BACKGROUND:Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder in childhood. Although viral infections and some vaccinations are recognized triggers, data on the onset or exacerbation of ITP following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in pediatric patients remain limited. OBJECTIVES:To evaluate the incidence and clinical characteristics of new-onset ITP and the safety of SARS-CoV-2 vaccination in children with preexisting or resolved ITP. METHODS:We evaluated the incidence and clinical characteristics of ITP occurring after SARS-CoV-2 vaccination, as well as the effects of vaccination in children with preexisting ITP. RESULTS:De novo ITP: five cases of new-onset ITP were identified nationwide, most of which occurred after the first vaccine dose (80%). Despite low median platelet counts at presentation, no major or fatal bleeding events were observed. Most patients responded favorably to first-line treatments (intravenous immunoglobulins and/or corticosteroids), and 80% achieved normal platelet counts at the last follow-up. Preexisting ITP: among 164 vaccinated patients with complete clinical data, only 8.5% (n = 14) experienced a transient platelet count decline or new bleeding manifestations. Notably, no relapses occurred among the 34 patients who were in clinical remission at the time of vaccination. CONCLUSIONS:ITP following SARS-CoV-2 vaccination in the pediatric population is exceedingly rare and generally mild. Moreover, SARS-CoV-2 vaccination appears safe in children with preexisting or resolved ITP.

Five-year survival rates after childhood cancer have improved in recent decades: despite these promising survival rates, survivorship is associated with a lifelong increased risk of morbidity and mortality due to late effects of cancer and its treatments. Numerous studies have elucidated the long-term health consequences, and endocrine disorders are identified as among the most prevalent ones, impacting over 40

The hemostatic system in the newborn is a complex entity, characterized by dynamism in its development; therefore, the correct measurement of its potential is challenging. In this narrative review, we analyzed the current knowledge of the “developmental hemostasis” of the newborn; we also studied the performance of routine coagulation tests in its evaluation, with considerations about the establishment of neonatal age-specific normal ranges and about the role of preanalytical variables, in particular, hematocrit (which could represent an important cause of error); we also focused on the increasing importance of viscoelastic coagulation tests, which are becoming increasingly widespread (especially in some settings such as intensive care unit) and are able to quickly provide information about the hemostatic function of the newborn, even if they lack adequate standardization in the neonatal period.

BACKGROUND:Immune thrombocytopenia (ITP) is an acquired immune-mediated bleeding disorder characterized by isolated thrombocytopenia. Its estimated yearly incidence in the pediatric population is 1.9-6.4/100,000. ITP in children is usually a self-limiting and benign disorder. The clinical management of children with ITP often remains controversial, as robust randomized trials on the management of this disorder are lacking. Treatments vary widely in clinical practice and existing guidelines from hematology societies on clinical management offer indications based largely on expert opinion rather than strong evidence. MATERIALS AND METHODS:The Coagulative Disorder Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) developed this document to collect shared expert opinions on the management of newly diagnosed ITP, updating previous guidelines and providing recommendations to pediatricians. Each statement has been given a score expressing the strength of evidence, appropriateness and agreement among participants. RESULTS:Clear-cut definitions of the clinical phases of the disease and clinical response are stated. Recommendations are given regarding the classification of bleeding symptoms, evaluation of bleeding risk, diagnosis, and prognostic factors. Specific recommendations for treatment include indications for first-line (intravenous immunoglobulins, steroids) and second-line (combined therapy, thrombopoietin receptor agonists, immunosuppressive drugs, rituximab) therapeutic agents, as well as hemorrhagic emergency and supportive treatment, including emergency splenectomy. The optimal follow-up schedule, the relation between ITP and vaccines and health-related quality-of-life issues are also discussed. DISCUSSION:The panel achieved broad consensus on issues related to how to treat children with newly diagnosed ITP, providing a comprehensive review of all relevant clinical aspects.

Objective To develop and validate a weighted score, the ONCOREUM score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA). Study design Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The beta coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively). Results Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively. Conclusions The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA.

• We report on a large kindred affected by ALPS due to a novel pathogenetic TNFRSF6 heterozygous mutations. • Clinical and immunological disease activity decreases during adulthood. • Long-term follow-up of adult ALPS patients and their disease activity is warranted

Abstract 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.

Autoimmune diseases are usually associated with environmental triggers and genetic predisposition. However, a few number of autoimmune diseases has a monogenic cause, mostly in children. These diseases may be the expression, isolated or associated with other symptoms, of an underlying inborn error of immunity (IEI). Autoimmune cytopenias (AICs), including immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), autoimmune neutropenia (AN), and Evans' syndrome (ES) are common presentations of immunological diseases in the pediatric age, with at least 65% of cases of ES genetically determined. Autoimmune cytopenias in IEI have often a more severe, chronic, and relapsing course. Treatment refractoriness also characterizes autoimmune cytopenia with a monogenic cause, such as IEI. The mechanisms underlying autoimmune cytopenias in IEI include cellular or humoral autoimmunity, immune dysregulation in cases of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure, myelodysplasia, or secondary myelosuppression. Genetic characterization of autoimmune cytopenias is of fundamental importance as an early diagnosis improves the outcome and allows the setting up of a targeted therapy, such as CTLA-4 IgG fusion protein (Abatacept), small molecule inhibitors (JAK-inhibitors), or gene therapy. Currently, gene therapy represents one of the most attractive targeted therapeutic approaches to treat selected inborn errors of immunity. Even in the absence of specific targeted therapies, however, whole exome genetic testing (WES) for children with chronic multilineage cytopenias should be considered as an early diagnostic tool for disease diagnosis and genetic counseling.

On March 12th 2021 the Italian Government decided to implement a national lockdown in almost all the regions of the country. It was the second most severe measure taken after the March 2020 national lockdown, due to the rising of coronavirus disease 2019 (COVID-19) cases and the overcrowding of the hospitals. Italy was the first European country hit by the COVID-19 pandemic in February 2020. The first ‘red’ zones under severe lockdown in the Regions of Northern Italy were established on February 26th 2020, when all the schools were closed. Phase I of a nationwide lockdown began on March 8th and lasted until April 30th 2020. The Regions of Northern Italy were the most impacted by the COVID-19 pandemic in the first months of 2020, with the highest incidence of COVID-19 cases, leading to a dramatic surge in the need for emergency rooms (ERs) and wards, and a high mortality rate.1 The first peak of 29 000 hospitalised individuals, including children, except those in intensive care units (ICUs) was recorded in April 2020. Most hospitals had to rapidly implement strategies to ensure care for non-COVID-19 patients.2 The majority of children with sickle cell disease (SCD) live in the Northern regions of Italy.3 Therefore, the dramatic scenario represented an opportunity to explore the challenges presented for children with SCD who lived in Italy during the first outbreak, so that the lessons learned could be used to guide clinical management in the upcoming months. SCD is characterised by the presence of unpredictable and frequent acute events such as painful vaso-occlusive crises (VOCs), acute chest syndrome (ACS) and febrile episodes with risk of severe infections.4 VOCs, ACS and fever are the most frequent reasons for access to the ER and for hospitalisation. In previous years, data from the Network of Centres belonging to the Italian Association of Paediatric Haematology and Oncology [Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)] showed a high frequency of access to the ER and admission to hospital for VOCs, ACS and fever for children with SCD living in Italy during the coldest months, due to the trigger of seasonal infections (January–March).3, 5, 6 The viral pandemic and the presence of febrile respiratory tract symptoms characteristic of the COVID-19 infection suggested a greater risk of acute events in children with SCD. Several reports have focussed on service provision to children with SCD7 or the clinical manifestations of COVID-19 infection in children with SCD,8, 9 but to date, less information is available on the burden of acute events in children with SCD during the COVID-19 pandemic. The primary aim of the present multicentre retrospective study was to evaluate acute disease burden for children with SCD in Italy, measured as acute events (VOCs, ACS, fever), accesses to the ER and hospitalisations during the national lockdown of the first wave (21 February–30 April 2020), in which the same restrictive measures were applied homogeneously nationwide, compared to the same period in 2019. The secondary aim was to assess if the care provided to manage acute events had to be modified from the best practices recommended by the AIEOP National Guidelines due to the pandemic.10 A standardised survey in Excel (Data S1) was sent to the AIEOP Centres. Summary data were collected from individual chart review, or through specific queries in health databases, according to the usual practices in place in each centre. Fisher’s exact test was used to compare dichotomous data or low frequencies and Pearson chi-square test for analysing associations. A total of 839 patients (male 419 and female 420) with SCD (63% SS, 10% Sβ°, 17% SC, 8% Sβ+, 2% other) were followed in 22 AIEOP Centres at the time of the survey in 2020; 782 were followed in 2019 (62% SS, 10% Sβ°, 17% SC, 8% Sβ+, 3% other). Overall, 721/839 (86%) and 671/782 (86%) were living in the Northern regions of Italy in 2020 and 2019 respectively. In 2020, overall, there was a significant reduction in ER access compared to the previous year (43% vs. 73%, −40%; P = 0·001) with no differences in the three areas (Northern, Central, Southern) of the country. Hospitalisations also decreased (55% vs. 77%, −30%; P = 0·025), but the majority of the reduction occurred in the Northern Regions that were most impacted by the pandemic (P = 0·016) (Fig 1). Considering the causes of hospitalisation, admissions due to VOCs, ACS and fever were reduced overall, but those due to other causes (haemolytic crises/seizures/other) remained unchanged (Fig 2). No deaths occurred. In Italy, surprisingly, compared to all other European countries,8, 9 there were no positive cases of COVID-19 in children with SCD during the first national lockdown, despite the very high number of COVID-19-positive cases in the general population, including children.1 Moreover, unlike other European countries,8, 9 children with SCD had fewer accesses for acute events than are typical of SCD and they did not present serious acute events or deaths at home due to delayed treatment, or a lack of adequate care. In fact, between February and April 2020, only one of the 22 AIEOP expert centres implemented alternative pathways for fever management, suggesting that children with SCD should not come to the ER in cases of fever >38°C, but should remain at home and start oral antibiotic, in contrast to pre-existing AIEOP guidelines. The other 21 centres continued to follow the usual AIEOP guidelines for fever, VOCs and ACS and advised patients and families to comply with the usual protocols.10 Therefore, it is unlikely that the reduction of VOCs was due to more home pain management, although our survey was not designed to specifically assess consumption of pain medication at home. Most of the centres made organisational changes and established ad hoc ‘dirty/clean’ paths within the ER, nevertheless ensuring adequate access and management for the acute complications of SCD. All centres implemented telephone surveillance and when in good health, routine clinical laboratory checks were postponed. In some centres, chronic organ damage monitoring (including Transcranial Doppler) was delayed, and exchange transfusion sessions sometimes were rescheduled with a maximum delay of 4 weeks, without any impact on acute manifestations, or short-term survival. In Italy, in general, children experienced reduced access to the ER during the pandemic with short-term worsening of underlying chronic conditions, delayed diagnosis, or increased severity of clinical manifestations upon admission.11-13 This does not appear to be the case for children with SCD. Reduced access to ER services for the typical acute manifestations of SCD was not due to a barrier, but to a reduction of the clinical complications themselves. This could be due to several reasons. First of all, the general situation in Italy, with sudden widespread COVID-19 fear prompted the entire population to stay at home and limit contacts. Parents, teenagers and children with SCD, immediately and willingly, complied with isolation measures with reduced opportunity to be infected by COVID-19.14 Secondly, the widely adopted infection containment measures, such as masks or social distancing, combined with early school closure, reduced the diffusion of seasonal infections (a known trigger for VOCs and ACS in children with SCD), the access to the ER for blood analysis and intravenous antibiotics administration in case of fever >38°C and hospitalisation for ACS. Finally, the prompt reorganisation of care for patients with SCD by telephone and long-distance surveillance played a key role in encouraging patients and families to remain at home.14 The above reasons were taken into consideration to plan care management, including acute events, during the successive waves of the pandemic, characterised by heterogeneous activation of lockdowns in various areas of the country up to March 12th 2021. The frequency and severity of acute complications during other periods, in which the restrictive measures were looser and heterogeneous, due to a lower infection rate, are still to be determined. At the beginning of the second national lockdown, in order to continue to guarantee a low incidence of the acute manifestations of SCD in the following months in which ERs and hospitals could continue to be overburdened, adequate telephone surveillance, maintaining the necessary access to ER for acute emergencies and reduced contacts are recommended. Our present survey has confirmed that infections are the most frequent trigger of morbidity in patients with SCD, especially in the paediatric age group and infection prevention measures can effectively limit acute events. The overall consumption of pain medication will need further evaluation. The research was partially supported by a grant from the Fondazione Città della Speranza. Vania Munaretto, Laura Sainati, Raffaella Colombatti, Giovanni Palazzi, Giovanna Russo designed the study and drafted the manuscript; Beatrice Coppadoro performed statistical analysis; all authors reviewed the abstract; all authors contributed to data collection, data interpretation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited. Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected. Recurrent infections were registered in 6/12 patients (50%), while bleeding episodes in 2/12 (16.7%). White blood cell and absolute lymphocyte counts were reduced in 8/12 (66.7%) and 7/12 (58.3%) patients, respectively. Absolute numbers of CD3+ and CD4+ T cells were reduced in 8/12 (66.7%) and 7/12 (58.3%), respectively. Of note, recent thymic emigrants (RTE) were reduced in all tested patients (9/9), with T-cell receptor excision circle analysis (TRECs) showing a similar trend in 8/9 patients; naïve CD4+ T cells were low only in 5/11 patients (45.4%). Interestingly, B-cell counts, IgM memory B cells, and IgM serum levels were reduced in 10/12 (83.3%) patients. Natural killer (NK) cell counts were mostly normal but the percentages of CD16+CD56low/− cells were expanded in 7/7 patients tested. The observed immunological alterations did not correlate with patients’ age. Finally, responses to proliferative stimuli were normal at presentation for all patients, although they may deteriorate over time. Our data suggest that patients affected with JS may display important numeric and maturational alterations in the T-, B-, and NK-cell compartments. These findings suggest that JS patients should be regularly monitored from an immunological point of view.

Objective: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.Materials and Methods: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.Results: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.Conclusion: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.

BACKGROUND:Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. METHODS:We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. FINDINGS:Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0-27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2-4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89-408·12]), followed by weight loss (59·88 [6·34-565·53]), thrombocytopenia (12·67 [2·40-66·92]), monoarticular involvement (11·30 [4·09-31·19]), hip involvement (3·30 [1·13-9·61]), and male sex (2·40 [1·03-5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01-0·20]), joint swelling (0·03 [0·01-0·09]), and involvement of the small hand joints (0·02 [0-1·05]). INTERPRETATION:Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. FUNDING:Associazione Lorenzo Risolo.

OBJECTIVES:HbS/β+ patients' presence in Italy increased due to immigration; these patients are clinically heterogeneous, and specific guidelines are lacking. Our aim is to describe a cohort of HbS/β+ patients, with genotype-phenotype correlation, in order to offer guidance for clinical management of such patients. METHODS:Retrospective cohort study of HbS/β+ patients among 15 AIEOP Centres. RESULTS:A total of 41 molecularly confirmed S/β+ patients were enrolled (1-55 years, median 10.9) and classified on β+ mutation: IVS-I-110, IVS-I-6, promoter, and "others." Prediagnostic events included VOC 16/41 (39%), ACS 6/41 (14.6%), sepsis 3/41 (3.7%), and avascular necrosis 3/41 (7,3%). Postdiagnostic events were VOC 22/41 (53.6% %), sepsis 4/41 (9.7%), ACS 4/41 (9.7%), avascular necrosis 3/41 (7.3%), aplastic crisis 2/41 (4.8%), stroke 1/41 (2.4%), ACS 1/41 (2.4%), and skin ulcerations 1/41 (2.4%). The IVS-I-110 group presented the lowest median age at first SCD-related event (P = .02 vs promoter group) and the higher median number of severe events/year (0.26 events/patient/year) (P = .01 vs IVS-I-6 and promoter groups). Promoter group presented a specific skeletal phenotype. Treatment regimen applied was variable among the centers. CONCLUSIONS:HbS/β+ is not always a mild disease. Patients with IVS-I-110 mutation could benefit from a standard of care like SS and S/β° patients. Standardization of treatment is needed.

Musculoskeletal pain is a common complaint in the pediatric population and the children affected are often referred to the rheumatologist. Indeed, although the differential diagnosis in these children may be wide, a carefully guided anamnesis allows to orientate it in the majority of cases.