Clinical and Laboratory Features of 184 Italian Pediatric Patients Affected with Selective IgA Deficiency (SIgAD): a Longitudinal Single-Center Study.

PURPOSE: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. METHODS: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. RESULTS: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). CONCLUSIONS: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.

Gastrointestinal Pathologic Abnormalities in Pediatric- and Adult-Onset Common Variable Immunodeficiency.

BACKGROUND: Common variable immunodeficiency is the most common form of primary symptomatic immunodeficiency. Gastrointestinal manifestations, such as gastritis, diarrhea, gastrointestinal infections, and malabsorption, may complicate the clinical history in almost 50 % of patients. AIM: To evaluate gastrointestinal histopathological findings in pediatric- and in adult-onset common variable immunodeficiency patients. METHODS: Twenty-two patients with common variable immunodeficiency (13 children, nine adults) were retrospectively studied from a clinical and histopathological point of view. RESULTS: Increased T lymphocyte infiltrate and the absence of plasma cells in duodenal lamina propria and submucosa were the most frequent findings, independently from onset age, whereas follicular lymphoid hyperplasia and polymorphonuclear infiltrate, as well as parasitic and viral infections, were only present in the adult group. Common variable immunodeficiency patients with minor gastrointestinal symptoms also presented pathological findings, mainly the absence of plasma cells, T cell infiltrate, and infections, independently of age. CONCLUSIONS: Gastrointestinal pathological abnormalities are common in both pediatric- and adult-onset common variable immunodeficiency patients. Histological alterations may vary depending upon the age of onset, possibly due to duration of disease. Minor gastrointestinal symptoms are also associated with pathological findings; therefore, these should be searched in all symptomatic patients.

Dilated intercellular spaces in eosinophilic esophagitis.

OBJECTIVES: Dilated intercellular spaces (DIS) in the esophageal epithelium can be induced by acid and reduced by proton pump inhibitors (PPI), and are thus considered a marker of gastroesophageal reflux disease (GERD). Over the years, however, DIS have also been reported in esophagitis unrelated to GERD. Because DIS have never been formally measured in eosinophilic esophagitis (EoE), we aimed at detecting and measuring DIS in EoE before and after nutritional or pharmacological therapy. METHODS: In 22 children with EoE, DIS were measured by morphometry and transmission electron microscopy (TEM), before and after treatment with topical steroids (n = 16) and/or exclusion diet (n = 13). A total of 30 children undergoing upper gastrointestinal endoscopy with biopsy for nonesophageal disorders acted as controls. RESULTS: In controls, the mean (± standard deviation [SD]) number of esophageal eosinophils was 0.91 (± 0.47) and the mean DIS values were 0.62 (± 0.08) µm at morphometry and 0.33 (± 0.24) µm at TEM. In patients with EoE, the mean (± SD) number of esophageal eosinophils decreased from 31.8 (± 6.96) to 6.64 (± 5.01) (P < 0.0001), and the mean DIS values decreased from 2.26 (± 0.21) to 1.23 (± 0.20) µm at morphometry (P < 0.0001), and from 2.24 (± 0.28) to 0.98 (± 0.19) µm at TEM (P < 0.0001), respectively, before and after treatment. CONCLUSIONS: DIS are a prominent morphological feature of EoE, in which they can be significantly reduced by an appropriate non-PPI therapy.

Disease course of ulcerative proctitis in children: A population-based study on behalf of the SIGENP IBD Group.

BACKGROUND: The natural history of ulcerative proctitis (UP) has been poorly investigated in children. AIMS: We aimed to compare the disease course of children with UP at diagnosis to the other locations and to identify extension predictors. METHODS: This was a multicenter, observational study carried out from data prospectively entered in the SIGENP-IBD-Registry. Children with ulcerative colitis (UC) diagnosis and at least 1-year follow-up were included. On the basis of Paris classification UP patients were identified and compared with the other locations. RESULTS: 872 children were enrolled (median age at diagnosis: 11.2 years; M/F: 426/446), of whom 78 (9%) with UP. Kaplan-Meier analysis demonstrated increased cumulative probabilities of disease extension in the E1 group [1 year: 20.3%; 5 years: 52.7%; 10 years: 72.4%] compared to E3 group [1 year: 8.5%; 5 years: 24.9% and 10 years: 60.1%, p=0.001]. No differences were observed comparing E1 and E2 groups [p=0.4]. Cumulative probabilities of surgery at 1, 5 and 10 years were 1.3, 2.8 and 2.8% in the E1 group and 2.5, 8 and 12.8% in the E2-E3-E4 group, respectively (p=0.1). Cox regression analysis demonstrated that PUCAI>35 at diagnosis was associated with endoscopic extension (HR=4.9; CI 95% 1.5-15.2, p=0.006). CONCLUSIONS: UP is associated with similar short and long-term outcomes compared to other locations.

Treatment with an ileal bile acid transporter inhibitor in patients with TJP2 deficiency.

There are no published data on the use of odevixibat, a selective ileal bile acid transporter (IBAT) inhibitor, in children with tight junction protein 2 (TJP2) deficiency (also named as PFIC-4). We describe a case series of five children treated with odevixibat. After treatment, serum bile acids (sBA) decreased compared to baseline [mean value: 244 (±125), vs 38 (±34) µmol/L; p = 0.007]; reduction in sBA was >70% from baseline (or <70 µmol/L) in all. Improvements in pruritus were reported in all patients. The drug was well tolerated. IBAT inhibitors should be considered a valuable treatment option in patients with TJP2 deficiency.

Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group.

Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

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.

Phenotype and Natural History of Children With Coexistent Inflammatory Bowel Disease and Celiac Disease.

BACKGROUND: Adult patients with both inflammatory bowel disease (IBD) and celiac disease (CeD) have peculiar phenotypic features. This study aimed at describing the characteristics and natural history of children with both IBD and CeD. METHODS: This was a case-control study based on a national registry. Cases included children diagnosed with both IBD and CeD. Two matched IBD controls without CeD, and 2 matched CeD controls were selected for each case. Inflammatory bowel disease phenotype and natural history, comprising growth and pubertal development, were compared between groups. RESULTS: Forty-nine (1.75%) patients with IBD and CeD were identified out of 2800 patients with IBD. Compared with patients with IBD alone, patients with IBD and CeD presented more frequently with autoimmune diseases (odds ratio, 2.81; 95% CI, 0.97-8.37; P = 0.04). Ileocolonic localization (46.1% vs 73.1%), treatment with azathioprine (46.2% vs 71.2%), and anti-TNF biologics (46.2% vs 69.2%) were less common in patients with Crohn's disease and CeD than in patients with Crohn's disease alone. Patients with ulcerative colitis and CeD had an increased risk of colectomy despite similar medical treatments compared with patients with ulcerative colitis alone (13.0% vs 0%). Pubertal delay was more common in patients with IBD and CeD compared with patients with IBD alone (14.9% vs 3.2%; odds artio, 5.24; 95% CI, 1.13-33.0; P = 0.02) and CeD alone (14.9% vs 1.1%; P = 0.002). CONCLUSIONS: Children with IBD and CeD may have peculiar features with a higher risk for autoimmune diseases, colectomy, and pubertal delay compared with IBD alone.

Management of paediatric IBD after the peak of COVID-19 pandemic in Italy: A position paper on behalf of the SIGENP IBD working group.

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2, spreading in Italy during the first months of 2020, abruptly changed the way of practicing medicine in this country. As a consequence of the lockdown, the diagnostic and therapeutic management of paediatric chronic conditions, such as inflammatory bowel disease (IBD) has been affected. During the peak of COVID-19 pandemic, elective visits, endoscopies and infusions have been postponed, with potential clinical and psychological impact on disease course and a high likelihood of increasing waiting lists. While slowly moving back towards normality, clinicians need to recognize the best ways to care for patients with IBD, carefully avoiding risk factors for new potential epidemic outbreaks. In this uncertain scenario until the development and spread of COVID-19 vaccine, it is necessary to continue to operate with caution. Hereby we provide useful indications for a safer and gradual restarting of routine clinical activities after COVID-19 peak in Italy.

Impact of COVID-19 pandemic on the management of paediatric inflammatory bowel disease: An Italian multicentre study on behalf of the SIGENP IBD Group.

BACKGROUND: IBD management has been significantly affected during the COVID-19 lockdown with potential clinical issues. AIMS: The aim of this study was to analyse the impact of COVID-19 pandemic on the Italian paediatric IBD cohort. METHODS: This was a multicentre, retrospective, cohort investigation including 21 different Italian IBD referral centres. An electronic data collection was performed among the participating centres including: clinical characteristics of IBD patients, number of COVID-19 cases and clinical outcomes, disease management during the lockdown and the previous 9 weeks. RESULTS: 2291 children affected by IBD were enrolled. We experienced a significant reduction of the hospital admissions [604/2291 (26.3%) vs 1281/2291 (55.9%); p < 0.001]. More specifically, we observed a reduction of hospitalizations for new diagnosis (from n = 44 to n = 27) and endoscopic re-evaluations (from n = 46 to n = 8). Hospitalization for relapses and surgical procedures remained substantially unchanged. Biologic infusions did not significantly vary [393/2291 (17.1%) vs 368/2291 (16%); p = 0.3]. Telemedicine services for children with IBD were activated in 52.3% of the centres. In 42/2291(1.8%) children immunosuppressive therapies were adapted due to the concurrent COVID-19 pandemic. CONCLUSION: Due to the several limitations of the lockdown, cares for children with IBD have been kept to minimal standards, giving priorities to the urgencies and to biologics' infusions and implementing telemedicine services.

Genetic Variants Assessing Crohn's Disease Pattern in Pediatric Inflammatory Bowel Disease Patients by a Clinical Exome Survey.

BACKGROUND: Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Recent discoveries have brought much attention to the genetic predisposition of patients with IBD. Here we evaluate the interaction between IBD genetic risk factors susceptibility and CD occurrence in an IBD pediatric patient population, performing a clinical exome survey. METHODS: From February 2018 to April 2019, we collected blood samples from 7 pediatric patients with IBD concerns from several collaborating health centers and/or hospitals. Blood samples were processed by extracting and sequencing DNA for a clinical exome survey. Shophia-DDM-v3-4 platform allowed sequenced reads alignment on hg19 genome as well as genetic variant calling. Both IBD risk and pathogenic genetic variants covered by at least 20 reads were selected for subjacent analysis. RESULTS: Normality and Bartlett tests of both risk and pathogenic genetic variants suggested random and heterogeneous distribution of these variants in this group of IBD pediatric patients. P value clustering analysis by processing 157 IBD risk factors revealed genetic heterogeneity in IBD population and suggested two pathways influencing IBD development. In particular, (1) genetic variants associated with autoimmune and (2) metabolic diseases and CD risk factors (rs2066844 and rs2241880 single nucleotide polymorphism variants, respectively, of genes NOD2 and ATG16L) were identified in distinct clusters of IBD patients (P < .05). Moreover, the heterogeneous distribution of the following variants rs10065172 (IRGM), rs1805010 (IL4R), rs5030737 (MBL2), and rs33995883 (LRRK2) in this group of IBD patients was consistent with their random distribution in that population. CONCLUSION: Our study revealed specific genetic variants linked to CD susceptibility, autoimmune and/or innate immunodeficiency as well as to metabolic defects, as favoring factors of IBD, suggesting the valuable role of next generation sequencing (NGS) approaches in IBD molecular diagnostic procedures.

[Acute hepatitis as a side effect of albendazole: a pediatric case]. / Epatite acuta itterica da albendazolo: un caso pediatrico.

We describe a case of acute hepatitis with jaundice in a patient of seven years of age in oral treatment with albendazole; a mild increase of liver function tests is a well-known side effect after prolonged administration but acute hepatitis has never been described in childhood.

[Acute hepatitis as a side effect of albendazole: a pediatric case]. / Epatite acuta itterica da Albendazolo: un caso pediatrico.

We describe a case of acute hepatitis with jaundice in a patient of seven years of age in oral treatment with albendazole; a mild increase of liver function tests is a well-known side effect after prolonged administration but acute hepatitis has never been described in childhood.

Dietary protein-induced proctocolitis in childhood.

Cow's milk protein-induced proctocolitis presents with overt rectal bleeding in otherwise healthy infants and is characterized by an eosinophilic infiltrate of the left colonic mucosa. Although it is the most common cause of proctocolitis in infancy, dietary protein-induced proctocolitis had hardly ever been reported in childhood so far. We hereby report 16 otherwise healthy children aged 2-14 yr, who presented over a 6-yr period with persistent or recurrent rectal bleeding related to a mild form of left-sided colitis characterized by a prominent eosinophilic infiltration, focal lymphoid follicle hyperplasia, and a prompt clinical and histological response to a cow's milk-free diet. No patient had a history of food-induced proctocolitis during infancy, and most patients did not show an IgE-mediated response to cow's milk protein. Half of the patients did have other gastrointestinal symptoms, but no systemic symptoms were present and other causes of colitis were excluded by appropriate investigation. Tolerance to cow's milk protein developed in half of the patients within a year. Dietary protein-induced proctocolitis is a relatively common cause of overt rectal bleeding in childhood, and its features are remarkably similar to those of dietary protein-induced proctocolitis of infancy.

Growth retardation and reduced growth hormone secretion in cystic fibrosis. Clinical observations from three CF centers.

OBJECTIVE: Growth delay in cystic fibrosis is frequent and is usually the result of several interacting causes. It most often derives from severe respiratory impairment and severe malabsorption. There are however patients whose clinical condition is not severe enough to be held accountable for this phenomenon. We aimed at describing patients who showed growth delay, who were not affected by severe pulmonary disease or malabsorption and who, when tested, showed a reduced GH secretion after stimulation with conventional agents. We noticed a disproportionately large prevalence of growth hormone (GH) release deficit (GHRD) in pediatric cystic fibrosis (CF) patients. PATIENTS AND METHODS: We examined all patients under our care in the period 2006-11, who were older than 5 and younger than 16 years old. We focussed on those who fell below the 3rd height percentile, or whose growth during the previous 18 months faltered by >2SD, and who did not present clinical conditions that could reasonably explain their failure to thrive. These patients were subjected to standard GH provocative tests. RESULTS: Out of 285 who matched the age criterion, 33 patients also matched the height percentile criterion. While 15/33 suffered clinical conditions that could reasonably explain their failure to thrive, 18/33 underwent GH release provocative tests and 12/18 showed a release deficit. CONCLUSIONS: We conclude that impaired GH secretion is more frequent among CF patients compared to the prevalence of GH deficiency in the general population and that GH release impairment may be an independent cause of growth delay in CF. Our findings are in agreement with recent studies that have described low GH levels in CF piglets and in neonates with CF [1].