Fatigue perception in a cohort of children with chronic immune thrombocytopenia and their caregivers using the PedsQL MFS: Real-life multicenter experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP).

BACKGROUND: Fatigue is an important clinical and psychological aspect for a significant number of children affected by immune thrombocytopenia (ITP). To date, few studies have explored fatigue and its relationship with chronic ITP in pediatric age. The aim of the present multicentric pilot study is to determine fatigue perception in a large group of children with chronic ITP and their caregivers using the PedsQL Multidimensional Fatigue Scale (PedsQL MFS), and to compare the results with those of healthy control subjects. PROCEDURE: Children with chronic ITP aged 5-18 years and/or caregivers of children aged 2-18 years were enrolled. Child/adolescent self-report was used for patients aged 5-18 years, and parent proxy-report for patients aged 2-18 years. The questionnaire was offered as online survey. PedsQL MFS is composed of 18 items covering three dimensions: General Fatigue Scale, Sleep/Rest Fatigue Scale, and Cognitive Fatigue Scale. RESULTS: One hundred ninety-one patients affected by chronic ITP and 248 caregivers answered the PedsQL MFS. We have highlighted that lower values of PedsQL MFS scores are obtained in the 13-18 age group. Moreover, sleep/rest fatigue domain appears to be more compromised in all age groups. For all PedsQL MFS scores, pediatric patients with chronic ITP and their caregivers reported statistically significant worse fatigue than healthy children. CONCLUSIONS: This study suggests that fatigue is relevant among children and adolescents affected by chronic ITP. The PedsQL MFS represents an adequate instrument for measuring fatigue in patients with chronic ITP. Therefore, symptoms of fatigue should be routinely assessed in clinical practice.

Biweekly Hizentra® in Primary Immunodeficiency: a Multicenter, Observational Cohort Study (IBIS).

Immunoglobulin G (IgG) replacement therapy is a standard treatment for patients with primary immunodeficiency diseases (PIDs). Hizentra®, a 20% human subcutaneous IgG (SCIG), is approved for biweekly administration for PIDs. The aim of the multicenter IBIS study was to prospectively investigate the efficacy of biweekly Hizentra® compared with previous IVIG or SCIG treatment regimens in patients with PIDs. The study consisted of a 12-month retrospective period followed by 12-month prospective observational period. The main endpoints included pre-infusion IgG concentrations, proportion of patients with serious bacterial infections (SBIs), other infections, hospitalizations due to PID-related illnesses, and days with antibiotics during the study periods. Of the 36 patients enrolled in the study, 35 patients continued the study (mean age 26.1 ± 14.4 years; 68.6% male). The mean pre-infusion IgG levels for prior immunoglobulin regimens during the retrospective period (7.84 ± 2.09 g/L) and the prospective period (8.55 ± 1.76 g/L) did not show any significant variations (p = 0.4964). The mean annual rate of SBIs/patient was 0.063 ± 0.246 for both prospective and retrospective periods. No hospitalizations related to PIDs were reported during the prospective period versus one in the retrospective period. All patients were either very (76.5%) or quite (23.5%) satisfied with biweekly Hizentra® at the end of the study. In conclusion, the IBIS study provided real-world evidence on the efficacy of biweekly Hizentra® in patients with PIDs, thus verifying the data generated by the pharmacometric modeling and simulation study in a normal clinical setting.

Long term use of eltrombopag in children with chronic immune thrombocytopenia: extended real life retrospective multicenter experience of the Italian Association of Pediatric Hematology and Oncology.

Background: The present multicenter retrospective study on eltrombopag administration in Italian children with chronic ITP aims to extend follow-up of our previous study. Materials and methods: This retrospective multicenter study was conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). Patients were classified into three subgroups: group 1 included patients who discontinued treatment due to a stable platelet count; group 2 included patients who discontinued treatment due to ineffectiveness; group 3 included patients who did not permanently discontinue treatment. Results: 56 patients were eligible for analysis. The median duration of eltrombopag treatment was 40 months (7-71 months). Twenty patients (36%) discontinued permanently eltrombopag. The reasons of permanent discontinuation were adverse effects (n = 1), inefficacy (n = 10), stable platelet count (n = 9). All patients of group 1 maintained a durable response without additional treatments after eltrombopag discontinuation. We found that patients of group 2 were on treatment for less time (median treatment time: 13.5 months, min: 6.0 - max: 56.0) than patients of group 1 (median treatment time: 34 months, min: 16.0 - max: 62.0) (p < 0.05). Patients of group 2 mostly did not achieve a stable platelet count in the first 6 months of treatment and underwent concomitant therapies during follow-up respect of group 1 and group 3 (p < 0.01). Conclusion: Our study found that the benefits of eltrombopag treatment, in terms of platelet count improvement and use of additional therapies, are identifiable from the first 6 months of treatment.

Quick drop of platelet counts in children with chronic immune thrombocytopenia after COVID-19 mRNA vaccination: case reports.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia. Many viruses and some vaccines have been identified as triggering the autoimmune process, including parvovirus, human immunodeficiency virus, Epstein-Barr virus, rubella, and measles. However, ITP in association with coronavirus disease 2019 (COVID-19) vaccination has not been reported so far. We describe the cases of two young girls affected by ITP presenting a quick reduction of platelet count after receiving Pfizer-BioNTech COVID-19 vaccine.

Successful Eltrombopag Therapy in a Child with MYH9-Related Inherited Thrombocytopenia.

Inherited thrombocytopenias represents a heterogenous group of diseases characterized by a congenital reduction in the platelet count that could lead to a bleeding tendency. MYH9-related disorders are characterized by large platelets and congenital thrombocytopenia. Thrombopoietin-receptor agonists: eltrombopag and romiplostim are currently approved in many countries for the treatment of different forms of acquired thrombocytopenia, such as immune thrombocytopenia. We report, instead, the successful use of eltrombopag to treat inherited thrombocytopenia in a patient with an MHY9-related disease. This is the first report of a chronic use of eltrombopag to elevate platelets in MYH9-related disorders without side effects.

Eligibility for competitive sport medical certification of children with severe hemophilia: Italian observational study.

Background ad aim of workː the position of Italian law regarding participation of prophylactically treated hemophiliacs to organized sport trainings and competitions remains unclear and this study focuses on the eligibility of pediatric patients in particular. Methodsː 16 patients age 3 to 15 years old, with severe haemophilia and prophylaxis starting age of 20,2 ± 2,2 months were enrolled. Weight, height, body mass index (BMI) and joint status (Hemophilia Joint Health Score [HJHS] and Haemophilia Early Arthropathy Detection with UltraSound, HEAD-US score) of patients were evaluated at start (T0) and after 12 months (T12) of a HIITS sport activity program. Resultsː All patients qualified for Italian competitive sport medical certification. Their weight and height increased after 12 months, without an increase in BMI (T0= 17,2; T1= 18,7; p>0,05). HJHS score did not change significantly (T0: 1.6 ± 1; T1: 2.1 ± 1.3; p>0.05). All children were right-handed and atrophy for the muscles of the right elbow significantly decreased (no atrophy seen at T0 in 4 of 16 patients and at T1 in 8 of 16 patients; p=0.045). Conclusionsː Hemophilic children, prophylactically treated, are capable to be included in sport groups and physical activity programs.

"CHildren with Inherited Platelet disorders Surveillance" (CHIPS) retrospective and prospective observational cohort study by Italian Association of Pediatric Hematology and Oncology (AIEOP).

Background: 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. Material and methods: "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. Results: 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. Conclusion: Our study provides a descriptive collection of ITs in the pediatric Italian population.

The risk of venipuncture in newborn with severe hemophilia: Case report of a large elbow hemorrhage and literature review of compartment syndrome.

Hemophilias are hemorrhagic congenital rare diseases. The gold standard of therapy in hemophilics is the intravenously replacement therapy. We can infuse intravenously plasma derived factors (FVIII for Hemophilia A and FIX for Hemophilia B) or recombinant products (i.e. clotting factor synthetically produced). Venipuncture is not a safe procedure in subjects with hemorrhagic diseases. It is considered an invasive technique with potential massive bleeding and it requires standardized procedures to prevent complications. Local pressure after the procedure (with eventually ice rest) must be always done. In case of bleeding a rapid replacement therapy must be conducted. A severe complication in hemophilia is compartment syndrome. We report a case of massive bleeding in a hemophilic newborn after venipuncture and a literature review of compartment syndrome in hemophiliacs. The aim of this paper is to help physicians in the clinical management to prevent the evolution of a massive bleeding in compartment syndrome.

Focus on MicroRNAs as Biomarker in Pediatric Diseases.

BACKGROUND: MiRNAs are a class of small non-coding RNAs that are involved in the post-transcriptional regulation of gene expression. MiRNAs are considered a class of epigenetic biomarkers. These biomarkers can investigate disease at different stages: diagnosis, therapy or clinical follow-up. OBJECTIVE: The aim of this paper is to highlight the innovative use of miRNAs in several childhood diseases. METHODS: We conducted a literature review to search the usage of miRNAs in pediatric clinical routine or experimental trials. RESULTS: We found a possible key role of miRNAs in different pediatric illnesses (metabolic alterations, coagulation defects, cancer). CONCLUSION: The modest literature production denotes that further investigation is needed to assess and validate the promising role of miRNAs as non-invasive biomarkers in pediatric disorders.

Psychophysical health and perception of well-being between master badminton athletes and the adult Italian population.

BACKGROUND AND AIM OF THE WORK: Sport participation, regular exercise and physical activity in general exert many benefits on wellness, perceived health related quality of life and social satisfaction. As the people age, physical and mental deterioration occur. Master athletes are older adults that practice different sports, such as running, swimming and badminton. This is a widespread sport practiced by over 200 million people and is one of the most exerted sport in the world. In our study we compared the health perception of Italian Badminton Master athletes and normal Italian population of same age. METHODS: Thirty (22 males, 8 females) Master badminton athletes between 18 and 69 years old participating to 2018 edition of the Italian Master Badminton Championship were enrolled for the study. All athletes compiled a six questions questionnaire, about perceived quality of life, included in the 2014-2017 Italian surveillance database "PASSI" questionnaire and answers were compared to 18-69 y/o Italian population results included in the public database. RESULTS: Statistically significative differences were not detected between genders of master athletes. There was only a significative better psychological perception of quality of life in younger class of master athletes (p<0.05).  A significative better perception was detected in Master athletes compared to normal Italian population. CONCLUSIONS: Aerobic sports, such as badminton, represent positive factors for improving health, psychological wellness and social engagement. Sport has a crucial role for the positive influence on growth in youngers and on the preventive role on typical diseases of older age, such as diabetes, ischemic cardiomyopathy and mental illness.

Red blood cell transfusions and potentially related morbidities in neonates under 32 weeks' gestation.

BACKGROUND: Preterm neonates are likely to require red blood cell (RBC) transfusion, and extremely low birth weight infants almost invariably receive multiple transfusions. Transfusion-reduction strategies can reduce transfusion rates, and might diminish certain adverse outcomes associated with transfusions. MATERIALS AND METHODS: In a single centre, we retrospectively evaluated RBC transfusion rates among preterm infants ≤32 weeks' gestational age (GA), over a 6-year period before and after adopting national transfusion-reduction strategies. We compared demographic data, adverse events, and outcomes between transfused vs not-transfused neonates. Univariate logistic regression was used to evaluate associations between dichotomous outcomes and number of transfusions, and day of first transfusion. Multivariate logistic regression evaluated the correlation between dichotomous outcomes and transfusion as an independent risk factor. RESULTS: During the 6 years studied, 181 infants born at ≤32 weeks' GA were admitted to our Neonatal Intensive Care Unit of whom 80 (44%) received at least one RBC transfusion. The transfusion rate tended downwards after adopting transfusion-reduction strategies, reaching 31% in 2018. The reduction was largely due to a marked fall in transfusions of neonates born at 29-32 weeks' GA (p<0.001). The number of transfusions received correlated with odds of having intraventricular haemorrhage (IVH) (OR=1.9; 95% CI: 1.3-2.7; p=0.0001) and the duration of oxygen supplementation (rho=0.51; 95% CI: 0.33-0.66; p≤0.0001). In multivariate logistic regression analysis, transfusion was an independent risk factor for IVH (adjusted OR=7.38; 95% CI: 2.24-24.30; p=0.0001). DISCUSSION: The application of national, standardised transfusion-reduction strategies was associated with a lower transfusion rate in neonates born at 29-32 weeks' GA, but was less effective among neonates ≤28 weeks, in whom transfusions appeared to be an independent risk factor for severe IVH.

Thrombopoietin Receptor Agonists in Children with Immune Thrombocytopenia: A New Therapeutic Era.

BACKGROUND AND OBJECTIVE: Immune thrombocytopenia (ITP) is a common bleeding disorder in childhood. The management of ITP in children is controversial, requiring personalized assessment of patients and therapeutic choices. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, have been shown to be safe and effective for the treatment of pediatric ITP. The aim of our research is to define the role of thrombopoietin receptor agonists in the management of pediatric ITP. METHODS: This review focuses on the use of TPO-RAs in pediatric ITP, in randomized trials and in clinical routine, highlighting their key role in the management of the disease. RESULTS: Eltrombopag and romiplostim appear effective treatment options for children with ITP. Several clinical studies have assessed that the use of TPO-RAs increases platelet count, decreases bleeding symptoms and improves health-related quality of life. Moreover, TPO-RAs are well tolerated with minor side effects. CONCLUSION: Although long term efficacy and safety of TPO-RAs still require further investigations, their use is gradually expanding in the clinical practice of children with ITP.

Children in Coronaviruses' Wonderland: What Clinicians Need to Know.

Human coronaviruses (HCoVs) commonly cause mild upper-respiratory tract illnesses but can lead to more severe and diffusive diseases. A variety of signs and symptoms may be present, and infections can range in severity from the common cold and sore throat to more serious laryngeal or tracheal infections, bronchitis, and pneumonia. Among the seven coronaviruses that affect humans (SARS)-CoV, the Middle East respiratory syndrome (MERS)-CoV, and the most recent coronavirus disease 2019 (COVID-19) represent potential life-threatening diseases worldwide. In adults, they may cause severe pneumonia that evolves in respiratory distress syndrome and multiorgan failure with a high mortality rate. Children appear to be less susceptible to develop severe clinical disease and present usually with mild and aspecific symptoms similar to other respiratory infections typical of childhood. However, some children, such as infants, adolescents, or those with underlying diseases may be more at-risk categories and require greater caution from clinicians. Available data on pediatric coronavirus infections are rare and scattered in the literature. The purpose of this review is to provide to clinicians a complete and updated panel useful to recognize and characterize the broad spectrum of clinical manifestations of coronavirus infections in the pediatric age.

Venous Thromboembolism in Children: From Diagnosis to Management.

Venous thromboembolism (VTE) in children is a rare occurrence, although in recent decades we have seen an increase due to several factors, such as the rise in survival of subjects with chronic conditions, the use of catheters, and the increased sensitivity of diagnostic tools. Besides inherited thrombophilia, acquired conditions such as cardiovascular diseases, infections, chronic disorders, obesity and malignancy are also common risk factors for paediatric VTE. The treatment of paediatric VTE consists of the use of heparins and/or vitamin K antagonists to prevent dissemination, embolization, and secondary VTE. Randomized clinical trials of direct oral anticoagulants in paediatric VTE are ongoing, with the aim to improve the compliance and the care of patients. We reviewed the physiological and pathological mechanisms underlying paediatric thrombosis and updated the current diagnosis and treatment options.

Can Anti-Thyroid Antibodies Influence the Outcome of Primary Chronic Immune Thrombocytopenia in Children?

BACKGROUND: Immune thrombocytopenia (ITP) is an acquired immune mediated disorder characterized by isolated thrombocytopenia. Pediatric ITP patients can develop autoantibodies such as anti-thyroglobulin (TG) and anti-thyroperoxidase (TPO), even in the absence of clinical signs of autoimmune disease. OBJECTIVE: The purpose of this article is to provide a review about: 1) the prevalence of positivity of anti-thyroid antibodies (TPO and TG) in pediatric patients with chronic ITP; 2) the role of autoimmune thyroiditis on the outcome of chronic ITP. METHODS: The authors individually completed a review of the literature for this article. Retrospective and prospective clinical studies with pediatric cohorts were considered. RESULTS: From the analysis of data, we found 4 papers which included studies only on pediatric population, and which corresponded to selected criteria. Pediatric ITP patients have been shown to have a statistically significant prevalence of anti-thyroid antibodies over healthy controls (11.6-36% versus 1.2-1.3%). No correlation has been found between the platelet count and the prevalence of positive anti-thyroid antibodies at any time of the follow up. CONCLUSION: The results of our bibliographic research demonstrated that: a) pediatric patients with chronic ITP tend to have a statistically significant prevalence of anti-thyroid antibodies positivity respect to general pediatric population; b) there are no clear data about the role of autoimmune thyroiditis as prognostic factor for chronic course of ITP in pediatric age.

May Failure to Thrive in Infants Be a Clinical Marker for the Early Diagnosis of Cow's Milk Allergy?

Objectives-Failure to thrive (FTT) in infants is characterized by growth failure. Although, cow's milk allergy (CMA) may have an impact on growth and leads to FTT, data are still limited. We focused on FTT as a possible clinical marker for an early diagnosis of CMA. The aim of the present study was to evaluate the implications of cow's milk hypersensitivity in infants with FTT and the growth catch-up after a cow's milk-free diet (CMFD). Methods-A cross-sectional study of all consecutive infants evaluated at the Pediatric Nutrition and Allergy Unit of the University Hospital of Bari (Italy) from January 2016 to April 2018 with a medical-driven diagnosis of FTT. Eligible infants were investigated for possible IgE mediated or non-IgE mediated CMA. Results-43 infants were included, mean age 5.7 months. 33/43 (77%) FTT presented a CMA related disease: 3/43 (7%) were diagnosed as presenting an IgE mediated CMA, 30 (93%) had a non IgE-mediated CMA, confirmed by the elimination diet for diagnostic purposes, that led to a significant improvement of symptoms and recrudescence after milk reintroduction. A total of 29 out of 30 patients (one patient was lost at follow-up) moved up to their original growth percentile after dietary changes. Growth z-scores were computed based on WHO anthropometric data. In 10 out of 43 patients (23%) were diagnosed with gastro-esophageal reflux disease (GERD). Conclusions-when evaluating an infant with FTT, physicians should include in their evaluation an extensive search for IgE mediated and non IgE mediated CMA. When in vivo and in vitro analysis are not conclusive, a 4- to 8-weeks trial of CMFD and a consecutive re-introduction of milk proteins may be helpful in less common diagnoses.

Serum Vitamin D Levels in Children with Immune Thrombocytopenia.

OBJECTIVE: Immune thrombocytopenia (ITP) is an acquired immuno-mediated disorder characterized by thrombocytopenia with an increased risk of bleeding. In recent years 1,25[OH]2D3 has been rediscovered as an immune modulator. We decided to evaluate serum Vitamin D levels in a cohort of children with immune thrombocytopenia in order to discover if Vitamin D concentrations may predict ITP duration. METHODS: Thirty children were enrolled in this study (sixteen with chronic ITP and fourteen with newly diagnosed ITP) to assess serum Vitamin D levels. RESULTS: The results showed that 80% of the enrolled children presented a D hypovitaminosis status. Children with newly diagnosis ITP showed no statistically significantly higher median values of Vitamin D compared to chronic ITP. CONCLUSION: This study may suggest that Vitamin D deficiency does not represent a chronicity factor for ITP. However, further studies are needed to understand the role of Vitamin D in ITP pathogenesis.

Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience.

BACKGROUND: In GM1 gangliosidosis the lack of function of ß-galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce. METHODS: We report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20-125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases. CONCLUSION: This treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.

Use of Eltrombopag in Children With Chronic Immune Thrombocytopenia (ITP): A Real Life Retrospective Multicenter Experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP).

Background: The thrombopoietin receptor agonist eltrombopag has been shown to be safe and effective for children with chronic immune thrombocytopenia (ITP). The aim of the present study was to characterize eltrombopag use in current clinical practice. Material and Methods: This is a retrospective multicenter study conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). The primary objective of the study was to determine the prevalence of eltrombopag use in Italian children affected by chronic ITP, after EMA authorization for pediatric age. The secondary objective was to assess efficacy in the first 6 months and safety during the whole period of eltrombopag treatment in current clinical practice. A total of 386 children with chronic ITP were retrospectively enrolled and eligible for analysis. Among these patients, 71 received eltrombopag. Results: The prevalence of eltrombopag use was 19% (95% CI 0.15-0.23). Thirty-one patients (44%) were male and 40 patients (56%) were female. The median age at the first dose of eltrombopag was 12 years (3-17 years). The median duration of eltrombopag treatment was 11 months (1-32 months) and the median starting dose was 50 mg/day (12, 5-75 mg/day). Thirty-two patients (45%) required one or more concomitant ITP medications during the first 6 months of treatment with eltrombopag. Thirty-nine patients (55%) never required concomitant medications. Median platelet counts and proportion of patients achieving the target platelet count of at least 30 × 109/L and 100 × 109/L significantly increased during the first 6 months of treatment (p < 0.0001). Additionally, eltrombopag has been proved effective in the absence of concomitant therapies. The most common Adverse Events were headache (7%) and thrombocytosis (6%). Conclusion: Our study highlighted the crucial role of eltrombopag as second line treatment in children with chronic ITP.