Expression profiles of the lncRNA antisense GAS5-AS1 in colon biopsies from pediatric inflammatory bowel disease patients and its role in regulating sense transcript GAS5.

The long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) level was demonstrated as involved in pediatric inflammatory bowel disease (IBD) pathogenesis. Since its antisense transcript GAS5-AS1 has never been investigated in IBD, this study aims to detect whether GAS5-AS1 and GAS5 levels are related to IBD clinical parameters and investigate their correlation in vitro. Twenty-six IBD pediatric patients were enrolled; paired inflamed and non-inflamed intestinal biopsies were collected. We evaluated GAS5 and GAS5-AS1 levels by real-time PCR. The role of GAS5 and GAS5-AS1 was assessed in vitro by transient silencing in THP1-derived macrophages. GAS5-AS1 and GAS5 levels were associated with patients' clinical parameters; GAS5-AS1 expression was downregulated in inflamed tissues and inversely correlated with disease activity. A positive correlation between GAS5-AS1 and GAS5 levels was observed in non-inflamed biopsies. On THP1-derived macrophages, a reduced amount of both GAS5-AS1 and GAS5 was observed; accordingly, matrix metalloproteinase (MMP) 9 was increased. After GAS5-AS1 silencing, a downregulation of GAS5 was found, whereas no effect was detected on GAS5-AS1 after GAS5 silencing.    Conclusion: This study provided for the first time new insights into the potential role of GAS5-AS1 in IBD. GAS5-AS1 modulates GAS5 levels in vitro and may serve as a potential IBD diagnostic biomarker. What is Known: • GAS5 is involved in regulating intestinal MMP-2 and MMP-9 in pediatric patients with IBD; • GAS5-AS1 has never been investigated in the context of IBD; • GAS5-AS1 regulates the expression of GAS5, increasing its stability in tissues and in vitro cell models of cancer. What is New: • GAS5-AS1 correlated with GAS5 and IBD clinical parameters; • GAS5-AS1 can modulate GAS5 levels in macrophages; • GAS5-AS1 may serve as potential IBD diagnostic biomarker.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in pediatric Inflammatory Bowel Disease: clinical characteristics and outcomes.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in children with inflammatory bowel disease (IBD) has been reported only anecdotally. This study aimed at describing the clinical features and outcomes of children diagnosed with both IBD and HLH/MAS. Data on IBD and HLH/MAS characteristics, biochemical, microbiological and genetic assessments, treatments, and outcomes were collected from the Italian Pediatric IBD Registry and presented using descriptive statistics. Out of 4643 patients with IBD, 18 (0.4%) were diagnosed with HLH/MAS, including 12 with ulcerative colitis and 6 with Crohn disease. Among the 18 patients, 7 (39%) had early-onset IBD, but the median age at HLH/MAS diagnosis was 14.0 years (IQR 11.9-16.0). Half of the patients had active IBD at HLH/MAS diagnosis, 11 (61%) patients were on thiopurines, and 6 (33%) were on anti-TNF biologics. An infectious trigger was identified in 15 (83%) patients. One (5%) patients was diagnosed with XIAP deficiency. All patients discontinued thiopurines and 5 (83.3%) discontinued anti-TNF biologics; 16 (80%) patients received steroids for HLH/MAS. Three (17%) patients had a relapse of HLH/MAS. No patient developed lymphoma or died during a median follow-up of 2.7 years (IQR 0.8-4.4). Conclusions: HLH/MAS mainly affects children with early-onset IBD but primarily develops during adolescence, following an infection while on immunosuppressant treatment. Although the prognosis is generally favorable, it is crucial to investigate an underlying immune deficiency.

Rapid Immunochromatography on Fresh Intestinal Biopsy Is Highly Accurate in Detecting Intestinal Antitransglutaminase Antibodies.

INTRODUCTION: Intestinal antitransglutaminase antibodies (I-anti-TG2) are a specific marker of celiac disease (CeD). The aim of this study was to evaluate the diagnostic accuracy of a novel application of an immunochromatographic assay referred to as Rapid_AntiTG2 to detect I-anti-TG2 on intestinal biopsy lysate. METHODS: Consecutive pediatric patients referred to a single center for elective upper endoscopy were enrolled. Biopsies were taken from duodenal bulb and distal duodenum. For each sampling site, 2 biopsies were analyzed for standard histology, 1 biopsy was cultured to perform the reference standard assay for I-anti-TG2 detection (endomysium [EMA] biopsy), and 1 biopsy was mechanically lysed to perform Rapid_AntiTG2. The primary outcome was the diagnostic accuracy of Rapid_AntiTG2 on biopsy lysate compared with that of the gold standard (serology + histopathology) for CeD diagnosis. The secondary outcome was the agreement of Rapid_AntiTG2 with EMA biopsy. RESULTS: One hundred forty-eight patients were included. Of them, 79 were those with CeD (64 classical CeD, 2 seronegative CeD, and 13 potential CeD) and 69 were controls. Rapid_AntiTG2 on biopsy lysate had very high diagnostic accuracy (sensitivity 100%, specificity 97%, LR+ 34.1, LR- 0.01) in separating patients with CeD from controls. Diagnostic accuracy was unchanged in patients with potential and seronegative CeD. Rapid_AntiTG2 on biopsy lysate had almost perfect agreement with the EMA biopsy reference test (99% agreement, Cohen K 0.97). DISCUSSION: I-anti-TG2 can be detected with an immunochromatographic assay after simple mechanical lysis of fresh intestinal biopsy with very high diagnostic accuracy. The test is quick and easy to perform and can be widely available in any endoscopy unit. Its implementation would allow a better understanding of the prognostic value of I-anti-TG2 and help clinicians in cases of suspected CeD that are difficult to classify.

Celiac Disease Frequency Is Increased in IgE-Mediated Food Allergy and Could Affect Allergy Severity and Resolution.

OBJECTIVES: An increased frequency of celiac disease (CeD) has been reported in severe Immunoglobulin E (IgE) -mediated food allergy (FA). This observation requires confirmation, and whether CeD affects FA severity and resolution is unknown. The study aims to estimate the prevalence of CeD in patients with FA and to investigate whether CeD affects FA severity and oral tolerance. METHODS: Consecutive patients with FA referred for allergen reintroduction, either to evaluate allergy resolution or to start oral immunotherapy (OIT), were evaluated for CeD and for FA severity. The primary outcome was the prevalence of CeD. Secondary outcomes were the frequency of severe FA and the level of clinical tolerance at study entry and at last follow-up in patients with isolated FA versus patients with FA + CeD. RESULTS: Two hundred twenty-eight patients were included. CeD was confirmed in 15 patients (6.6%) of whom, 8 patients had a previously established diagnosis of CeD and were on a gluten-free diet. Severe FA was observed in 12 patients with FA + CeD (80%) versus 88 patients with FA (42%) ( P = 0.006). At baseline, patients with FA + CeD had significantly higher median allergen-specific IgE levels [61.8 kU/L; interquartile range (IQR) 11.6-279.0] compared to patients with FA (20.3 kU/L; IQR 2.9-72.7) ( P < 0.001). Complete clinical tolerance was observed in 1 of 15 patients (7%) with FA + CeD versus 98 of 205 patients (48%) with FA ( P = 0.002). CONCLUSIONS: CeD is highly prevalent in patients with FA and could affect FA severity and response to OIT. CeD screening should be considered in patients with severe or persistent FA.

Dietary Beliefs in Children and Adolescents with Inflammatory Bowel Disease and their Parents.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) may have diet-related beliefs that lead to restrictive dietary behaviours. This study aimed to evaluate dietary beliefs in young patients with IBD and their parents and the presence of restrictive behaviours. METHODS: A questionnaire regarding dietary beliefs was administered to IBD patients aged 8-17 years and their parents. A Food Frequency Questionnaire was administered to patients with IBD and a peer control group. RESULTS: Seventy-five patients and 105 parents were interviewed. Twenty-seven (36%) patients and 39 (37.1%) parents believed that dietary modifications could control the IBD course.Twenty-five (33.0%) patients and 33 (33.0%) parents believe that some dietary components can prevent relapse or improve symptoms (mainly abdominal pain and diarrhoea), while 36 (48%) patients and 60 (60.0%) parents believe that some foods can induce or worsen symptoms during an IBD flare.Patients believe that milk, dairy, fried and spicy foods, sweets and carbonated drinks could have a negative effect on IBD while fruits, vegetables and rice could have a positive impact. Parents believe that fruits and vegetables have a negative effect.Responses did not differ among patients classified according to IBD phenotype, activity status, or current therapies.Compared to controls, young patients with IBD have reduced daily consumption of milk, lunch meat, raw and cooked vegetables. CONCLUSIONS: About one-third of paediatric patients with IBD and their parents have dietary beliefs that lead to restrictive dietary behaviours.

Characteristics and risk factors for SARS-CoV-2 in children tested in the early phase of the pandemic: a cross-sectional study, Italy, 23 February to 24 May 2020.

BackgroundVery few studies describe factors associated with COVID-19 diagnosis in children.AimWe here describe characteristics and risk factors for COVID-19 diagnosis in children tested in 20 paediatric centres across Italy.MethodsWe included cases aged 0-18 years tested between 23 February and 24 May 2020. Our primary analysis focused on children tested because of symptoms/signs suggestive of COVID-19.ResultsAmong 2,494 children tested, 2,148 (86.1%) had symptoms suggestive of COVID-19. Clinical presentation of confirmed COVID-19 cases included besides fever (82.4%) and respiratory signs or symptoms (60.4%) also gastrointestinal (18.2%), neurological (18.9%), cutaneous (3.8%) and other unspecific influenza-like presentations (17.8%). In multivariate analysis, factors significantly associated with SARS-CoV-2 positivity were: exposure history (adjusted odds ratio (AOR): 39.83; 95% confidence interval (CI): 17.52-90.55; p < 0.0001), cardiac disease (AOR: 3.10; 95% CI: 1.19-5.02; p < 0.0001), fever (AOR: 3.05%; 95% CI: 1.67-5.58; p = 0.0003) and anosmia/ageusia (AOR: 4.08; 95% CI: 1.69-9.84; p = 0.002). Among 190 (7.6%) children positive for SARS-CoV-2, only four (2.1%) required respiratory support and two (1.1%) were admitted to intensive care; all recovered.ConclusionRecommendations for SARS-CoV-2 testing in children should consider the evidence of broader clinical features. Exposure history, fever and anosmia/ageusia are strong risk factors in children for positive SARS-CoV-2 testing, while other symptoms did not help discriminate positive from negative individuals. This study confirms that COVID-19 was a mild disease in the general paediatric population in Italy. Further studies are needed to understand risk, clinical spectrum and outcomes of COVID-19 in children with pre-existing conditions.

Intranasal Dexmedetomidine Sedation as Adjuvant Therapy in Acute Asthma Exacerbation With Marked Anxiety and Agitation.

We describe 2 patients with acute asthma exacerbation who were admitted to the emergency department (ED) with severe agitation and restlessness as a prominent finding, for which bedside asthma treatment sedation with intranasal dexmedetomidine was performed. In both cases, dexmedetomidine allowed the patients to rest and improved tolerance to treatment. Dexmedetomidine is a unique sedative with an excellent safety profile and minimal effect on respiratory function. These properties render it particularly promising for the management of severe agitation in children admitted to the ED with acute asthma exacerbation.

Severe neonatal hyperbilirubinemia and UGT1A1 promoter polymorphism.

OBJECTIVE: To assess whether UGT1A1 promoter polymorphisms associated with Gilbert Syndrome (GS) occur with a greater frequency in neonates with severe hyperbilirubinemia. STUDY DESIGN: In a case-control study performed at a single hospital center in Italy, 70 case subjects with severe hyperbilirubinemia (defined as bilirubin level ≥20 mg/dL or 340 µmol/L) and 70 controls (bilirubin level <12 mg/dL or 210 µmol/L) were enrolled. Both case and control subjects were full term newborns. Polymerase chain reaction analysis on blood spot was performed to determine the frequency of UGTA1A1 promoter polymorphisms in cases and controls. RESULTS: No statistical difference in the prevalence of UGTA1A1 gene variants was found between cases and controls (P = 1). Thirteen infants homozygous for (TA)7 polymorphism associated with GS were in the case group (18.6%) and 14 in the control group (20.0%). A heterozygous group was also equally distributed between cases (44.3%) and controls (42.9%). No (TA)8 repeat was found in the 2 groups. CONCLUSIONS: In our study population, GS polymorphism alone does not appear to play a major role in severe neonatal hyperbilirubinemia in neonates without signs of hemolysis.

Characterization of the Gut Microbiota and Mycobiota in Italian Pediatric Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis, often associated with inflammatory bowel diseases. Recent evidence ascribes, together with immunologic and environmental components, a significant role to the intestinal microbiota or its molecules in the PSC pathogenesis. METHODS: By metagenomic sequencing of 16S rRNA and ITS2 loci, we describe the fecal microbiota and mycobiota of 26 pediatric patients affected by PSC and concomitant ulcerative colitis (PSC-UC), 27 patients without PSC but with UC (UC), and 26 healthy subjects (CTRLs). RESULTS: Compared with CTRL, the bacterial and fungal gut dysbiosis was evident for both PSC-UC and UC groups; in particular, Streptococcus, Saccharomyces, Sporobolomyces, Tilletiopsis, and Debaryomyces appeared increased in PSC-UC, whereas Klebsiella, Haemophilus, Enterococcus Collinsella, Piptoporus, Candida, and Hyphodontia in UC. In both patient groups, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma and Malassezia were decreased. Co-occurrence analysis evidenced the lowest number of nodes and edges for fungi networks compared with bacteria. Finally, we identified a specific patient profile, based on liver function tests, bacterial and fungal signatures, that is able to distinguish PSC-UC from UC patients. CONCLUSIONS: We describe the gut microbiota and mycobiota dysbiosis associated to PSC-UC disease. Our results evidenced a gut imbalance, with the reduction of gut commensal microorganisms with stated anti-inflammatory properties (ie, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma, and Malassezia) and the increase of pathobionts (ie, Streptococcus, Saccharomyces, and Debaryomyces) that could be involved in PSC progression. Altogether, these events may concur in the pathophysiology of PSC in the framework of UC.

In this study, we report the gut microbiota and mycobiota dysbiosis in pediatric patients affected by primary sclerosing cholangitis (PSC) associated with ulcerative colitis (UC), with an increase in pro-inflammatory pathobionts and a reduction in anti-inflammatory commensals.

Intestinal Anti-Endomysium Antibodies Are a Useful Tool for Diagnosing Celiac Disease in Pediatric and Adult Patients.

Intestinal anti-endomysium antibodies are a specific marker of celiac disease. The diagnostic accuracy of this marker seems high in pediatric patients and has not yet been investigated in adults, so the aim of this prospective multicentric study was to evaluate the specificity and sensitivity of this marker in childhood and adulthood. Pediatric and adult patients undergoing intestinal endoscopy for any intestinal condition were enrolled. Serological celiac disease markers and HLA type were evaluated in all patients. Intestinal biopsies were analyzed for standard histology and for intestinal anti-endomysium antibodies with biopsy culture assay. In this study, 291 patients (145 adults and 146 children) were included. In the adult population, 34 were diagnosed with celiac disease, 105 were controls, and, in 6, celiac disease was not confirmed. In the pediatric population, 77 were diagnosed with celiac disease, 57 were controls, and, in 12, celiac disease was not confirmed. High diagnostic sensitivity and specificity of intestinal anti-endomysium antibodies were confirmed in children and additionally proven in adults. To conclude, we can affirm that intestinal anti-endomysium antibodies can be detected with high diagnostic accuracy in both children and adults. The implementation of this marker in the diagnostic work-up would help clinicians to correctly identify celiac disease.

Effect of Overweight and Obesity on the Response to Anti-TNF Therapy and Disease Course in Children With IBD.

BACKGROUND: This study aimed to evaluate the effect of overweight and obesity at the start of anti-TNF therapy on treatment response and relapse rate in children with inflammatory bowel disease (IBD). METHODS: This multicenter, retrospective cohort study included 22 IBD centers in 14 countries. Children diagnosed with IBD in whom antitumor necrosis factor (anti-TNF) was introduced were included; those who were overweight/obese were compared with children who were well/undernourished. RESULTS: Six hundred thirty-seven children (370 [58%] males; mean age 11.5 ±â€…3.5 years) were included; 140 (22%) were in the overweight/obese group (OG) and 497 (78%) had BMI ≤1 SD (CG). The mean follow-up time was 141 ±â€…78 weeks (median 117 weeks). There was no difference in the loss of response (LOR) to anti-TNF between groups throughout the follow-up. However, children in OG had more dose escalations than controls. Male sex and lack of concomitant immunomodulators at the start of anti-TNF were risk factors associated with the LOR. There was no difference in the relapse rate in the first year after anti-TNF introduction; however, at the end of the follow-up, the relapse rate was significantly higher in the OG compared with CG (89 [64%] vs 218 [44%], respectively, P < .001). Univariate and multivariate analysis revealed that being overweight/obese, having UC, or being of male sex were factors associated with a higher risk for relapse. CONCLUSIONS: Overweight/obese children with IBD were not at a higher risk of LOR to anti-TNF. Relapse in the first year after anti-TNF was introduced, but risk for relapse was increased at the end of follow-up.

Overweight and obese children with inflammatory bowel disease required more frequent dose escalations, but overall loss of response to anti-TNF therapy was not increased. Furthermore, in the long term, they tend to have a higher risk for relapse.

Infantile and Very Early Onset Inflammatory Bowel Disease: A Multicenter Study.

OBJECTIVES: This study described disease characteristics and long-term outcomes in patients diagnosed with very early onset inflammatory bowel disease (VEOIBD) (diagnosed before 6 years of age) and infantile-IBD (before 2 years). METHODS: Cases from 21 centers worldwide diagnosed with VEOIBD (2008-2018), with minimum 2 years of follow-up, were retrospectively reviewed. RESULTS: The cohort included 243 patients (52% males, median follow-up of 5.8 [range 2-18] years, including 69 [28%]) with infantile-IBD. IBD subtypes included Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU) in 30%, 59%, and 11%, respectively. Among patients with CD, 94% had colonic involvement, and among patients with UC/IBDU, 75% had pancolitis. Patients with infantile-IBD presented with higher rates of IBDU, lower hemoglobin and albumin levels, and higher C-reactive protein, and had lower response rates to first-induction therapy and corticosteroids therapy (P < .05 for all). Colectomy and diversion surgeries were performed in 11% and 4%, respectively, with no significant differences between age groups. Corticosteroid-free remission rates were 74% and 78% after 3 and 5 years, respectively, and 86% at end of follow-up. Genetic testing was performed in 96 (40%) patients. Among tested population, 15 (16%) were identified with monogenic disease. This group demonstrated lower response rates to induction therapies, higher rates of surgical intervention, and higher rates of major infections (P < .05 for all). CONCLUSIONS: Patients with VEOIBD, including infantile-IBD, exhibit low rate of complications and surgical interventions at the long term. Patients with monogenic IBD are at risk for more severe disease course.

Gastrointestinal Disorders and Food Selectivity: Relationship with Sleep and Challenging Behavior in Children with Autism Spectrum Disorder.

The aim of this study was to evaluate the interaction between gastrointestinal (GI) disorders, sleep problems, and challenging behaviors in children with a diagnosis of Autism Spectrum Disorder (ASD) and their effect on parental stress. The secondary objective was to assess the frequency and type of GI and feeding disorders in a sample of children with ASD through a multidisciplinary assessment and, finally, to investigate families' perceptions and satisfaction with the proposed multidisciplinary approach. All children underwent a comprehensive gastroenterological and neuropsychiatric evaluation supported by standardized questionnaires. Pediatric gastroenterologists, specifically trained in Applied Behavior Analysis (ABA), provided advice for parent-delivered behavioral intervention for food selectivity. Thirty-six children with an autism diagnosis (29 males, age 4.5 +/-2.2 years, mean +/- SD) were enrolled. A positive correlation between sleep problems and aggressive behavior was found, and this association was stronger in children experiencing more problematic mealtime behaviors (b = 0.788, p = 0.014). Sleep difficulties were associated with stereotyped behaviors and parent-perceived stress. Parents interviewed about the gastroenterology visit perceived this multidisciplinary approach as helpful in addressing food selectivity. This study shows that sleep and mealtime issues can have a synergistic negative impact on ASD symptoms. A multidisciplinary approach and an integrated assessment of GI, feeding problems, and sleep disorders could be helpful in diagnosing comorbidities and to provide targeted advice to parents.

Gene expression profiling in white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease.

Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon (CRBN), a component of E3 protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, has been identified as the primary target of thalidomide. CRBN plays a crucial role in thalidomide teratogenicity, however it is unclear whether it is also involved in the therapeutic effects in IBD patients. This study aimed at identifying the molecular mechanisms underpinning thalidomide action in pediatric IBD. In this study, ten IBD pediatric patients responsive to thalidomide were prospectively enrolled. RNA-sequencing (RNA-seq) analysis and functional enrichment analysis were carried out on peripheral blood mononuclear cells (PBMC) obtained before and after twelve weeks of treatment with thalidomide. RNA-seq analysis revealed 378 differentially expressed genes before and after treatment with thalidomide. The most deregulated pathways were cytosolic calcium ion concentration, cAMP-mediated signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling also emerged. Connectivity Map analysis revealed that thalidomide gene expression changes were similar to those exposed to MLN4924, an inhibitor of NEDD8 activating enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on the ubiquitin-proteasome pathway. In vitro experiments on cell lines confirmed the effect of thalidomide on candidate altered pathways observed in patients. These results represent a unique resource for enhanced understanding of thalidomide mechanism in pediatric patients with IBD, providing novel potential targets associated with drug response.

Induction of Remission With Exclusive Enteral Nutrition in Children With Crohn's Disease: Determinants of Higher Adherence and Response.

BACKGROUND: Exclusive enteral nutrition (EEN) is the first choice to induce remission and promote mucosal healing in pediatric Crohn's disease (CD). However, full adherence to EEN treatment may be problematic for children with CD. METHODS: The goal of the current multicenter retrospective study was to define predictive factors of nonadherence to treatment and nonremission at the end of induction treatment. Those data together were analyzed with the ultimate goal of trying to define an individualized induction treatment for children with CD. RESULTS: Three hundred seventy-six children with CD from 14 IBD pediatric referral centers were enrolled in the study. The rate of EEN adherence was 89%. Colonic involvement and fecal calprotectin >600 µg/g at diagnosis were found to be associated with a reduced EEN adherence. Exclusive enteral nutrition administered for 8 weeks was effective for inducing clinical remission in 67% of the total cohort. Factors determining lower remission rates were age >15 years and Pediatric Crohn's Disease Activity Index >50. CONCLUSION: Although EEN is extremely effective in promoting disease remission, several patients' related factors may adversely impact EEN adherence and response. Personalized treatments should be proposed that weigh benefits and risks based on the patient's disease location, phenotype, and disease activity and aim to promote a rapid control of inflammation to reduce long-term bowel damage.

Case Report: Refractory Autoimmune Gastritis Responsive to Abatacept in LRBA Deficiency.

Primary immunodeficiency (PID) with immune dysregulation may present with early onset gastrointestinal autoimmune disorders. When gastrointestinal autoimmunity is associated with multiple extraintestinal immune system dysfunction the diagnosis of PID is straightforward. However, with the advent of next generation sequencing technologies, genetic defects in PID genes have been increasingly recognized even when a single or no extraintestinal signs of immune dysregulation are present. A genetic diagnosis is especially important considering the expanding armamentarium of therapies designed to inhibit specific molecular pathways. We describe a boy with early-onset severe, refractory autoimmune gastritis and biallelic mutations in the LRBA gene causing a premature STOP-codon who was successfully treated with CTLA4-Ig, abatacept, with long term clinical and endoscopic remission. The case underscores the importance to consider a monogenetic defect in early onset autoimmune disorders, since the availability of targeted treatments may significantly improve patient prognosis.

Factors associated with quality of life in Italian children and adolescents with IBD.

Improving the quality of life (QoL) is crucial in the management of pediatric inflammatory bowel disease (IBD). We aimed to (1) Validate the IMPACT-III questionnaire in Italian IBD children; (2) explore factors associated to QoL in pediatric IBD. Internal consistency, concurrent validity, discriminant validity and reproducibility of the Italian version of the IMPACT-III questionnaire was measured in IBD children/adolescents in 8 centers. Associations between patient and disease characteristics and the IMPACT-III domains were analyzed through quantile regression analysis. The IMPACT-III questionnaire, collected in 282 children with IBD (median age: 14.8 years; IQR 12.4-16.4) showed a median total score of 76 (IQR 67-83). Female gender, active disease and age were negatively associated with the total IMPACT-III score. Specifically, female gender was negatively associated with the Bowel/Systemic Symptoms, Emotional and Treatment domain scores, while disease activity was significantly associated with Bowel Symptoms and Treatment/Interventions reported QoL. The IMPACT- III showed good internal consistency (Cronbach's alpha coefficient = 0.87, 95% CI 0.85-0.89) and reproducibility (Concordance Correlation Coefficient = 0.66, 95% CI 0.57-0.74). In Italian children with IBD active disease, female gender and adolescence are associated to a worse QoL, indicating the need of more attention in this subgroup of young patients. IMPACT-III questionnaire is a reliable instrument to measure QoL in Italian children.

Recent Insight into SARS-CoV2 Immunopathology and Rationale for Potential Treatment and Preventive Strategies in COVID-19.

As the outbreak of the new coronavirus (SARS-CoV-2) infection is spreading globally, great effort is being made to understand the disease pathogenesis and host factors that predispose to disease progression in an attempt to find a window of opportunity for intervention. In addition to the direct cytopathic effect of the virus, the host hyper-inflammatory response has emerged as a key factor in determining disease severity and mortality. Accumulating clinical observations raised hypotheses to explain why some patients develop more severe disease while others only manifest mild or no symptoms. So far, Covid-19 management remains mainly supportive. However, many researches are underway to clarify the role of antiviral and immunomodulating drugs in changing morbidity and mortality in patients who become severely ill. This review summarizes the current state of knowledge on the interaction between SARS-CoV-2 and the host immune system and discusses recent findings on proposed pharmacologic treatments.

Diagnostic Approach to Monogenic Inflammatory Bowel Disease in Clinical Practice: A Ten-Year Multicentric Experience.

BACKGROUND AND AIMS: Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients' management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis. METHODS: Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008-2017 who underwent a genetic workup were collected. RESULTS: Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT. CONCLUSION: A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients' management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.