2) and ultrasound features were compared between subgroups who had a early or late post-surgical assessment. Univariate and multivariate analyses were done to identify variables associated with recurrence (clinical and surgical). RESULTS: Of 201 patients, 70 (32%) had a early and 39 (19%) had a late post-surgical assessment. The Early and Late subgroups had similar clinical characteristics. Overall, clinical relapse was observed in 131 patients (66%), surgical relapse in 31 (16%), endoscopic recurrence in 149 (75%) and ultrasonographic recurrence in 132 (66%), without significant differences in frequencies between subgroups. By Cox proportional hazard regression, endoscopic recurrence was a significant predictor of clinical recurrence overall (HR=2.31, P = 0.002) and in the Early (HR=3.85, P = 0.002) but not Late subgroup. DISCUSSION: The most informative postoperative CD assessment is the one done within the first year of surgery. Later endoscopic evaluations have no prognostic value and should be done only for clinical needs or for research purposes.

Management of Hepatitis-B Virus Infection in Immunocompromised Children: A Single Center Experience.

OBJECTIVES: The aims of the study was to expand the pediatric experience on hepatitis-B virus (HBV) reactivation, a known complication in patients with hematologic malignancies or on immunosuppression. METHODS: Retrospective appraisal of HBV therapy/prophylaxis in immunocompromised children, studied from April 2006 to March 2020. RESULTS: Eighteen HBV-positive patients, 5 girls, median age 11.1 (4.1--17.9) years were included. Seventeen of 18 were immunosuppressed at HBV-infection diagnosis. Seventeen were at high risk of reactivation, 1 at moderate risk. Five of 18 had acute hepatitis B as first infection or reactivation, 6 had HBeAg-positive infection, 1 an HBeAg-negative infection and 6 HBsAg-negative infection. Median follow-up was 2.7 (0.7--12.5) years. No HBV-related mortality was observed. Prophylaxis had to be repeated in 1. Lamivudine was used in 6/12 viremic patients and HBV-DNA negativization obtained in 2/6 (33%). Tenofovir-DF was used in 2/12 and entecavir in 4/12: 100% attained HBV-DNA negativization. Therapy had to be switched from tenofovir-DF to entecavir in 1 patient because of renal impairment. Virological breakthroughs were observed in 1 lamivudine-treated patient, leading to a hepatitis flare; 1 patient on entecavir had a hepatitis flare at immunoreconstitution. Mortality was 33% in the HBsAg-positive group. Seven prophylactic treatments were administered to 6 patients with HBsAg-negative infection: tenofovir-DF in 2 HBV-DNA-positive, lamivudine in 5 HBV-DNA-negative, without reverse HBsAg seroconversion, morbidity or mortality. CONCLUSIONS: There is a residual risk of acute hepatitis B in immunocompromised children, mortality rate was substantial, potentially related to the delays in commencing chemotherapy caused by liver dysfunction. Tenofovir-DF or entecavir are the drugs of choice for HBV treatment in immunocompromised children.

Foreign-body Ingestions in Children During COVID-19 Pandemic in a Pediatric Referral Center.

In February 2020, the COVID-19 pandemic overwhelmed Italy. We retrospectively reviewed all attendances and emergency (A&E) admissions due to foreign-body ingestions (FBIs) to an Italian pediatric referral hospital, from February 24 to April 24, 2020, COVID-19 lockdown and compared them with the same period in the previous 4 years. A total of 101 cases were recorded. Mean age of admission was 4.6 years. Groups did not differ for gender (P = 0.4) or age (P = 0.3). Among FBIs ingestions, 24.0% occurred in children with <2 years of age and 47.5% in children from 2 to 6 years of age. In the 2020 study period, 9 patients were seen for batteries ingestion compared with a median value of one among compared periods. The rates of batteries ingestions increased significantly over the observational period (P < 0.001). We report a dramatic increase in batteries ingestions in children, a potentially fatal event, during the COVID-19 pandemic lockdown.

Fecal calprotectin in the pediatric population: a 2020 update.

Calprotectin is a calcium and zinc-binding protein, formed by a hetero complex of S100A8 and S100A9 proteins, which belong to the S-100 protein family consisting in more than 20 different proteins with a tissue-specific expression pattern. This protein is secreted extracellularly from stimulated neutrophils or released by cell disruption or death. The presence of calprotectin in feces quantitatively relates to neutrophil migration toward the gastrointestinal (GI) tract; thus, it represents a useful marker of intestinal inflammation. Fecal calprotectin (FC) has been proven largely useful for determining the inflammatory origin of GI symptoms differentiating between organic and non-organic diseases. Indeed, increased FC levels are also seen in gastroenteritis, microscopic colitis, polyps, malignancies and cystic fibrosis. To date, there are many evidences regarding usefulness in the detection of fecal calprotectin for the management of gastrointestinal disorders, both in children and adults but, especially in the pediatric population, still clear indications for its use are lacking. Its incorporation in primary care reduces the risk of missing an organic disease and facilitates the indication for expensive and invasive investigations as colonoscopy. We herein review and discuss the last evidence on the usefulness of FC in children, with its current indications and future prospective.

Switching from infliximab originator to a first biosimilar is safe and effective. Results of a case-control study with drug levels and antibodies evaluation.

BACKGROUND: Inflammatory bowel disease is treated with anti-TNF agents such as infliximab and its biosimilars, but use of biosimilars is limited due to perceived risks of adverse events. AIM: To explore safety and effectiveness of switching from the infliximab originator to a first biosimilar. PATIENTS AND METHODS: Clinical and biological outcomes were compared between 53 patients who switched from the infliximab originator to the biosimilar CT-P13 (Switched group) and 13 patients treated with CT-P13 from the beginning (Naïve group). Infliximab trough levels and antidrug antibodies were measured. RESULTS: At enrolment, patients in the Switched group had a longer median duration of infliximab treatment than Naïve (4.0 vs. 0.6 years, p < 0.0001) but similar proportions of patients were in remission (77% and 62%, respectively). Infliximab discontinuation due to adverse events or loss of efficacy was less common in the Switched (26%) than Naïve group (62%, p = 0.017). Variables independently associated with time to discontinuation were disease activity (p < 0.0001) and immunomodulating treatment (p = 0.019) at enrolment. Trough levels and antidrug antibodies were similar between groups during observation. CONCLUSION: This study confirms that switching from infliximab originator to a first biosimilar is safe and effective. Patients at highest risk of losing treatment efficacy are those with active disease, irrespective of the therapeutic switch.

Intraoperative ultrasonography in patients undergoing surgery for Crohn's disease. Prospective evaluation of an innovative approach to optimize staging and treatment planning.

Percutaneous ultrasonography (perc-US) and magnetic resonance enterography (e-MR) are the present standards for staging patients with Crohn's disease (CD). However, intraoperative data still have some discrepancies with preoperative ones. The contribution of intraoperative ultrasonography (IOUS) has never been evaluated. Sixty-five consecutive patients scheduled for ileal/colonic resection for CD between 2010 and 2014 were prospectively enrolled. All patients had perc-US, e-MR and IOUS. Data from different imaging modalities were compared. The reference standard was the final pathology. Surgery was scheduled because of intestinal obstruction (n = 31 patients), inflammatory mass (n = 21), fistula (n = 10), or abdominal pain/sepsis (n = 3). Fourteen (21.5%) patients had a major discrepancy between preoperative and intraoperative data that required a modification of the surgical planning (five additional ileal lesions, three unknown ileo-sigmoid fistulas, and six not confirmed CD sites). IOUS correctly staged CD in all but one patients (missed ileo-colonic fistula). Pathology data differed from Perc-US data in 13 (20%) patients, from e-MR data in 14 (21.5%), and from IOUS data in one (1.5%). The sensitivity of Perc-US, e-MR and IOUS was: for the identification of CD sites 84.2%, 86.1%, and 100%; for the identification of stenoses 86.8%, 86.8%, and 100%; for the identification of fistulas 75.0%, 81.3%, and 93.8%, respectively. IOUS contributed to the surgical planning in 8 (12.3%) patients. IOUS is a safe, feasible and easy-to-perform procedure that optimizes staging of CD and, in some patients, helps to better define the treatment strategy. It could be helpful to face complex disease presentations on the basis of objective and reproducible data.

Role of bowel ultrasound in the management of postoperative Crohn's disease.

The use of biological and immunosuppressive therapy in Crohn's disease (CD) changed favorably the course of the disease and is currently suggested in the prevention of clinical recurrence. Symptomatic exacerbation is a feature of the natural course of the disease. Endoscopic recurrence may occur earlier than clinical manifestations and its rate is still high ever since the first year after surgery. The severity of mucosal lesions is highly predictive of a new flare of the disease so that the early detection of recurrence warrants strong therapeutic changes or a closer monitoring of the case. Endoscopy is at present the gold-standard technique for the diagnosis and grading of recurrence severity, but is poorly accepted by patients for its invasiveness. A simple and easy repeatable examination able to detect early signs of recurrence could be useful in the follow-up as an alternative or as a backing in the choice of the right timing for endoscopy in questionable cases. The use of bowel ultrasound (B-US) in the management of CD has grown in the past twenty years. Its accuracy in the real time detection of the disease and its complications, known since the 80's, together with the non-invasiveness, low cost and wide availability of the technique have influenced the extension of its clinical use in many referral centers in Europe. The latest generation of ultrasound scanners allows a precise and reproducible morphological assessment of the intestinal tract and the surrounding tissues and enables a complete evaluation of the disease. This review analyzes the literature history about B-US in the diagnosis of postoperative recurrence of CD and outlines the clinical implications of its use. Published works confirm a very good accuracy of B-US in the diagnosis of CD recurrence compared to endoscopy, also in the early phase. B-US shows a good correlation with Rutgeert's score grading, but does not prove significant association with C-reactive protein or CD Activity Index values. A wider use of B-US in the daily practice could allow to set a prompt diagnosis and an earlier and targeted treatment, probably sparing more invasive tests.

Referrals for bowel ultrasound in clinical practice: a survey in 12 nationwide centres in Italy.

BACKGROUND: The value of ultrasound (US) in assessing gastrointestinal diseases is well documented, but its demand in clinical practice is unknown. This survey evaluated the demand for bowel US in Italy. METHODS: Twelve sonographers of the Gastroenterology Section of the Italian Society of Ultrasound participated in a 1-month survey; they compiled a questionnaire assessing total number of patients referred for abdominal US and for gastrointestinal tract US, type of referring physician, indications and results of examinations. RESULTS: The survey included 2424 examinations, 586 of which (24%) investigated the gastrointestinal tract: 280 for signs or symptoms and 268 for follow-up of pre-existing gastrointestinal diseases. Referring physicians were mainly gastroenterologists (78%) and general practitioners (13%). Organic lesions were found or suspected in 292 examinations. CONCLUSIONS: Bowel US is used in Italy in routine practice, mainly by gastroenterologists and general practitioners, both for follow-up of pre-existing diseases and for gastrointestinal complaints.

Abdominal bowel ultrasound can predict the risk of surgery in Crohn's disease: proposal of an ultrasonographic score.

OBJECTIVE: Abdominal bowel ultrasound (US) is widely used in the management of Crohn's disease (CD). The aim of this study was to evaluate the prognostic role of bowel-wall US morphology on the short-term risk of surgery. MATERIAL AND METHODS: The 147 CD patients recruited in a case-control study comprised 49 cases operated on within 30 days after US examination and 98 matched non-operated controls. Clinical and US characteristics were analysed. Bowel-wall thickness was recorded, bowel-wall patterns were grouped into five types, but for final analysis they were grouped as "preserved" or "disrupted stratification". RESULTS: Wall thickness and US patterns were significantly different between cases and controls (p<0.0001). A wall thickness >4.5 mm was observed in 45/49 cases and 47/98 controls (OR = 12.21), while "disrupted stratification" was observed in 34/49 cases and 12/98 controls (OR = 16.24). Among the clinical and US characteristics recorded, only 4 US variables were independently associated with surgery (pattern, thickness, presence of fistulae/abscesses and stenoses) and considered for the US score=(2.5*US pattern)+(1.5*Bowel thickness)+(3*Presence of fistulae/abscesses)+(1.5*Presence of stenoses). Based on this score, up to 84% of patients were correctly classified according to actual status (operated/non-operated). CONCLUSIONS: Although it needs further prospective validation, the score we propose seems to be a reliable prognostic marker for the short-term risk of surgery in CD. In particular, the score points out those patients with an impending risk of surgery who need careful and frequent control in order to decide on the right time for surgery.

EUS diagnosis and simultaneous endoscopic retrograde cholangiography treatment of common bile duct stones by using an oblique-viewing echoendoscope.

BACKGROUND: MRCP and EUS have replaced ERCP in the diagnosis of biliary diseases, but the latter is needed for treatment. This study evaluates a new approach in the management of common bile duct stones, by using an oblique-viewing echoendoscope. METHODS: Nineteen patients with acute abdominal pain associated with increased liver tests entered the study. Evaluation of the biliary tree was performed by using an oblique-viewing echoendoscope (JF-UM20; Olympus Europe GmbH, Hamburg, Germany). When biliary stones or sludge were found, bile duct cannulation and sphincterotomy were performed in the same session. RESULTS: Bile duct stones were diagnosed by EUS in 4 patients and biliary sludge in 12; the subsequent cholangiography and sphincterotomy with stone extraction confirmed the diagnosis in all patients. Bile duct cannulation failed in 1 patient. EUS showed features of chronic pancreatitis in 3 cases. The mean time for the whole procedure (EUS plus endoscopic retrograde cholangiography with biliary treatment) was 27 minutes. No procedure-related complications were observed. CONCLUSION: This new approach appears to be feasible and safe, providing an accurate diagnosis and, at the same time, an appropriate treatment of common bile duct stones when needed. With technical improvements, this extended EUS technique could be used as the first-line procedure in patients with biliopancreatic diseases.