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.

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.

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.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

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.

HbS/ß+ thalassemia: Really a mild disease? A National survey from the AIEOP Sickle Cell Disease Study Group with genotype-phenotype correlation.

OBJECTIVES: HbS/ß+ 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/ß+ patients, with genotype-phenotype correlation, in order to offer guidance for clinical management of such patients. METHODS: Retrospective cohort study of HbS/ß+ patients among 15 AIEOP Centres. RESULTS: A total of 41 molecularly confirmed S/ß+ patients were enrolled (1-55 years, median 10.9) and classified on ß+ 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/ß+ is not always a mild disease. Patients with IVS-I-110 mutation could benefit from a standard of care like SS and S/ß° patients. Standardization of treatment is needed.

Hydroxyurea prescription, availability and use for children with sickle cell disease in Italy: Results of a National Multicenter survey.

BACKGROUND: The number of patients with sickle cell disease (SCD) has increased in Italy in the past decade due to immigration. In spite of the established efficacy of hydroxyurea (HU) in childhood, population-based data regarding its prescription and effectiveness come mainly from studies performed in adults or outside Europe. POPULATION AND METHODS: The Hydroxyurea in SCD: A Large Nation-wide Cohort Study from Italy was a retrospective cohort study of adult and pediatric patients with SCD attending 32 centers. Pediatric data are analyzed separately. RESULTS: Out of 504 children followed in 11 centers, 206 (40%) were on HU (194 SS/Sß°, 12 SC/Sß+); 74% came from Sub-Saharian Africa and 18% from Europe. HU therapy indications for SS/Sß° patients were as follows: 57% painful vaso-occlusive crisis, acute chest syndrome or both, 24% anemia, 8% anemia, and other reasons (the majority had Hb ≤ 8-8.5 g/dl, revealing scarce acceptance of low Hb values by pediatric hematologist). Mean starting dose was 15.5 mg/kg, and dose at full regimen was 17.1 mg/kg. Mean age at HU therapy was 7.68 years, although it was lower for SS/Sß° patients. Only 10% started HU before 3 years. In 92%, 500 mg capsule was used; in 6%, the galenic was used; and in 2%, 100 mg tablet was used. Significant reduction of clinical events and inpatients admissions, with improvement in hematological parameters, was observed for SS/Sß° patients and a trend toward improvement for SC/Sß+ patients was also observed. CONCLUSIONS: HU effectiveness is demonstrated in a national cohort of children with SCD living in Italy, even at a lower dose than recommended, revealing good adherence to a treatment program by a socially vulnerable group of patients such as immigrants.

The Italian multiregional thalassemia registry: Centers characteristics, services, and patients' population.

OBJECTIVES: The prognosis of beta-Thalassemia major and other congenital hemoglobinopathies has profoundly changed over the last decades. Moreover, only few countries in Europe provide dedicated services and the description of the measures for patients monitoring and treatment is overall very scarce. The HTA-Thal project is aimed to identify the services available in Italy and to collect epidemiological and clinical data on the thalassemic population (HTA-Thal Registry). METHODS: A map of the existing centers was created and two electronic questionnaires were completed with information on the services and patients. RESULTS: On 182 centers identified, 60 completed the two questionnaires. Centers resulted to be extremely heterogeneous in terms of size, age of patients in care, and services availability. The transition of pediatric patients to adult centers was not guaranteed. Thousand eight hundred and seventy-three beta-Thalassemia major patients (of which 259 pediatrics), regularly transfused, were registered. Deferasirox is the most used chelator as monotherapy (616 patients) and its use prevails in younger patients. A higher number of patients (847 patients) use Deferoxamine, either alone (448 patients) or in combination with DFP (399 patients), while 782 patients use Deferiprone alone (383 patients) or in combination (399 patients). 31.6 and 66.6% of centers were not equipped for specialized visits or local MRI, respectively. Centers with 30-80 patients show the high percentage of patients appropriately monitored when compared to smaller or bigger centers. CONCLUSIONS: This analysis confirms the importance of patients' registries for the collection of large datasets and the need for dedicated 'specialized centers' equipped to provide the best standard treatment to patients.

Guillain-Barré-like syndrome in a child with lead poisoning.

Lead poisoning is a medical condition caused by increased levels of the heavy metal lead in the body, generally resulting from environmental exposure. Lead poisoning can cause a variety of symptoms which vary depending on the individual and the duration of lead exposure; lead poisoning is more noxious to children than adults, because it can damage the brain and nerve development of children.We report a case of lead poisoning in a 5-year-old girl caused by accidental ingestion of a metal ring. Simultaneously, the child showed anemia, encephalopathy, and peripheral neuropathy with albuminocytological dissociation mimicking Guillain-Barré syndrome.This case suggests that anemia with signs of peripheral and central nervous system damage could be considered as a possible manifestation of lead poisoning in children.

Association of interleukin-(IL)10 haplotypes and serum IL-10 levels in the progression of childhood immune thrombocytopenic purpura.

Derangement of genetic and immunological factors seems to have a pivotal role in the pathophysiology of immune thrombocytopenic purpura (ITP). We investigated interleukin(IL)-10 genetically determined expression in children with an acute progression of ITP (n=41) compared to young patients with chronic ITP (n=44) and healthy controls (n=60), and attempted to correlate IL-10 production with the course of the disease. We genotyped our study population for three single nucleotide polymorphisms at positions -1082 (A/G), -819 (C/T) and -592 (C/A) in the promoter region of the IL-10 gene. IL-10 levels were measured by enzyme-linked immunoassay. The IL-10 production in our study population was significantly higher in patients carrying the GCC haplotype than those bearing ACC and ATA haplotypes (6.9 ± 1.5 vs 3.6 ± 0.8 vs 3.3 ± 0.3, p=0.03). The serum concentration of IL-10 was significantly higher in patients with an acute course of their disease, who mainly carried the GCC haplotype (92%), compared to chronic subjects, bearing the non-GCC haplotypes, and controls [17 pg/mL (1.7-18) vs 3.5 pg/mL (0.6-11) vs 3 pg/mL (1-7), p<0.01)]. Our findings show that patients carrying the GCC-high producer IL-10 haplotype have an acute development of ITP and that IL-10 levels might represent a useful predictive biomarker of the disease course.

Clinical and laboratory characteristics of children positive for antiphospholipid antibodies.

BACKGROUND: It is difficult to estimate the actual prevalence of antiphospholipid syndrome (APS) in the paediatric population since there are no standardised criteria. We aimed to assess clinical and laboratory characteristics of a cohort of children positive for antiphospholipid antibodies (aPL) to contribute to the understanding of the heterogeneous aPL-related features in childhood. MATERIALS AND METHODS: Forty-four patients with prolonged activated partial thromboplastin time were enrolled and assigned to group I ("transiently positive") or group II ("persistently positive"), based on the detection of elevated aPL plasma levels [lupus anticoagulant (LA), anticardiolipin (aCL), and anti-ß2-glycoprotein I (anti-ß2GPI) antibodies] on, respectively, one or more occasions, at least 12 weeks apart, by standard procedures. The clinical history and symptoms of all patients were recorded. RESULTS: Thirty-three (75%) patients were assigned to group I, while the other 11 (25%) formed group II. Major associated diseases in group I were urticarial vasculitis (21%), acute infections (18%) and thalassaemia (12%). Five subjects (15%) were asymptomatic. Four out of the 11 subjects (36%) in group II had thrombotic events; they were all persistently aPL-positive and two of them had concomitant systemic lupus erythematosus. The rate of detection of LA-positivity was not significantly different between the two groups (76% vs 91%, p>0.05), whereas the percentage of patients positive for overall aCL was higher in group II than in group I (54% vs 42%, respectively; p<0.05). Specifically, aCL IgG and anti-ß2GPI IgM subtypes were significantly more represented in group II than in group I (100% vs 62% and 75% vs 33%, respectively; p<0.05). DISCUSSION: Our study shows that aPL-positive children have different features that should be taken into account in the classification of criteria for paediatric APS.

Clinical significance of serum cytokine levels and thrombopoietic markers in childhood idiopathic thrombocytopenic purpura.

BACKGROUND: Biological markers useful for defining children with newly diagnosed immune thrombocytopenic purpura (ITP) who are likely to develop the chronic form of the disease are partially lacking. The purpose of this study was to assess the clinical role of both immunological and thrombopoietic markers in children with ITP and correlate their levels with different disease stages. MATERIALS AND METHODS: We enrolled 28 children with ITP at the onset of their disease, who were followed-up for a whole year and divided according to whether their disease resolved within the 12 months (n=13) or became chronic (n=15), 11 subjects with chronic ITP off therapy for at least 1 month at the time of enrolment, and 30 healthy matched controls. Serum levels of T helper type 1 and 2 and T regulatory-associated cytokines, such as interferon γ, tumour necrosis factor α, interleukin (IL) 2, IL6, IL10, and thrombopoietin were measured in all children using quantitative immunoenzymatic assays, while reticulated platelets were evaluated by flow cytometric analysis. RESULTS: Serum IL10 levels were significantly higher in patients with an acute evolution of ITP than in either healthy controls (p<0.001) or patients with chronic progression of ITP (p<0.05). Reticulated platelet count and thrombopoietin levels were significantly higher in ITP patients at the onset of their disease, whether with acute resolution or chronic progression, than in healthy subjects (p<0.01; p<0.001), but did not differ between the groups of patients. CONCLUSION: IL-10 seems to predict the clinical course of ITP, as it is significantly higher at the onset of disease in patients who obtain disease remission in less than 1 year.

Metabolic, inflammatory, endothelial and haemostatic markers in a group of Italian obese children and adolescents.

Childhood obesity and its related comorbidities are increasingly recognised in children, predisposing them to early cardiovascular disease and metabolic syndrome. The objective of the study was to investigate markers of metabolism, inflammation and haemostasis in a group of Italian obese children and adolescents. Fifty-nine obese and 40 non-obese subjects were recruited. Fasting glucose and insulin, total cholesterol, HDL and LDL cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor alpha (TNF-α), and adiponectin were measured. Hypercoagulability was assessed by measuring the circulating levels of thrombin-antithrombin complex (TAT), D: -dimer, fibrinogen, plasminogen activator inhibitor 1 (PAI-1) and von Willebrand Factor (vWF). A significant degree of insulin resistance was present in obese subjects compared with controls (p < 0.0001). The obese showed higher levels of total cholesterol, LDL cholesterol and triglycerides, and lower levels of HDL cholesterol than controls (p < 0.0001). Circulating levels of hsCRP and TNF-α were significantly higher in obese than in controls while serum adiponectin levels were significantly lower in obese than non-obese subjects (p < 0.001; p = 0.031; p < 0.0001, respectively). vWF, TAT, D-dimer, fibrinogen and PAI-1 levels were significant higher in obese subjects compared with control group (p = 0.02; p < 0.0001; p = 0.0037; p < 0.0001; p = 0.017, respectively). In conclusion, our results suggest that childhood obesity per se is associated with a proinflammatory and prothrombotic state.

Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia.

In a group of newly diagnosed acute lymphocytic leukemia (ALL) children we evaluated a number of hemostatic and inflammatory markers at diagnosis and at different time points during chemotherapy for the remission induction to identify alterations in the plasma levels of prothrombotic markers before and during the course of chemotherapy. The following plasma markers were evaluated: thrombin-antithrombin complex (TAT), D-Dimer, plasminogen activator inhibitor 1 (PAI-1), antithrombin, fibrinogen, von Willebrand factor (VWF) antigen and high molecular weight VWF (HMW-VWF) multimers, P-selectin, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6). Plasma samples were collected at the following time points: at T0 (baseline) and T1 (+24 days of therapy), T2 (+36 days therapy), and T3 (+64 days therapy). The results show that, at diagnosis, ALL children presented with laboratory signs of increased thrombin generation and fibrin formation (i.e. high TAT and D-dimer levels), fibrinolysis inhibition (i.e. high PAI-1 level), endothelial activation (i.e., high HMW-VWF and soluble P-selectin levels) and inflammation (i.e. high TNF-alpha and IL-6 levels). After starting induction therapy, the thrombin generation markers and inflammatory cytokines significantly decreased. To the opposite, PAI-1 and P-selectin significantly increased, suggesting an insult by chemotherapy on the vascular endothelium. These effects were more evident during steroid administration. Symptomatic venous thromboembolism (VTE) episodes developed in two cases during induction therapy, which did not allow the evaluation of the predictive value for VTE of laboratory markers.

Management of chronic childhood immune thrombocytopenic purpura: AIEOP consensus guidelines.

BACKGROUND/OBJECTIVE: The management of chronic childhood idiopathic thrombocytopenic purpura (ITP) is distinct from acute ITP. Similar to the publication on acute ITP guidelines, the AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) considered it appropriate to develop consensus guidelines for chronic childhood ITP to provide useful and shared information for physicians, healthcare professionals, parents and patients. DESIGN/METHODS: A preliminary, evidence-based document issued by a select group of AIEOP pediatric hematologists was discussed, modified and approved during a Consensus Conference according to procedures previously validated by the AIEOP Board. RESULTS: The guidelines give prominence to the periodical reevaluation of all the etiological hypotheses of thrombocytopenia in relation to its clinical condition. The majority of chronic ITP children do not require treatment, especially if bleeding is absent or minimal. The treatment decision depends on several factors other than the platelet count, and treatment options are suggested in relation to the therapeutic scenarios. Recommendations are given regarding support for surgery, particular hemorrhagic conditions, daily activities/sports, as well as for vaccines and drugs. Experimental treatments are also discussed.

Osteoclastogenesis in children with 21-hydroxylase deficiency on long-term glucocorticoid therapy: the role of receptor activator of nuclear factor-kappaB ligand/osteoprotegerin imbalance.

CONTEXT: Children with 21-hydroxylase deficiency (21-OHD) need chronic glucocorticoid (cGC) therapy to replace congenital deficit of cortisol synthesis. cGC therapy is the most frequent and severe form of drug-induced osteoporosis, and different mechanisms have been proposed to explain its pathogenesis. OBJECTIVE: We investigated the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs) from 18 children with 21-OHD on cGC therapy and 25 controls who never received GCs. We also evaluated the presence of circulating osteoclast precursors (OCPs) and the role of T cells in osteoclast formation. RESULTS: Spontaneous osteoclastogenesis, without adding macrophage-colony stimulating factor and receptor activator of nuclear factor-kappaB ligand (RANKL), and significantly higher osteoclasts resorption activity occurred in 21-OHD patients. Conversely, macrophage-colony stimulating factor and RANKL were essential to trigger and sustain osteoclastogenesis in controls. Furthermore, in 21-OHD patients, we identified a significant percentage of CD11b-CD51/CD61 and CD51/61-RANK-positive cells, which are OCPs strongly committed. Additionally, we demonstrated a T cell-dependent osteoclastogenesis from 21-OHD patients' PBMCs. T cells from patients expressed high levels of RANKL and low levels of osteoprotegerin (OPG) with respect to controls. Moreover, 21-OHD patients had higher soluble RANKL and lower OPG serum levels compared with controls; thus, soluble RANKL to OPG ratio was significantly higher in patients than controls. CONCLUSIONS: The present study showed for the first time a high osteoclastogenic potential of PBMCs from 21-OHD patients on cGC therapy. This spontaneous osteoclastogenesis seems to be supported by both the presence of circulating OCPs and factors released by T cells.

Reduced interleukin-5 production by peripheral CD4+ T cells in common variable immunodeficiency patients.

We evaluated the capacity of peripheral CD4+ T helper cells in four Common Variable Immunodeficiency (CVI) patients to secrete interleukin-4 (IL-4) and IL-5. While in control CD4+ T cells, stimulated via CD3 and cultured in presence of IL-2 or IL-15, a 10 fold increased production of IL-5 (146 +/- 30; 142 +/- 25 pg/ml) was found, a 4 fold increment of this cytokine was, instead, detected in 3 out of 4 CVI patients (34 +/- 13; 39 +/- 12 pg/ml) (p < 0.05). In conclusion, the reduction of IL-5, involved in the late regulation of B cell differentiation into Ig-secreting plasma cells, may contribute to the defective antibody production in CVI patients.

Cytokine pattern and endothelium damage markers in Henoch-Schönlein purpura.

In a longitudinal cohort study our aim was to evaluate the cytokine pattern of children affected by Henoch-Schonlein purpura (HSP) and to correlate this pattern to vascular endothelium damage and to nephropathy. The following parameters were monitored at the onset of the disease (T0) and after 6 months of follow-up (T1): clinical scores, serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), soluble IL-2 receptor (IL-2sRalpha), fibrinogen, von Willebrand factor antigen (vWf:Ag) and soluble thrombomodulin (TMD) levels. A total of 24 children (9 M, 15 F), affected by HSP, aged between 3-14 years (median 6 years), were enrolled into the study. IL-2 serum levels were significantly increased at the onset of the disease compared to control group and T1. The same pattern was observed for IL-2sRalpha and TNF-alpha. Fibrinogen and vWf:Ag concentrations were significantly higher at the onset of disease than t1 and in control group. TMD levels resulted constantly within the normal range. Concerning the analyzed parameters, no significant difference resulted to be in subjects with and without renal involvement (hematuria and/or proteinuria). Finally, raised serum TNF-alpha concentration, related to vascular endothelium damage as shown by increased vWf:Ag levels, occurred invariably in children affected by HSP both with and without renal involvement.

Hemarthrosis due to a rare cause of hemorrhagic diathesis: Ehlers-Danlos syndrome.

The authors report a case of hemarthrosis complicated by severe anemia related to a congenital connective tissue disease: Ehlers-Danlos syndrome. A boy fell down and suffered tumefaction of both knees with bilateral rupture of the rotula tendon. He underwent surgical reinsertion of each tendon on the rotula. He later showed an unexpected ongoing hematic effusion, with severe anemia. He was screened for coagulation disorders with no results. On taking a more detailed history and investigating the patient's phenotypical features, the authors diagnosed Ehlers-Danlos syndrome, hypermobile variant. The hemarthrosis and anemia were thus concluded to be consequences of excessive tissue fragility due to a congenital connective tissue disease.