Sofia Maria Rosaria Matarese

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

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.

Long‐term follow‐up analysis after rituximab therapy in children with refractory symptomatic ITP: identification of factors predictive of a sustained response

We report the long‐term follow‐up (median 39·5 months) of 49 paediatric patients (33 females and 16 males) with refractory symptomatic immune thrombocytopenic purpura (ITP) treated with rituximab. The overall response rate was 69% (34/49 patients). Twenty‐one responders had a platelet count >50 × 109/l at a median 20·2 months from treatment. Kaplan–Meier analysis showed a probability of relapse‐free survival (RFS) of 60% at 36 months from the first rituximab infusion. The number of infusions and a previous splenectomy did not influence overall response rate. Patients who achieved complete response were significantly older at diagnosis and first rituximab infusion than partial responders (P = 0·027). Older children displayed a significantly greater probability of sustained response (RFS) at 36 months than younger children (88·9% vs. 56·7%, P = 0·037). Earlier responses (within 20 d from treatment) were significantly associated with both complete (P = 0·004) and sustained response (P = 0·002). Only mild and transient side‐effects were observed in 9/49 children; no major infections nor delayed toxicities were recorded during the follow‐up.

Rituximab (anti-cd20 monoclonal antibody) in children with chronic refractory symptomatic immune thrombocytopenic purpura: efficacy and safety of treatment

This retrospective study investigated the effects of rituximab in 19 pediatric patients (15 girls and 4 boys) with chronic refractory symptomatic immune thrombocytopenic purpura (ITP). Patients received from 2 to 5 weekly infusions of rituximab (375 mg/m2); 15 patients were younger than 12 years when treated. The median follow-up time was 30 months (range, 9–43 months). The overall response rate was 68% (13/19 patients). Six responders relapsed at a median of 4.5 months (range, 3–8 months). Seven patients still displayed a platelet count >150,000/μL at a median of 33 months (range, 14-43 months) after rituximab treatment. Six of 15 patients treated with 4 or 5 weekly infusions and 1 of 4 patients treated with 2 or 3 infusions are still in remission. No difference was detected between splenectomized and nonsplenectomized patients. The duration of ITP disease at the time of treatment did not influence the response rate. Patients still in remission showed significantly lower levels of CD19+ cells after 4 and 6 months than nonresponding or relapsed patients (P < .05). No major infections were reported during follow-up. Our data show the efficacy and tolerability of rituximab in young children with refractory symptomatic ITP. Nonrelapsed patients showed a more prolonged B-cell depletion.

CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura

Immune thrombocytopenic purpura is an acquired autoimmune disorder that is the most common cause of thrombocytopenia in children. The endocannabinoid system is involved in immune regulation. We evaluated a common missense variant (CAA/CGG; Q63R) of the gene encoding the cannabinoid receptor type 2 (GeneID 1269) in 190 children with immune thrombocytopenic purpura and 600 healthy controls. The allelic frequencies and genotype distribution of the polymorphism in the patients were significant compared to control samples (P=0.006 and P=0.0001, respectively). Interestingly, when acute and chronic immune thrombocytopenic purpura patients were analyzed separately with respect to controls, a significant overrepresentation of the RR genotype and of the R allele was observed only for the chronic form (P=0.00021 and P=0.011, respectively). The relative odds ratio suggested the risk of developing chronic form was more than double in immune thrombocytopenic purpura children homozygous for the variant (odds ratio=2.349, 95% CI: 1.544–3.573; P<0.001).

Effect of VDR polymorphisms on growth and bone mineral density in homozygous beta thalassaemia

Summary. We examined the effect of vitamin D receptor (VDR) polymorphisms at exon 2 (FokI) and intron 8 (BsmI) on the stature and bone mineral density at femoral neck (FBMD) and lumbar spine (LBMD) in 108 prepubertal and pubertal homozygous β thalassaemic patients, regularly treated. We found significantly shorter stature and lower LBMD and FBMD in all patients with CC VDR genotype, and significant shorter height and lower LBMD in prepubertal and pubertal female patients with BB VDR genotype. Because homozygous CC and BB VDR genotypes influence Vitamin D activity, they can be considered additional risk factors for bone disease in β thalassaemia.

Cardiac Involvement in β‐Thalassemia Major and β‐Thalassemia Intermedia

The forms and severity of cardiac complications were investigated in patients with asymptomatic thalassemia intermedia and thalassemia major by M‐mode, bi‐dimensional echocardiography (ECHO) and echo‐Doppler. Twenty‐eight patients of both sexes with β‐thalassemia intermedia (β‐TI), mean age 23.2 ± 6.3 years, untransfused or minimally transfused, were compared to 42 age‐ and sex‐matched subjects with thalassemia major, who were regularly treated with hemotransfusive therapy [pre‐transfusion hemoglobin (Hb) values 9.5 ± 0.9 g/dL] and iron chelation. All patients were splenectomized. Age and sex matched healthy control subjects were randomly selected. β‐Thalassemia major (β‐TM) patients showed a marked reduction in contractile state and a milder left ventricular (LV) enlargement than β‐TI patients. Cardiac output (CO) and cardiac index (CI) were increased in both groups of patients but appeared significantly higher in β‐TI patients with consequent altered LV diastolic function indices. In addition, β‐TI patients had reduced indices of pulmonary artery flow related to long‐term chronic anemia rather than iron overload. The progressive rise in CO and CI casts doubts on the current management of β‐TI syndromes.

Evaluation of body iron status in Italian carriers of beta-thalassemia trait

Abstract Iron deficiency is the most common single nutrient disorder in humans. Carriers of β-thalassemia have frequently been considered patients in whom iron deficiency difficulty may co-exist because dyserythropoiesis enhances enteric iron absorption. We studied 185 normal children and 146 heterozygous children for β-thalassemia. Furthermore, 51 normal men and 45 men with β-thalassemia trait as well as 43 normal women of childbearing age and 25 carriers of the same age were studied. Serum ferritin estimations were performed by RIA technique. No difference in iron deficiency prevalence was found among heterozygous children for β-thalassemia compared to normal children. The same was observed in adults. As for iron overload, the only statistically significant difference has been observed among men. Affected men tend to develop iron overload. Carriers of β-thalassemia are world-wide with a high rate among people of Mediterranean ancestry and in some developing countries. This condition concerns millions of people and, therefore, physicians should be aware that iron deficiency might co-exist or develop in many of them.

Role of polymorphic sequences 5′ to the Gγ gene and 5′ to the β gene on the homozygous β thalassemic phenotype

Sixty‐seven homozygous male and female thalassemic patients with different phenotypes, aged between 8 and 33 years, were divided into three groups, according to the severity of their β‐thalassemia (thal) mutations. We investigated whether some co‐inherited genetic factors could influence the phenotype. Patients with milder β‐thal defects, homozygotes or compound heterozygotes for the IVS‐I‐6 (T→C) or −87 (C→G) mutations had a milder disease. In addition, determination of the co‐inheritance of the −158 (C→T) Gγ polymorphism and the (AT)9T5 repeat motif in the region −540 to −525, 5′ to the β‐globin gene, showed that in some patients with severe or mild/severe β‐thal mutations, linked to haplotype III, there was higher Hb F expression. We conclude that in homozygous β‐thal patients, the severity of the mutations is the most important factor influencing the phenotype, but some polymorphisms such as the −158 (C→T) Gγ and (AT)9T5 repeat motif, increasing the Hb F expression and ameliorate the clinical course of the disease.

Amoxicillin-Induced Hemolytic Anemia in a Child with Glucose 6-Phosphate Isomerase Deficiency

Objective: To describe the first case of amoxicillin-induced nonimmune hemolytic anemia in a child with glucose-6-phosphate isomerase (GPI) deficiency. Case Summary: A 3-year-old boy with GPI deficiency was admitted for upper respiratory tract infection and fever. The patient was treated with a standard dose of amoxicillin (50 mg/kg/day). On hospital admission, the child had a chronic moderately low hemoglobin level (8.6 g/dL), but within 24 hours of the first amoxicillin dose, the hemoglobin level markedly decreased (5.8 g/dL), the reticulocyte level increased (58%), and the urine darkened. Results of the direct and indirect Coombs tests were negative and the acute hemolytic phase ended spontaneously 8 days after amoxicillin withdrawal (hemoglobin 9.5 g/dL, reticulocytes 22%). Discussion: All previous cases of amoxicillin-induced hemolytic anemia have been attributed to an immune mechanism. Given the absence of anti-reticulocyte antibodies (Coombs test), we suggest that the amoxicillin-induced hemolytic anemia in our patient occurred via a nonimmune mechanism favored by the childs GPI deficiency. Based on a MEDLINE search, we believe this to be the first report of amoxicillin-induced nonimmune hemolytic anemia in a child with GPI deficiency. GPI deficiency has been associated with well-compensated chronic hemolytic anemia that can become clinically relevant consequent to the administration of drugs. GPI deficiency can lead to impairment of the system that removes free radicals generated by amoxicillin, thereby resulting in oxidation of hemoglobin and destabilization of red cell membranes, with acute hemolysis and severe hemoglobinuria. The Naranjo probability score was consistent with a probable relationship between the hemolytic anemia and amoxicillin therapy. Conclusions: This report reinforces the hypothesis that a drug-sensitivity reaction is closely related to a genetically transmitted enzyme deficiency.

HEMATOLOGICAL AND MOLECULAR ANALYSIS OF β-THALASSEMIA AND Hb LEPORE IN CAMPANIA, ITALY

This epidemiological study was based on a hematological and a molecular analysis of 310 heterozygous β thalassemic and 75 carriers of Hb Lepore out of 3,000 microcythemic subjects from the Campania region of Italy. The molecular analysis of β chains and the δβ hybrid gene has shown different β chain defects, but only the Hb Lepore-Boston-Washington type in association with haplotypes I and V. The prevalence and distribution of these molecular defects in Campania show that they are linked to historical events and to the geographical characteristics of this region.