Celiac disease (CD) is a multisystem disease in which different organs may be affected. We investigate whether circulating innate lymphoid cells (ILCs) contribute to the CD peripheral inflammatory ...status. We find that the CD cytokine profile is characterized by high concentrations of IL-12p40, IL-18, and IFN-γ, paralleled by an expansion of ILC precursors (ILCPs). In the presence of the gliadin peptides p31–43 and pα-9, ILCPs from CD patients increase transglutaminase 2 (TG2) expression, produce IL-18 and IFN-γ, and stimulate CD4+ T lymphocytes. IFN-γ is also produced upon stimulation with IL-12p40 and IL-18 and is inhibited by the addition of vitamin D. Low levels of blood vitamin D correlate with high IFN-γ and ILCP presence and mark the CD population mostly affected by extraintestinal symptoms. Dietary vitamin D supplementation appears to be an interesting therapeutic approach to dampen ILCP-mediated IFN-γ production.
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•ILCPs are enriched in the peripheral blood of celiac patients•ILCPs react to gliadin peptides by producing cytokines and stimulating T cells•ILCP production of IFN-γ can be inhibited by vitamin D•High IFN-γ and low vitamin D correlate with more extraintestinal symptoms
Ercolano et al. illustrate how gliadin peptide-driven ILCP activation contributes to the peripheral, extraintestinal inflammation characterizing celiac patients. ILCP activation is dampened by vitamin D, which is low in patients experiencing severe systemic inflammation and showing more extraintestinal symptoms.
The diagnosis of cow's milk allergy (CMA) is particularly challenging in infants, especially with non-Immunoglobulin E (IgE)-mediated manifestations, and inaccurate diagnosis may lead to unnecessary ...dietary restrictions. The aim of this study was to assess the accuracy of the cow's milk-related symptom score (CoMiSS
) in response to a cow's milk-free diet (CMFD). We prospectively recruited 47 infants (median age three months) who had been placed on a CMFD due to persisting unexplained gastrointestinal symptoms. We compared data with 94 healthy controls (median age three months). The CoMiSS
score was completed at recruitment and while on the exclusion diet. In 19/47 (40%) cases a response to the diet occurred. At recruitment CoMiSS
was significantly higher in cases compared to controls (median score 8 vs. 3;
-value: <0.05), 9 cases had a score ≥12 and 8/9 normalized on CMFD. An oral milk challenge was performed in all 19 responders and six of these had a positive reaction to cow's milk (CM). In eight infants IgE allergy tests were positive. The receiver operation characteristic (ROC) curve identified a CoMISS
score of 9 to be the best cut-off value (84% sensitivity, 85% specificity, 80% positive (PPV) and 88% negative predictive value (NPV)) for the response to CMFD. We found CoMiSS
to be a useful tool to help identify infants with persisting gastrointestinal symptoms and suspected CMA that would benefit from CMFD.
Oral ferrous salts are standard treatment for children with iron deficiency anemia (IDA). The objective of our study was to monitor oral iron therapy in children, aged 3 months–12 years, with IDA. We ...prospectively collected clinical and hematological data of children with IDA, from 15 AIEOP (Associazione Italiana di Ematologia ed. Oncologia Pediatrica) centers. Response was measured by the increase of Hb from baseline. Of the 107 analyzed patients, 18 received ferrous gluconate/sulfate 2 mg/kg (ferrous 2), 7 ferrous gluconate/sulfate 4 mg/kg (ferrous 4), 7 ferric iron salts 2 mg/kg (ferric), 62 bis-glycinate iron 0.45 mg/kg (glycinate), and 13 liposomal iron 0.7–1.4 mg/kg (liposomal). Increase in reticulocytes was evident at 3 days, while Hb increase appeared at 2 weeks. Gain of Hb at 2 and 8 weeks revealed a higher median increase in both ferrous 2 and ferrous 4 groups. Gastro-intestinal side effects were reported in 16% (ferrous 2), 14% (ferrous 4), 6% (glycinate), and 0 (ferric and liposomal) patients. The reticulocyte counts significantly increased after 3 days from the start of oral iron supplementation. Bis-glycinate iron formulation had a good efficacy/safety profile and offers an acceptable alternative to ferrous iron preparations.
Patients with Down syndrome (DS) are characterized by increased susceptibility to autoimmunity and respiratory tract infections that are suggestive of humoral immunity impairment. Here, we sought to ...determine the follicular helper (Tfh) and follicular regulatory (Tfr) T cell profile in the blood of children with DS. Blood was collected from 24 children with DS, nine of which had autoimmune diseases. Children with DS showed skewed Tfh differentiation towards the CXCR3
+
phenotype: Tfh1 and Tfh1/17 subsets were increased, while Tfh2 and Tfh17 subsets were reduced. While no differences in the percentage of Tfr cells were seen, the ratio of Tfh1 and CXCR3
+
PD-1
+
subsets to Tfr cells was significantly increased in the affected children. The excessive polarization towards a CXCR3
+
phenotype in children with DS suggests that re-calibration of Tfh subset skewing could potentially offer new therapeutic opportunities for these patients.
Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, ...diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
Inherited thrombocytopenias (ITs) are rare congenital bleeding disorders characterized by different clinical expression and variable prognosis. ITs are poorly known by clinicians and often ...misdiagnosed with most common forms of thrombocytopenia.
"CHildren with Inherited Platelet disorders Surveillance" study (CHIPS) is a retrospective - prospective observational cohort study conducted between January 2003 and January 2022 in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). The primary objective of this study was to collect clinical and laboratory data on Italian pediatric patients with inherited thrombocytopenias. Secondary objectives were to calculate prevalence of ITs in Italian pediatric population and to assess frequency and genotype-phenotype correlation of different types of mutations in our study cohort.
A total of 139 children, with ITs (82 male - 57 female) were enrolled. ITs prevalence in Italy ranged from 0.7 per 100,000 children during 2010 to 2 per 100,000 children during 2022. The median time between the onset of thrombocytopenia and the diagnosis of ITs was 1 years (range 0 - 18 years). A family history of thrombocytopenia has been reported in 90 patients (65%). Among 139 children with ITs, in 73 (53%) children almost one defective gene has been identified. In 61 patients a pathogenic mutation has been identified. Among them, 2 patients also carry a variant of uncertain significance (VUS), and 4 others harbour 2 VUS variants. VUS variants were identified in further 8 patients (6%), 4 of which carry more than one variant VUS. Three patients (2%) had a likely pathogenic variant while in 1 patient (1%) a variant was identified that was initially given an uncertain significance but was later classified as benign. In addition, in 17 patients the genetic diagnosis is not available, but their family history and clinical/laboratory features strongly suggest the presence of a specific genetic cause. In 49 children (35%) no genetic defect were identified. In ninetyseven patients (70%), thrombocytopenia was not associated with other clinically apparent disorders. However, 42 children (30%) had one or more additional clinical alterations.
Our study provides a descriptive collection of ITs in the pediatric Italian population.
The association between inflammatory bowel disease (IBD) and immune thrombocytopenia (ITP) is still uncertain. In this multicenter retrospective study, the coexistence of both diseases was ...investigated in children diagnosed from 1 January 2000 to 31 December 2019.
Clinical characteristics of both IBD and ITP, onset of disorders, and patient's response to treatment were collected through a structured form sent to 55 Italian pediatric referring centers for hematological disorders.
Centers responded to the survey and reported the coexistence of IBD and ITP in 14 children. The first diagnosis was ITP in 57.1% and IBD in 35.7% of patients: it was simultaneous in 7.1%. IBD was classified as ulcerative colitis (57.1%), Crohn disease (35.7%), and unclassified (7.1%). No therapy for IBD other than steroids had any effect on ITP course. Colectomy resulted in recovery from ITP in 1 of the 2 patients surgically treated. ITP was always mild but turned to be chronic in half of patients.
In all patients, ITP was mild without any evident impact on IBD severity, but the incidence of chronic ITP seems to be higher than what is usually observed in the pediatric age group. Colectomy had unpredictable effects on ITP.
The association between celiac disease (CD) and immune thrombocytopenia (ITP) is still uncertain. The aim of this study was to characterize the coexistence of these two diseases in Italian children.
...This is a retrospective multicenter study investigating the occurrence of CD in 28 children with ITP diagnosed from January 1, 2000, to December 31, 2019.
The first diagnosis was ITP in 57.1% and CD in 32.1% of patients. In 3 patients (10.7%), the two diagnoses were simultaneous. All the potential and silent cases of CD in our cohort were diagnosed in the groups of “ITP first” and “simultaneous diagnosis”. In all children ITP was mild, and in 2 out of 8 not recovered from ITP at the time of CD diagnosis a normalization of platelet counts (>100,000/μL) occurred 3 and 5 months after starting a gluten-free diet, respectively.
We think that screening for CD should be considered in children with ITP regardless of the presence of gastrointestinal symptoms. Furthermore, some patients may recover from ITP after starting a gluten-free diet.
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