Diagnostic Delay of Celiac Disease in Childhood.

Importance: The extent and factors associated with risk of diagnostic delay in pediatric celiac disease (CD) are poorly understood. Objectives: To investigate the diagnostic delay of CD in childhood, and to assess factors associated with this delay. Design, Setting, and Participants: Multicenter, retrospective, cross-sectional study (2010-2019) of pediatric (aged 0-18 years) patients with CD from 13 pediatric tertiary referral centers in Italy. Data were analyzed from January to June 2023. Main Outcomes and Measures: The overall diagnostic delay (ie, the time lapse occurring from the first symptoms or clinical data indicative of CD and the definitive diagnosis), further split into preconsultation and postconsultation diagnostic delay, were described. Univariable and multivariable linear regression models for factors associated with diagnostic delay were fitted. Factors associated with extreme diagnostic delay (ie, 1.5 × 75th percentile) and misdiagnosis were assessed. Results: A total of 3171 patients with CD were included. The mean (SD) age was 6.2 (3.9) years; 2010 patients (63.4%) were female; and 10 patients (0.3%) were Asian, 41 (1.3%) were Northern African, and 3115 (98.3%) were White. The median (IQR) overall diagnostic delay was 5 (2-11) months, and preconsultation and postconsultation diagnostic delay were 2 (0-6) months and 1 (0-3) month, respectively. The median (IQR) extreme overall diagnostic delay (586 cases [18.5%]) was 11 (5-131) months, and the preconsultation and postconsultation delays were 6 (2-120) and 3 (1-131) months, respectively. Patients who had a first diagnosis when aged less than 3 years (650 patients [20.5%]) showed a shorter diagnostic delay, both overall (median [IQR], 4 [1-7] months for patients aged less than 3 years vs 5 [2-12] months for others) and postconsultation (median [IQR], 1 [0-2] month for patients aged less than 3 years vs 2 [0-4] months for others). A shorter delay was registered in male patients, both overall (median [IQR], 4 [1-10] months for male patients vs 5 [2-12] months for female patients) and preconsultation (median [IQR], 1 [0-6] month for male patients vs 2 [0-6] months for female patients). Family history of CD was associated with lower preconsultation delay (odds ratio [OR], 0.59; 95% CI, 0.47-0.74) and lower overall extreme diagnostic delay (OR, 0.75; 95% CI, 0.56-0.99). Neurological symptoms (78 patients [21.5%]; OR, 1.35; 95% CI, 1.03-1.78), gastroesophageal reflux (9 patients [28.1%]; OR, 1.87; 95% CI, 1.02-3.42), and failure to thrive (215 patients [22.6%]; OR, 1.62; 95% CI, 1.31-2.00) showed a more frequent extreme diagnostic delay. A previous misdiagnosis (124 patients [4.0%]) was more frequently associated with gastroesophageal reflux disease, diarrhea, bloating, abdominal pain, constipation, fatigue, osteopenia, and villous atrophy (Marsh 3 classification). Conclusions and Relevance: In this cross-sectional study of pediatric CD, the diagnostic delay was rather short. Some factors associated with risk for longer diagnostic delay and misdiagnosis emerged, and these should be addressed in future studies.

Parents' satisfaction of tele-rehabilitation for children with neurodevelopmental disabilities during the COVID-19 pandemic.

BACKGROUND: The use of tele-rehabilitation in children was limited before the COVID-19 pandemic, due to culture, technology access, regulatory and reimbursement barriers. METHODS: The study was conducted according to the CHERRIES (Checklist for reporting results of internet E-surveys) guidelines in order to provide quantitative and qualitative data about experience of patients with disabilities and their caregivers during Phase 1 of the COVID-19 pandemic, and their level of satisfaction. An online survey was developed using Google Forms and sent via email. The outcome measures were rated using a 5-point Likert Scale. Two additional open-ended questions were used to collect qualitative data. RESULTS: One hundred twenty-eight out of 261 families responded to the survey: 80.5% of the caregivers reported they were satisfied with the tele-rehabilitation. More than a half (53%) of the families reported a high level of satisfaction with the involvement they received in defining and sharing of rehabilitation goals. CONCLUSIONS: The implementation of telehealth during the COVID-19 lockdown has allowed us to gain more information about the potential of tele-rehabilitation, and resulted in an excellent satisfaction of caregivers. With appropriate education and consistent models of care, an increased use of telehealth may provide advances in remote patient care. TRIAL REGISTRATION: Not applicable.

Antibiotic Resistance in Pediatric Infections: Global Emerging Threats, Predicting the Near Future.

Antibiotic resistance is a public health threat of the utmost importance, especially when it comes to children: according to WHO data, infections caused by multidrug resistant bacteria produce 700,000 deaths across all ages, of which around 200,000 are newborns. This surging issue has multipronged roots that are specific to the pediatric age. For instance, the problematic overuse and misuse of antibiotics (for wrong diagnoses and indications, or at wrong dosage) is also fueled by the lack of pediatric-specific data and trials. The ever-evolving nature of this age group also poses another issue: the partly age-dependent changes of a developing system of cytochromes determine a rather diverse population in terms of biochemical characteristics and pharmacokinetics profiles, hard to easily codify in an age- or weight-dependent dosage. The pediatric population is also penalized by the contraindications of tetracyclines and fluoroquinolones, and by congenital malformations which often require repeated hospitalizations and pharmacological and surgical treatments from a very young age. Emerging threats for the pediatric age are MRSA, VRSA, ESBL-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae and the alarming colistin resistance. Urgent actions need to be taken in order to step back from a now likely post-antibiotic era, where simple infections might cause infant death once again.

Clinical manifestations and gastrointestinal pathology in 40 patients with autoimmune enteropathy.

Autoimmune enteropathy (AIE) is a rare condition that may affect pediatric and adult patients, frequently associated with primary immunodeficiencies. We performed a retrospective study on clinical and histological findings from 40 AIE patients. Histological presentation showed a prevalent celiac disease pattern (50%), followed by the mixed pattern (35%), independently of age, chronic active duodenitis (10%), and GVHD-like pattern (5%). Patients with primary immunodeficiencies (24/40) presented mainly with the celiac disease pattern (72.2% versus 22.2%; p < .0001), while patients without primary immunodeficiencies presented with a mixed histological pattern (61.1% versus 13.6%; p < .0001). Our study shows that the prevalent histological presentation is the celiac disease-like pattern, independently of age, and, for the first time, that the histological presentation of AIE differs significantly between patients with and without primary immunodeficiencies. These findings may be helpful for more precise and timely diagnosis and management of this rare disorder.

Efficacy of adalimumab as second-line therapy in a pediatric cohort of Crohn's disease patients who failed infliximab therapy: the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition experience.

BACKGROUND: Adalimumab (Ada) treatment is an available option for pediatric Crohn's disease (CD) and the published experience as rescue therapy is limited. OBJECTIVES: We investigated Ada efficacy in a retrospective, pediatric CD cohort who had failed previous infliximab treatment, with a minimum follow-up of 6 months. METHODS: In this multicenter study, data on demographics, clinical activity, growth, laboratory values (CRP) and adverse events were collected from CD patients during follow-up. Clinical remission (CR) and response were defined with Pediatric CD Activity Index (PCDAI) score ≤10 and a decrease in PCDAI score of ≥12.5 from baseline, respectively. RESULTS: A total of 44 patients were consecutively recruited (mean age 14.8 years): 34 of 44 (77%) had active disease (mean PCDAI score 24.5) at the time of Ada administration, with a mean disease duration of 3.4 (range 0.3-11.2) years. At 6, 12, and 18 months, out of the total of the enrolled population, CR rates were 55%, 78%, and 52%, respectively, with a significant decrease in PCDAI scores (P<0.01) and mean CRP values (mean CRP 5.7 and 2.4 mL/dL, respectively; P<0.01) at the end of follow-up. Steroid-free remission rates, considered as the total number of patients in CR who were not using steroids at the end of this study, were 93%, 95%, and 96% in 44 patients at 6, 12, and 18 months, respectively. No significant differences in growth parameters were detected. In univariate analysis of variables related to Ada efficacy, we found that only a disease duration >2 years was negatively correlated with final PCDAI score (P<0.01). Two serious adverse events were recorded: 1 meningitis and 1 medulloblastoma. CONCLUSION: Our data confirm Ada efficacy in pediatric patients as second-line biological therapy after infliximab failure. Longer-term prospective data are warranted to define general effectiveness and safety in pediatric CD patients.

Pediatric Dehydration Assessment at Triage: Prospective Study on Refilling Time.

PURPOSE: Dehydration is a paediatric medical emergency but there is no single standard parameter to evaluate it at the emergency department. Our aim was to evaluate the reliability and validity of capillary refilling time as a triage parameter to assess dehydration in children. METHODS: This was a prospective pilot cohort study of children who presented to two paediatric emergency departments in Italy, with symptoms of dehydration. Reliability was assessed by comparing the triage nurse's measurements with those obtained by the physician. Validity was demonstrated by using 6 parameters suggestive of dehydration. Comparison between refilling time (RT) and a validated Clinical Dehydration Score (CDS) was also considered. The scale's discriminative ability was evaluated for the outcome of starting intravenous rehydration therapy by using a receiver operating characteristic (ROC) curve. RESULTS: Participants were 242 children. All nurses found easy to elicit the RT after being trained. Interobserver reliability was fair, with a Cohen's kappa of 0.56 (95% confidence interval [CI], 0.41 to 0.70). There was a significant correlation between RT and weight loss percentage (r-squared=-0.27; 95% CI, -0.47 to -0.04). The scale's discriminative ability yielded an area under the ROC curve (AUC) of 0.65 (95% CI, 0.57 to 0.73). We found a similarity between RT AUC and CDS-scale AUC matching the two ROC curves. CONCLUSION: The study showed that RT represents a fast and handy tool to recognize dehydrated children who need a prompt rehydration and may be introduced in the triage line-up.

Novel NOD2 Mutation in Early-Onset Inflammatory Bowel Phenotype.

Background: Nucleotide-binding oligomerization domain 2 (NOD2) is a key intracellular protein of the innate immune system. NOD2 variants are associated with inflammatory bowel disease (IBD) and other inflammatory phenotypes. We described the case of a baby with a very early-onset IBD who is characterized by a rare homozygous variant in NOD2, found through whole-exome sequencing, Its pathogenic effect was investigated through bioinformatics and functional studies. Methods: The microbicide activity of the patient's phagocytes was analyzed using Escherichia coli. HEK293 and Caco2 cell lines were transfected with wild-type and mutated NOD2 cDNA to evaluate the NF-kB activity and the protein distribution. The functionality of the NOD2 pathway was assessed through analysis of the expression of tumor nectrosis factor alpha (TNFα) on monocytes. The levels of various cytokines were quantified in the patient plasma by a multiplex suspension array. Results: A missense NOD2 mutation, c.G1277A; p.R426H in homozygosis, was found. The patient's microbicide activity was comparable to that observed in controls. HEK293 cells transfected with the mutated cDNA showed a 20-fold increase of NF-kB activation in basal condition. Moreover, Caco2 immunostaining revealed a different cytoplasmic distribution of the mutated protein compared with wild-type. A higher production of TNFα by monocytes and elevated levels of plasmatic cytokines and chemokines were evidenced in the patient. Conclusions: This homozygous mutation is functionally relevant and shows a different NOD2 involvement in the IBD phenotype. In our patient, this mutation caused a gain of function typical of the Blau syndrome phenotype, manifesting, however, an IBD-like phenotype.

Clostridium Difficile Infection in Children: A Review.

Clostridium difficile is a sporogenic, anaerobic, Gram-positive, emerging enteric pathogen. It represents the most common cause of health care-associated diarrhoea in the United States, with significantly associated morbidity, mortality, and health care costs. Historically regarded as a little more than an innocent coloniser bystander of the gastrointestinal tract of children, C difficile has increasingly demonstrated its behaviour as a true pathogen in the paediatric age groups. This organism may be responsible for a broad spectrum of diseases in children, ranging from self-limiting secretory diarrhoea to life-threatening conditions, such as pseudomembranous colitis, toxic megacolon, intestinal perforation, and septic shock. The incidence and severity of C difficile infection are, however, not completely understood in this population. In particular, although asymptomatic carriage remains high among infants, the clinical significance of detecting C difficile in children aged 1 to 3 years is not fully understood. Moreover, recent epidemiological surveillance has demonstrated a rise in the incidence of C difficile infection, particularly in the community and in low-risk settings. Interestingly, such cases may not show the disease pattern to be associated with typical risk factors, such as recent exposure to antimicrobial drugs or on-going contacts with the health care system.The purpose of the present review is to present the features of C difficile infection that are unique to paediatric patients and to update paediatricians on information and recommendations regarding C difficile infection in children.

Neonatal Jaundice with Splenomegaly: Not a Common Pick.

The most common conditions causing cholestatic jaundice in infants are biliary atresia, neonatal hepatitis, and Alagille syndrome. In these disorders, the clinical presentation includes jaundice, pale stools, dark urine and hepatomegaly. Splenomegaly is not an early feature since it is due to portal hypertension, a later event. The finding of cholestatic jaundice and a large spleen usually raises the suspicion of Niemann-Pick type C disease (NP-C), a lysosomal storage disorder. We present and discuss here a case of an infant with liver disease and splenomegaly that were not ascribed to NP-C, but to Gaucher disease type 2. Liver biopsy, enzymatic studies and whole exome sequencing allowed to make the diagnosis. Although rare, Gaucher disease can cause neonatal hepatitis. A prompt recognition is advocated.

Community-acquired Clostridium difficile infection in children: A retrospective study.

BACKGROUND: Community acquired-Clostridium difficile infection (CDI) has increased also in children in the last years. AIMS: To determine the incidence of community-acquired CDI and to understand whether Clostridium difficile could be considered a symptom-triggering pathogen in infants. METHODS: A five-year retrospective analysis (January 2007-December 2011) of faecal specimens from 124 children hospitalized in the Niguarda Ca' Granda Hospital for prolonged or muco-haemorrhagic diarrhoea was carried out. Stool samples were evaluated for common infective causes of diarrhoea and for Clostridium difficile toxins. Patients with and without CDI were compared for clinical characteristics and known risk factors for infection. RESULTS: Twenty-two children with CDI were identified in 5 years. An increased incidence of community-acquired CDI was observed, ranging from 0.75 per 1000 hospitalizations in 2007 to 9.8 per 1000 hospitalizations in 2011. Antimicrobial treatment was successful in all 19 children in whom it was administered; 8/22 CDI-positive children were younger than 2 years. No statistically significant differences in clinical presentation were observed between patients with and without CDI, nor in patients with and without risk factors for CDI. CONCLUSIONS: Our study shows that Clostridium difficile infection is increasing and suggests a possible pathogenic role in the first 2 years of life.

Duodenal bulb biopsies in celiac disease: a multicenter study.

OBJECTIVES: Celiac disease (CD)-related lesions have been reported in duodenal bulb biopsies, sometimes the bulb mucosa being the only one affected. The aim was to verify in a significant series whether histological lesions are always present in the bulb of celiac patients, what is the prevalence of lesions when isolated to the bulb, and if similar lesions are present in nonceliac subjects. METHODS: We studied 665 children with CD (241 males, range 9 months-15 years, 8 months), at diagnosis on a gluten-containing diet, and 348 age- and sex-matched gastroenterological controls submitted to upper endoscopy for gastroenterological complaints. During endoscopy, multiple biopsies (1 bulb and 4 distal duodenum samples) were taken. Anti-endomysium antibodies were evaluated by immunofluorescence method, anti-human tissue-transglutaminase antibodies by an enzyme-linked immunosorbent assay or radioimmunoassay. Human leukocyte antigen-DRB1, -DQA1, and -DQB1 genes were typed by polymerase chain reaction sequence-specific primers repeat method. RESULTS: In all of the patients with CD, histological lesions were present in the bulb sample; in 16 of them, the lesions were present only in the bulb. Patchy villous atrophy was found in 20 children. All of the patients with CD were anti-endomysium and/or antitransglutaminase positive. The controls showed neither autoantibody positivity nor mucosal changes compatible with CD. CONCLUSIONS: This study demonstrated that CD-related histological lesions are always present in the bulb; sometimes this specific site is the only one affected. Therefore, we suggest taking 2 biopsies from the bulb and 2 from the distal duodenum for CD diagnosis.

Results from the pediatric European register for treatment of Helicobacter pylori (PERTH).

BACKGROUND AND AIM: Data on the eradication treatment for childhood Helicobacter pylori are scanty. A register was established on the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) website to collect data on treatment performed by European pediatricians to ascertain what is practiced in the field. SUBJECTS: From January 2001 to December 2002, information on 597 children were entered by 23 European Centers, but only data of 518 treated children were completed and analyzed (86.7%, 262 male subjects, median age 9 years, range 1-14). According to their nationality, 226 children were from Southern Europe, 132 from Eastern Europe, 68 from Western Europe, and 4 from northern Europe, 68 from North Africa, and 20 from Asia. At endoscopy, 454 children had gastritis and 64 had ulcer (12.3%). Antibiotic sensitivity, tested in 361 cases, revealed 18% clarithromycin-resistant and 19% metronidazole-resistant H. pylori strains. RESULTS: Treatment was performed for 1 week in 388 and for 2 weeks in 130 children. Antibiotics were associated with proton pump inhibitors (PPI) in 345 and with bismuth in 121 children. Triple therapy was given to 485 children, dual therapy to 26, quadruple to 7. Follow-up data, by (13)C-Urea-Breath Test or histology or both, were available for 480 children. Overall eradication rate was 65.6%, significantly higher in children with ulcer (79.7%) than without (63.9%, p = .001). When given as first treatment, bismuth-containing triple therapies were more efficacious than PPI-containing ones (77% versus 64%, p = .02, OR 1.88, 95% CI 1.1-3.3). Twenty-seven different treatment regimens were used, but only six were administered to at least 18 children (range 18-157). There was no difference between treatments given for 1 or 2 weeks, or given as first or second therapies. CONCLUSION: European pediatricians entering data in the register used 27 different regimens. Bismuth-containing therapies resulted in higher eradication rate. Omeprazole-containing triple therapies were the most used although their efficacy was low. Therapies recommended for adults do not appear to be suitable for children.

A population-based survey on gastrointestinal tract symptoms and Helicobacter pylori infection in children and adolescents.

BACKGROUND: Helicobacter pylori infection is a frequent infection mainly acquired in childhood. Even if the infection is almost invariably associated with mild to severe gastro-duodenal lesions, no specific clinical picture has been identified. The aim of this study was to evaluate the presence of dyspeptic symptoms and their relationship with the presence of H. pylori infection in the first two decades of life. MATERIALS AND METHODS: A school-population sample size of 808 subjects from 6- to 19-year-olds was investigated for the presence of gastrointestinal tract symptoms and evaluated by a 13C-urea breath test for H. pylori infection. The relationship between clinical findings and H. pylori infection was evaluated by chi2 statistic or Fisher's exact test, as appropriate. RESULTS: Symptoms of dyspepsia were identified in 45% of subjects, while the picture of ulcer-like and dysmotility-like forms were present in 3-4%. H. pylori infection was demonstrated in 95 (11.8%) subjects, 49.5% of them without symptoms. Severe epigastric pain and ulcer-like dyspepsia were significantly associated with H. pylori infection, while recurrent abdominal pain or dysmotility-like dyspepsia were not. CONCLUSIONS: Dyspeptic symptoms are frequent in children, and its association with H. pylori infection is more evident than with recurrent abdominal pain. The age at which the infection is acquired seems to be under 6 years of age.