Screening for sickle cell disease: focus on newborn investigations.

Drepanocytosis is a genetic disease relevant for its epidemiological, clinical and socio-economic aspects. In our country the prevalence is highly uneven with peaks in former malaria areas, but migration flows in recent years have led to significant changes. In this document we review the screening programs currently existing in Italy with particular emphasis on newborn screening, which in other countries around the world, including within Europe, is at most universal and mandatory. The essential laboratory issues are reviewed, from sampling aspects (cord blood or peripheral), to the analytical (analytical methods dedicated to neonatal screening and adult carrier detection) and post analytical (reporting, informative) ones. An economic analysis based on data collected in the province of Modena is also proposed, clearly showing that neonatal screening is also beneficial from an economic point of view.

Residential exposure to magnetic fields from transformer stations and risk of childhood leukemia.

BACKGROUND: Several studies have documented an increased risk of leukemia among children exposed to magnetic fields from high-voltage power lines, with some evidence of dose-response relation. However, findings in some studies have been inconsistent, and data on the effects of different sources of exposure are lacking. In this study, we evaluated the relation of childhood leukemia risk to exposure to magnetic fields from transformer stations. METHODS: We conducted a population-based case-control study in a pediatric population of two Northern Italian provinces of Modena and Reggio Emilia. We included 182 registry-identified childhood leukemia cases diagnosed during 1998-2019 and 726 population controls matched on sex, year of birth, and province of residence. We assessed exposure by calculating distance from childhood residence to the nearest transformer station within a geographical information system, computing disease odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for potential confounders. We evaluated exposure using two buffers (15 m and 25 m radius) and assessed two case groups: leukemia (all subtypes) and acute lymphoblastic leukemia (ALL). RESULTS: Residing within 15 m of a transformer station (vs. ≥15 m) was not appreciably associated with risk of leukemia (all subtypes) or ALL. We found similar results using a less stringent exposure buffer (25 m). Among children aged ≥5 years, the adjusted ORs were 1.3 (95% CI 0.1-12.8) for leukemia and 1.3 (95% CI 0.1-12.4) for ALL using the 15 m buffer, while they were 1.7 (95% CI 0.4-7.0) for leukemia and 0.6 (95% CI 0.1-4.8) for ALL using the 25 m buffer. CONCLUSIONS: While we found no overall association between residential proximity to transformer stations and childhood leukemia, there was some evidence for elevated risk of childhood leukemia among children aged ≥5 years. Precision was limited by the low numbers of exposed children.

Residential proximity to petrol stations and risk of childhood leukemia.

Petrol stations emit benzene and other contaminants that have been associated with an increased risk of childhood leukemia. We carried out a population-based case-control study in two provinces in Northern Italy. We enrolled 182 cases of childhood leukemia diagnosed during 1998-2019 and 726 age- and sex-matched population controls. We geocoded the addresses of child residences and 790 petrol stations located in the study area. We estimated leukemia risk according to distance from petrol stations within a 1000 m buffer and amount of supplied fuel within a buffer of 250 m from the child's residence. We used conditional logistic regression models to approximate risk ratios (RRs) and 95% confidence intervals (CIs) for associations of interest, adjusted for potential confounders. We also modeled non-linear associations using restricted cubic splines. In secondary analyses, we restricted to acute lymphoblastic leukemia (ALL) cases and stratifed by age (<5 and ≥5 years). Compared with children who lived≥1000 m from a petrol station, the RR was 2.2 (95% CI 0.5-9.4) for children living<50 m from nearest petrol station. Associations were stronger for the ALL subtype (RR=2.9, 95% CI 0.6-13.4) and among older children (age≥5 years: RR=4.4, 95% CI 0.6-34.1; age<5 years: RR=1.6, 95% CI 0.1-19.4). Risk of leukemia was also greater (RR=1.6, 95% CI 0.7-3.3) among the most exposed participants when assigning exposure categories based on petrol stations located within 250 m of the child's residence and total amount of gasoline delivered by the stations. Overall, residence within close proximity to a petrol station, especially one with more intense refueling activity, was associated with an increased risk of childhood leukemia, though associations were imprecise.

Residential exposure to magnetic fields from high-voltage power lines and risk of childhood leukemia.

BACKGROUND: Several studies have suggested an excess risk of leukemia among children living close to high-voltage power lines and exposed to magnetic fields. However, not all studies have yielded consistent results, and many studies may have been susceptible to confounding and exposure misclassification. METHODS: We conducted a case-control study to investigate the risk of leukemia associated with magnetic field exposure from high-voltage power lines. Eligible participants were children aged 0-15 years residing in the Northern Italian provinces of Modena and Reggio Emilia. We included all 182 registry-identified childhood leukemia cases diagnosed in 1998-2019, and 726 age-, sex- and province-matched population controls. We assessed exposure by calculating distance from house to nearest power line and magnetic field intensity modelling at the subjects' residence. We used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders (distance from nearest petrol station and fuel supply within the 1000 m-buffer, traffic-related particulate and benzene concentrations, presence of indoor transformers, percentage of urban area and arable crops). RESULTS: In multivariable analyses, the OR comparing children living <100 m from high-voltage power-lines with children living ≥400 m from power-lines was 2.0 (95% CI 0.8-5.0). Results did not differ substantially by age at disease diagnosis, disease subtype, or when exposure was based on modeled magnetic field intensity, though estimates were imprecise. Spline regression analysis showed an excess risk for both overall leukemia and acute lymphoblastic leukemia among children with residential distances <100 m from power lines, with a monotonic inverse association below this cutpoint. CONCLUSIONS: In this Italian population, close proximity to high-voltage power lines was associated with an excess risk of childhood leukemia.

Real-life experience with hydroxyurea in sickle cell disease: A multicenter study in a cohort of patients with heterogeneous descent.

We conducted the first nation-wide cohort study of sickle cell disease (SCD) in Italy, a Southern European country exposed to intense recent flux migration from endemic areas for SCD. We evaluate the impact of hydroxyurea on a total of 652 pediatric and adult patients from 33 Reference Centers for SCD (mean age 24.5±15years, 51.4% males). Hydroxyurea median treatment duration was 7years (range: <1year to 29years) at a mean therapeutic dose of 18±4.7mg/kg/day. Hydroxyurea was associated with a significant increase in mean total and fetal hemoglobin and a significant decrease in mean hemoglobin S, white blood and platelet counts, and lactate dehydrogenase levels. Hydroxyurea was associated with a significant reduction in the incidence of acute chest syndrome (-29.3%, p<0.001), vaso-occlusive crisis (-34.1%, p<0.001), hospitalization (-53.2%, p<0.001), and bone necrosis (-6.9%, p<0.001). New silent cerebral infarction (SCI) occurred during treatment (+42.4%, p<0.001) but not stroke (+0.5%, p=0.572). These observations were generally consistent upon stratification for age, descent (Caucasian or African), genotype (ßS/ßS, ßS/ß0 or ßS/ß+) and duration of treatment (< or ≥10years). There were no new safety concerns observed compared to those commonly reported in the literature. Our study, conducted on a large population of patients with different descent and compound state supports the benefits of hydroxyurea therapy as a treatment option. Registered at clinical trials.gov (NCT02709681).

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.

Primary Pediatric Cutaneous T-Cell Lymphoproliferative Disorders: 3 New Cases.

Primary cutaneous lymphoproliferative disorders are a composite group of diseases with considerable differences in histopathologic, immunophenotypic, and clinical features. They are exceedingly rare in children and in the literature only few cases are reported with extremely different therapeutic approaches. Because of the rarity of cutaneous lymphomas we consider crucial to increase the knowledge of these diseases providing every single case. We present 3 pediatric cases of primary cutaneous T-cell lymphomas occurred to our center with different features and therapeutic approach.

Universal Screening Program in Pregnant Women and Newborns at-Risk for Sickle Cell Disease: First Report from Northern Italy.

The implementation of screening programs for early detection of patients with sickle cell disease has become necessary in Italy as a result of the high rate of migration from areas with a high prevalence of the disease (Sub-Saharan Africa, Middle East and the Balkans). Following a pilot study performed in the province of Modena, Italy in 2011-2013, an official screening program was established on May 31 2014 for all pregnant women, free-of-charge for the family according to the National Guidelines for Physiological Pregnancy. Hemoglobin (Hb) profiles of pregnant women within 10 weeks of pregnancy, of new mothers at delivery and of the newborns of mothers with variant Hb profiles (newborns at-risk), were evaluated by high performance liquid chromatography (HPLC). Samples from 17,077 new mothers were analyzed and 993 showed alteration of Hb patterns (5.8%) (1.0% Hb AS carriers); of the 1011 at-risk newborns, four (0.4%) carried sickle cell disease and 90 (8.9%) were Hb AS carriers. These data show that early diagnosis of sickle cell disease or carrier status can be obtained in high-risk newborns, providing valuable information on the frequency of these conditions in geographic areas in which the disease is historically rare.

Effects of nutritional intake on disease severity in children with sickle cell disease.

BACKGROUND: Children with Sickle Cell Disease (SCD) may show growth failure in comparison to healthy peers. Many factors as hematological status, endocrine and/or metabolic dysfunction, and nutritional status, may play an important role in growth failure. The aim of this study was to assess whether impaired growth and nutritional intake can affect SCD severity during childhood. METHODS: We conducted an observational study on children with SCD referring to our clinic for routine follow-up visits in a 6-month period. We collected information on weight, height and body mass index (BMI) and calculated their respective standardized scores (z). The nutritional intake was assessed through the last 24-h recall intake of total calories, macro- (proteins, lipids, carbohydrates) and micronutrients (calcium, iron, phosphorus, vitamins B1, PP, A, C, B2). Disease severity was assessed through total hemoglobin (Hb) and fetal hemoglobin (HbF), and lactic dehydrogenase (LDH) levels, and through the total number and days of hospitalizations, as well as the lifetime episodes of acute chest syndrome (ACS). RESULTS: Twenty nine children (14 males, 15 females) with SCD were enrolled; their mean age was 9.95 years (SD 3.50, min 3.72, max 17.18). Z-weight and z-BMI were significantly directly related to total Hb. Food intake resulted significantly unbalanced in terms of total calorie intake, macro- and micronutrients, especially calcium, iron, vitamin B1 and C. Low intake of calcium and vitamin B1 were significantly inversely correlated with number and days of hospitalizations per year. Protein, lipid, phosphorus, and vitamin PP intakes resulted adequate but were inversely correlated with number and days of hospitalizations. Carbohydrate, lipid, iron, phosphorus, vitamins B1 and B2 intakes were significantly inversely correlated to HbF levels. CONCLUSIONS: This study showed that, in our population, inadequate nutritional intake, weight and BMI have a significant impact on SCD severity indices.

Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP).

Acquired aplastic anemia (AA) is a rare heterogeneous disease characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3/million inhabitants/year, in Europe, but higher in East Asia. Survival in severe aplastic anemia (SAA) has markedly improved in the past 2 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive and biologic drugs, and supportive care. In SAA hematopoietic stem cell transplant (HSCT) from a matched sibling donor (MSD) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary, evidence-based document issued by a group of pediatric hematologists was discussed, modified and approved during a series of "Consensus Conferences" according to procedures previously validated by the AIEOP Board. The guidelines highlight the importance of referring pediatric patients with AA to pediatric centers with long experience in diagnosis, differential diagnosis, management, supportive care and follow-up of AA.

Increased incidence of childhood leukemia in urban areas: a population-based case-control study.

OBJECTIVE: We carried out a population-based case-control study to assess the possibility of an excess risk of childhood leukemia in urban areas, independently from road traffic pollution. METHODS: Study subjects were the 111 cases of childhood leukemia diagnosed from 1998 to 2011 among residents of two provinces of the northern Italian Emilia-Romagna region, and 444 controls matched by age and sex. Through mapping of the region carried out by remote sensing, we examined the percentage of urban or rural area in the 100-meter circular buffer around each child's house. We also modeled annual average exposure to benzene and PM10 from vehicular traffic at each residence. RESULTS: In a multivariate model adjusting for benzene and PM10, the odds ratio of leukemia associated with residence in a highly urbanized area and residential area (≥95% land use of this type near the child's home) was 1.4 (95% confidence intervals 0.8-2.4) and 1.3 (0.8-2.2), respectively. An increased risk was also found in association with the proximity to «dumps, scrap yards, and building sites¼. No association emerged with residence in rural areas or near industrial plants. CONCLUSIONS: These results indicate that children living in urban areas experience an excess leukemia risk, independently from exposure to pollutants from vehicles.

Identifying skull fractures after head trauma in infants with ultrasonography: is that possible?

Management of pediatric head trauma requires a delicate balance between accuracy and safety, with a dual emphasis on prompt diagnosis while minimizing radiation exposure. Ultrasonography (US) shows promise in this regard. A case study involving a 10-month-old infant with acute right parietal swelling revealed the utility of US in detecting a corresponding hypoechoic lesion, along with an underlying suspected fracture line of the vault and subdural hematoma. Subsequent CT confirmed the fracture, while MRI confirmed the subdural hematoma. At one-month follow-up, MRI demonstrated hematoma reabsorption, while US revealed a bone callus in its advanced phase. Although US is not yet standard practice for pediatric head trauma, its ability to detect fractures in infants suggests its potential role: when a fracture is evident on US, it may serve as an indication to perform neuroimaging. Potentially, adoption of US could contribute to mitigation of children's exposure to ionizing radiation.

Management of the Sickle Cell Trait: An Opinion by Expert Panel Members.

The number of individuals with the sickle cell trait exceeds 300 million worldwide, making sickle cell disease one of the most common monogenetic diseases globally. Because of the high frequency of sickle cell disease, reproductive counseling is of crucial importance. In addition, unlike other carrier states, Sickle Cell Trait (SCT) seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and complications during pregnancy and surgery. This expert panel believes that increasing knowledge about these clinical manifestations and their prevention and management can be a useful tool for all healthcare providers involved in this issue.

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.

Leukemia risk in children exposed to benzene and PM10 from vehicular traffic: a case-control study in an Italian population.

Benzene, a recognized occupational leukemogen in adults, has been hypothesized to also increase the risk of childhood leukemia. We carried out a population-based case-control study in a northern Italy community involving 83 cases with acute childhood leukemia diagnosed in the years 1998-2009 and 332 matched controls. We assessed residential exposure to benzene and to particulate matter ≤10 µm (PM10) from motorized traffic using geocoded residences and detailed emission and dispersion modeling. Exposure to benzene, and to a lesser extent to PM10, appeared to be independently associated with an excess leukemia risk. When we stratified the study population by age and by leukemia subtype, the relative risk associated with benzene exposure was higher among children aged less than 5 years, and despite small numbers this relation appeared to be considerably stronger for acute myeloid leukemia than for acute lymphoblastic leukemia. Overall, these findings suggest that exposure to low levels of benzene released from motorized traffic may increase the risk of childhood leukemia, and suggest a possible independent effect of PM10, although unmeasured confounding due to other pollutants cannot be ruled out.

Environmental Factors in Northern Italy and Sickle Cell Disease Acute Complications: A Multicentric Study.

BACKGROUND: Environmental factors seem to influence clinical manifestations of sickle cell disease (SCD), but few studies have shown consistent findings. We conducted a retrospective multicentric observational study to investigate the influence of environmental parameters on hospitalization for vaso-occlusive crises (VOC) or acute chest syndrome (ACS) in children with SCD. METHODS: Hospital admissions were correlated with daily meteorological and air-quality data obtained from Environmental Regional Agencies in the period 2011-2015. The effect of different parameters was assessed on the day preceding the crisis up to ten days before. Statistical analysis was performed using a quasi-likelihood Poisson regression in a generalized linear model. RESULTS: The risk of hospitalization was increased for low maximum temperature, low minimum relative humidity, and low atmospheric pressure and weakly for mean wind speed. The diurnal temperature range and temperature difference between two consecutive days were determined to be important causes of hospitalization. For air quality parameters, we found a correlation only for high levels of ozone and for low values at the tail corresponding to the lowest concentration of this pollutant. CONCLUSIONS: Temperature, atmospheric pressure, humidity and ozone levels influence acute complications of SCD. Patients' education and the knowledge of the modes of actions of these factors could reduce hospitalizations.

Transfusional Approach in Multi-Ethnic Sickle Cell Patients: Real-World Practice Data From a Multicenter Survey in Italy.

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder characterized by recurrent acute vaso-occlusive crises (VOCs and anemia). Gold standard treatments are hydroxycarbamide (HC) and/or different red blood cell (RBC) transfusion regimens to limit disease progression. Here, we report a retrospective study on 1,579 SCD patients (median age 23 years; 802 males/777 females), referring to 34 comprehensive Italian centers for hemoglobinopathies. Although we observed a similar proportion of Caucasian (47.9%) and African (48.7%) patients, Italian SCD patients clustered into two distinct overall groups: children of African descent and adults of Caucasian descent. We found a subset of SCD patients requiring more intensive therapy with a combination of HC plus chronic transfusion regimen, due to partial failure of HC treatment alone in preventing or reducing sickle cell-related acute manifestations. Notably, we observed a higher use of acute transfusion approaches for SCD patients of African descent when compared to Caucasian subjects. This might be related to (i) age of starting HC treatment; (ii) patients' low social status; (iii) patients' limited access to family practitioners; or (iv) discrimination. In our cohort, alloimmunization was documented in 135 patients (8.5%) and was more common in Caucasians (10.3%) than in Africans (6.6%). Alloimmunization was similar in male and female and more frequent in adults than in children. Our study reinforces the importance of donor-recipient exact matching for ABO, Rhesus, and Kell antigen systems for RBC compatibility as a winning strategy to avoid or limit alloimmunization events that negatively impact the clinical management of SCD-related severe complications. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03397017.

Effect of eradication of Helicobacter pylori in children with chronic immune thrombocytopenia: a prospective, controlled, multicenter study.

BACKGROUND: The eradication of Helicobacter pylori has been associated with remission of immune thrombocytopenia (ITP) in approximately half of eradicated patients. Data on children are limited to small case series. PROCEDURE: Children from 16 centers in Italy, who were less than 18 years of age and diagnosed with chronic ITP (cITP), were screened for H. pylori infection. Positive patients underwent standard triple therapy with amoxicillin, clarithromycin, and omeprazole. The eradication response was defined as follows: complete response, platelet (PLT) count ≥ 150 × 10(9) /L; partial response, PLT count of at least 50 × 10(9) /L; no response, PLT count <50 × 10(9) /L. RESULTS: Of 244 screened patients, 50 (20%) had H. pylori infection, 37 of which received eradication therapy and completed follow-up. Eradication was successful in 33/37 patients (89%). PLT recovery was demonstrated in 13/33 patients after eradication (39%), whereas spontaneous remission was observed in 17/166 (10%) H. pylori-negative patients (P < 0.005). Responders more often required second line eradication (9/13), whereas a second cycle was required in 3/20 non-responders (P < 0.005). CONCLUSIONS: Among the large cohort of patients, those who underwent successful H. pylori eradication showed a significantly higher PLT response. Therefore, it may be appropriate to look for H. pylori and eventually eradicate it in children with cITP.