Haemochromatosis in children: A national retrospective cohort promoted by the A.I.E.O.P. (Associazione Italiana Emato-Oncologia Pediatrica) study group.

Haemochromatosis (HC) encompasses a range of genetic disorders. HFE-HC is by far the most common in adults, while non-HFE types are rare due to mutations of HJV, HAMP, TFR2 and gain-of-function mutations of SLC40A1. HC is often unknown to paediatricians as it is usually asymptomatic in childhood. We report clinical and biochemical data from 24 paediatric cases of HC (10 cases of HFE-, 5 TFR2-, 9 HJV-HC), with a median follow-up of 9.6 years. Unlike in the adult population, non-HFE-HC constitutes 58% (14/24) of the population in our series. Transferrin saturation was significantly higher in TFR2- and HJV-HC compared to HFE-HC, and serum ferritin and LIC were higher in HJV-HC compared to TFR2- and HFE-HC. Most HFE-HC subjects had relatively low ferritin and LIC at the time of diagnosis, so therapy could be postponed for most of them after the age of 18. Our results confirm that HJV-HC is a severe form already in childhood, emphasizing the importance of early diagnosis and treatment to avoid the development of organ damage and reduce morbidity and mortality. Although phlebotomies were tolerated by most patients, oral iron chelators could be a valid option in early-onset HC.

Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry.

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.

Maintenance Fluid Therapy with Saline, Dextrose-Supplemented Saline or Lactated Ringer in Childhood: Short-Term Metabolic Effects.

Maintenance with isotonic fluids is recommended in children with gastroenteritis and failure of oral rehydration therapy. However, little is known on the short-term effects of the commonly prescribed intravenous solutions on metabolic balance in children. The aim of this study is to report on our experience with normal saline, dextrose-supplemented saline and lactated Ringer solution. METHODS: A retrospective analysis from the charts of all previously apparently healthy children with acute gastroenteritis, mild to moderate dehydration and failure of oral rehydration, evaluated between January 2016 and December 2019 at our institution, was performed. Subjects prescribed the above-mentioned maintenance intravenous fluids and with blood testing immediately before starting fluid therapy and 4-6 h later, were eligible. The changes in bicarbonate, ionized sodium, potassium, chloride, anion gap and glucose were investigated. Kruskal-Wallis test with the post-hoc Dunn's comparison and the Fisher exact test were applied. RESULTS: A total of 134 out of 732 children affected by acute gastroenteritis were included (56 patients were prescribed normal saline, 48 dextrose-supplemented normal saline and 30 lactated Ringer solution). The effect of the three solutions on sodium and potassium was similar. As compared to non-supplemented normal saline (+0.4 (-1.9 - +2.2) mmol/L), dextrose-supplemented normal saline (+1.5 (+0.1 - +4.2) mmol/L) and lactated Ringer (+2.6 (+0.4 - +4.1) mmol/L) solution had a positive effect on plasma bicarbonate. Finally, the influence of dextrose-supplemented saline on blood glucose was different (+1.1 (+0.3 - +2.2) mmol/L) compared to that observed in cases hydrated with non-supplemented saline (-0.4 (-1.2 - +0.3) mmol/L) or lactated Ringer solution (-0.4 (-1.2 - +0.1) mmol/L). CONCLUSIONS: This study points out that maintenance intravenous therapies using normal saline, dextrose-supplemented saline or lactated Ringer solution have different effects on metabolic balance. A personalized fluid therapy that takes into account the clinical and biochemical variables is advised.

Idiopathic neutropenia of infancy: Data from the Italian Neutropenia Registry.

Autoimmune neutropenia of infancy (AIN) is characterized by low risk of severe infection, tendency to spontaneously resolve and typically onset at ≤4-5 years of age; it is due to auto-antibodies whose detection is often difficult. In case of negativity of 4 antineutrophils autoantibody tests, after having excluded ethnic, postinfection, drug induced, or congenital neutropenia, according to the Italian guidelines the patients will be defined as affected by "idiopathic neutropenia" (IN). We describe the characteristics of 85 IN patients enrolled in the Italian neutropenia registry: they were compared with 336 children affected by AIN. The 2 groups were clinically very similar and the main differences were detection age (later in IN), length of disease (longer in IN) and, among recovered patients, age of spontaneous recovery: the median age at resolution was 2.13 years in AINs and 3.03 years in INs (P = .00002). At bivariate analysis among AIN patients earlier detection age (P = .00013), male sex (P = .000748), absence of leucopenia (P = .0045), and absence of monocytosis (P = .0419) were significantly associated with earlier recovery; in the IN group only detection age (P = .013) and absence of monocytosis (P = .0333) were significant. At multivariate analysis detection age and absence of monocytosis were independently significant (P = 6.7e-05 and 4.4e-03, respectively) in the AIN group, whereas in the IN group only detection age stayed significant (P = .013).

Diagnostic value of cell bound and circulating neutrophil antibody detection in pediatric neutropenia.

BACKGROUND: Chronic benign neutropenia of infancy includes primary autoimmune neutropenia (pAIN) and chronic idiopathic neutropenia (CIN). A diagnosis of CIN is supported by the absence of free and/or cell-bound neutrophil autoantibodies, which can be detected by flow cytometry with the indirect-granulocyte immunofluorescence test (I-GIFT) and direct-granulocyte immunofluorescence test (D-GIFT), respectively. Conclusive evidence is lacking on the diagnostic value of the D-GIFT, whose performance requires specific laboratory expertise, may be logistically difficult, and hampered by very low neutrophil count in patient samples. This study investigated whether the evaluation of D-GIFT improves the diagnostic accuracy of pediatric neutropenia. PROCEDURE: I-GIFT and D-GIFT were performed in 174 pAIN, 162 CIN, 81 secondary AIN, 51 postinfection neutropenic, and 65 nonautoimmune neutropenic children referred to this laboratory during 2002-2014. RESULTS: Using 90% specific median fluorescence intensity cut-off values calculated by receiver operating characteristic curves, D-GIFT was positive in 49% of CIN patients, who showed similar clinical features as those with pAIN. In 44 (27%) of 162 CIN patients, I-GIFT was repeated two to three times in a year, resulting positive in 12 and two patients at second and third screening, respectively. Interestingly, 10 of the latter 14 patients showed a positive D-GIFT at the first serological screening. False positive D-GIFT was shown by 12% and 22% of nonneutropenic and nonautoimmune neutropenic patients, respectively. CONCLUSIONS: D-GIFT evaluation improves the diagnostic accuracy of pediatric neutropenia, but improvement of cell-bound antibody detection is needed to decrease false positive results.

Infectious complications in children with severe congenital, autoimmune or idiopathic neutropenia: a retrospective study from the Italian Neutropenia Registry.

We describe the incidence and characteristics of infections in children with severe congenital neutropenia (SCN), autoimmune neutropenia (AN) and idiopathic neutropenia (IN). Data extracted from the Italian Neutropenia Registry on 73 patients with 108 episodes of infections were collected from 2000 to 2009. All SCN patients with SCN and one third of AN and IN experienced at least 1 infectious episode, equating to 5.7 infections/patient in SCN and approximately 0.6 in AN and IN. The rate of infections before diagnosis of neutropenia was 6.35/1000 patient-days at risk in SCN, 0.48 in AN and 0.71 in IN (P < 0.001) and significantly decreased after diagnosis. Skin and subcutaneous abscesses and cellulitis were the most frequent types of infection encountered, followed by pneumonia. Infections are an important clinical issue in the management of neutropenic patients, even in those considered at lower risk.

Congenital and acquired neutropenias consensus guidelines on therapy and follow-up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica).

The management of congenital and acquired neutropenias presents some differences according to the type of the disease. Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is not standardized and scanty data are available on the best schedule to apply. The frequency and the type of longitudinal controls in patients affected with neutropenias are not usually discussed in the literature. The Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document that includes recommendations on neutropenia treatment and timing of follow-up.

Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica).

Congenital and acquired neutropenia are rare disorders whose frequency in pediatric age may be underestimated due to remarkable differences in definition or misdiagnosed because of the lack of common practice guidelines. Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document which includes a classification of neutropenia and a comprehensive guideline on diagnosis of neutropenia.

Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major.

Deferoxamine (DFO) therapy has been associated with improved survival of thalassemia patients. However, cardiac disease remains the main cause of death in those patients. In 1995, the oral chelator deferiprone became available for clinical use. We compared the occurrence of cardiac disease in patients treated only with DFO and in those whose therapy was switched to deferiprone during the period of observation, from January 31, 1995, to December 31, 2003. All patients with thalassemia major treated in 7 Italian centers who were born between 1970 and 1993 and who had not experienced a cardiac event prior to January 1995 were included. DFO only was given to 359 patients, and 157 patients received deferiprone for part of the time. A total of 3,610 patient-years were observed on DFO and 750 on deferiprone. At baseline, the 2 groups were comparable for age and sex, while ferritin levels were significantly higher in patients switched to deferiprone. Fifty-two cardiac events, including 10 cardiac deaths, occurred during therapy with DFO. No cardiac events occurred during deferiprone therapy or within at least 18 months after the end of it. In the setting of a natural history study, deferiprone therapy was associated with significantly greater cardiac protection than deferoxamine in patients with thalassemia major.

Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine.

BACKGROUND AND OBJECTIVES: Seven Italian centers reported data on survival, causes of death and appearance of complications in patients with thalassemia major. The interactions between gender, birth cohort, complications, and ferritin on survival and complications were analyzed. DESIGN AND METHODS: Survival after the first decade was studied for 977 patients born since 1960 whereas survival since birth and complication appearance was studied for the 720 patients born after 1970. Better survival was demonstrated for patients born in more recent years (p<0.00005) and for females (p=0.0003); 68% of the patients are alive at the age of 35 years. In the entire population 67% of the deaths were due to heart disease. RESULTS: There was a significant association between birth cohort and complication-free survival (p<0.0005). The prevalence of complications was: heart failure 6.8%, arrhythmia 5.7%, hypogonadism 54.7%, hypothyroidism 10.8%, diabetes 6.4%, HIV infection 1.7%, and thrombosis 1.1%. Lower ferritin levels were associated with a lower probability of heart failure (hazard ratio =3.35, p<0.005) and with prolonged survival (hazard ratio = 2.45, p<0.005), using a cut-off as low as 1,000 ng/mL. INTERPRETATION AND CONCLUSIONS: Survival and complication-free survival of patients with thalassemia major continue to improve, especially for female patients born shortly before or after the availability of iron chelation.