Vittorio Carnelli

The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients

Summary. In 1997, the Italian Ministry of Health created a special programme for the controlled distribution of deferiprone to collect data and to evaluate its safety and effectiveness in long‐term use. Five hundred and thirty‐two thalassaemia patients from 86 treatment centres were enrolled in this programme. One hundred and eighty‐seven patients (32%) experienced a total of 269 events that led to a temporary interruption or, in some cases, to a discontinuation of treatment. The incidence of agranulocytosis and milder neutropenias were 0·4/100 and 2·1/100 patient‐years respectively. Neutropenia occurred predominantly in younger and non‐splenectomized patients. Transient alanine transaminase increase, gastrointestinal discomfort and arthralgia were the other most commonly reported events. Ferritin levels showed a significant decrease in time after 3 years of therapy. This is the largest number of deferiprone‐treated patients to have been reported to date. These data show that the drug was effective in reducing serum ferritin levels and the incidence of adverse events was not greater than the frequency reported in clinical trials.

Leukocyte depletion of red cell units at the bedside by transfusion through a new filter

Standard packed red cell (PRC) units can be depleted of leukocytes and platelets if they are transfused through a blood administration set in which the usual 170‐mu filter has been replaced by a leukocyte removal filter (Sepacell R‐500). During a 6‐month period, 1550 PRC units were transfused through this filter in 611 transfusions to 80 multitransfused patients with thalassemia who had had a patient reaction rate (PRR) of 63 percent and a transfusion reaction rate (TRR) of 13 percent when given standard PRC or buffy‐coat‐depleted PRC. When given filtered PRC, PRR and TRR became 3.7 percent and 0.5 percent, respectively. The effectiveness of the filter was also evaluated in vitro. By filtering 2 standard PRC units through the same filter, median values (and ranges) for red cell recovery and for residual leukocytes and platelets were 87 percent (83–92), 6.1 × 10(6) (0–100), and 2.7 × 10(9) (0.6–9.7), respectively. Although refinements are needed to improve standardization of the filter and to increase red cell recovery (which is low when 1 unit is filtered through one filter) and blood administration rate, the ability to provide leukocyte‐free red cells prepared at the bedside for virtually all recipients appears to be a realistic goal.

Removal of white cells from red cells by transfusion through a new filter

The effectiveness of a new filter (RC100) for the preparation of white cell‐depleted red cells (RBCs) at the bedside was evaluated in vitro and in vivo using three RBC products: standard RBC concentrate (CPDA units), RBCs suspended in saline‐adenine‐glucose‐mannitol additive solution after the removal of plasma (SAGM units), and RBCs suspended in SAGM after the removal of plasma and buffy coat (SAGM‐BC units). Median RBC recovery was at least 92 percent when 2 units were administered through one filter; median values for residual white cells and platelets were less than or equal to 20 × 10(6) and less than or equal to 2.5 × 10(9) per 2 units, respectively. The in vivo study was carried out in 80 multiply transfused patients with thalassemia, 35 of whom had experienced frequent nonhemolytic transfusion reactions when given standard or buffy coat‐free RBCs. During the 6‐month study, each patient was given two transfusions of each type of RBC product One febrile nonhemolytic transfusion reaction occurred in each of two patients receiving SAGM‐BC units, but in no other case. If the flow rate is not reduced, the median transfusion time is 35 minutes per CPDA unit and 15 minutes per SAGM and SAGM‐BC unit. It is concluded that the transfusion of RBCs through the RC100 is a simple and effective procedure to administer white cell‐depleted RBCs prepared at the bedside.

Bone demineralization in adult thalassaemic patients: contribution of GH and IGF‐I at different skeletal sites

Background and objective  GH and IGF‐I exert an important role in the control of bone formation, as shown by decreased bone mineral density and increased fracture risk in adult hypopituitary patients untreated for GH deficiency (GHD). Different degrees of bone demineralization are frequently reported in patients affected by β‐thalassaemia. Considering the high prevalence of GHD recently observed by our group among adult thalassaemic patients, we elected to study the possible role of GH–IGF‐I abnormalities in the pathogenesis of the osteopenia/osteoporosis of this disease.

Early detection of cardiac dysfunction in thalassemic patients by radionuclide angiography and heart rate variability analysis

Abstract:  Background: Cardiac dysfunction remains the major cause of death in beta‐thalassemia. Aim of this study was to assess early myocardial damage in thalassemic patients with no symptoms or echocardiographic evidence of dysfunction at routine monitoring. Methods: Twenty patients (seven females; median 25 yr [first quartile 22,third quartile 28]) with beta‐thalassemia underwent radionuclide angiography (RNA) at rest and during low‐dose dobutamine infusion (5–10 γ/kg/min). Right and left ventricular ejection fractions (EF) were determined by first‐pass method and gated equilibrium acquisition, respectively. Twenty‐four‐hour Holter monitoring with time‐domain heart rate variability (HRV) assessment and echocardiographic follow‐up (21 months [5,27]) were performed. Results: Eleven patients showed regional wall motion abnormalities at RNA; left ventricular EF, HR and diastolic measurements significantly increased after dobutamine infusion. Patients with abnormal RNA right ventricular EF (n = 8, <0.45) showed lower echocardiographic left ventricular EF at the enrolment (0.54 [0.50,0.61] vs. 0.62 [0.56,0.67], P = 0.02) than those with a normal right ventricular EF. Patients with reduced standard deviation of the averages of RR intervals in all 5‐minute periods of entire recording (SDANN) (n = 6, <100 ms), a measure of HRV, had lower echocardiographic left ventricular EF (0.53 [0.49,0.62] vs. 0.62 [0.56,0.66], P = 0.03) and lower fractional shortening (0.28 [0.25,0.32] vs. 0.36 [0.30,0.39], P = 0.003) at the enrolment than those with normal SDANN. No significant association was found between RNA and HRV measurements and follow‐up left ventricular function. Conclusions: Right ventricular dysfunction and abnormal HRV may represent the early features of cardiac disease in thalassemic patients with no evidence of ventricular dysfunction at routine evaluation.

Growth hormone deficiency (GHD) in adult thalassaemic patients

Background and objective  Short stature and growth hormone deficiency (GHD) are frequent occurrences in thalassaemic children, while data on the prevalence of GHD in adult patients are lacking. Therefore, we elected to study the growth hormone and insulin‐like growth factor‐I (GH–IGF‐I) axis in a large group of adult thalassaemic subjects.

Safety and Immunogenicity of a Conjugate Vaccine against Haemophilus influenzae Type b in Splenectomized and Nonsplenectomized Patients with Cooley Anemia

Patients with thalassemia are at increased risk for infections, especially after undergoing splenectomy. Vaccinations and antimicrobial prophylaxis are recommended in these patients, but the optimal immunization schedule for Haemophilus influenzae type b (Hib) vaccine is unknown. The immunogenicity of a conjugate Hib vaccine was investigated in 57 patients with thalassemia, 32 of whom had undergone splenectomy. Anti-capsular antibodies to Hib (anti-polyribosylribitol phosphate) were measured before vaccination and 2, 6, 12, 24, and 36 months after vaccination. Immunization was well tolerated. All patients achieved protective (>1 microg/mL) antibody levels. Antibody titers declined after the initial postvaccination increase, becoming undetectable in 4 patients and decreasing to concentrations of 0.15-1 microg/mL in another 2 patients when tested 2-3 years after vaccination. Hib conjugate vaccine is safe and immunogenic in patients with thalassemia major; however, additional studies are needed to assess the need and timing of booster vaccination to maintain long-term immunity.

Assessment for evidence of non a-non b hepatitis in patients given n-heptane-suspended heat-treated clotting factor concentrates

Nineteen patients, (2 adults, 17 children) with inherited bleeding disorders were infused with n-heptane-suspended-heated clotting factor concentrates. Twelve of the nineteen were previously untreated. Six patients were infused with Profilnine Heat-Treated and 13 with Profilate Heat-Treated. Five separate centers participated and were given various lots of concentrates for use. Blood from the seventeen children was sampled prior to entry, at infusion, 2 weeks, 6 weeks, 12 weeks and 6 months after the first infusion. The two adults were sampled every 2 weeks. Twelve of the 19 patients were followed beyond six months. Three patients demonstrated a rise in ALT during the first six months of observation with levels above 2.5 times the upper limit of normal. One of these patients showed a parallel increment in a-CMV IgM titer and a second patient, an adult, had previously received many units of single donor blood components. During the second 6 month observation interval, two patients showed a rise in ALT. One of these patients had been exposed to only one lot of concentrate with no other viral cause being determined. Two additional patients had a moderate increase in ALT up to 98 U/L (normal less than 50). No patients were clinically ill or showed jaundice during these episodes. The hepatitis episode at 11 months in the patient using one lot of concentrate, might suggest a non-viral mechanism in this instance. This study indicates that these concentrates may be associated with episodes of ALT above 2.5 times the upper limit of normal in approximately 20% of the patients treated, but the etiology of the raised ALT may not always be Non A-Non B hepatitis.

Invasive Aspergillus nidulans infection in a patient with chronic granulomatous disease

The patient was a 21-year-old boy affected by X-linked chronic granulomatous disease (CGD-OMIM number 3064000), with a mutation in the gene encoding gp91 phox (deletion of a single G in position 767, with loss of gp91 phox and no residual NADPH oxidase activity), diagnosed at the age of 2, because of a positive family history for CGD. He had recurrent skin abscesses, lymphadenitis, bacterial pneumonia, and lung aspergillosis with probable brain dissemination. His parents compliance was poor and they had discontinued all therapies for a number of years without notice. The patient was referred to our hospital for the first time at the age of 10 because of a multifocal pneumonia with isolation of Aspergillus fumigatus in multiple sputum cultures. He was successfully treated with intravenous conventional amphotericin B and then a prophylactic regimen with trimethoprim–sulfamethoxazole, itraconazole and interferon gamma was prescribed. At the age of 13, the patient presented another brain focus, which resolved under a treatment with liposomal amphotericin B followed by oral itraconazole. His parents admitted once again their poor compliance with prophylactic treatment. When he was 21, the patient was hospitalised because of a large popliteal abscess in the right leg (Fig. 1) and a large area of parenchymal consolidation in the right lung. Right leg magnetic resonance imaging (MRI) excluded bone damage on multiple scans and a brain MRI did not reveal any new damage, but only traces of the old parenchymal lesions. Aspergillus spp. was isolated from a sputum sample and Aspergillus nidulans was isolated in repeated popliteal abscess cultures. An in vitro antifungal susceptibility test of the A. nidulans isolate was performed with Etest (AB-Biodisk, Solna, Sweden). The minimum inhibitory concentrations resulted in the following: itraconazole 0.12 lg ml, voriconazole 0.094 lg ml, amphotericin B 0.19 lg ml. Histological examination showed granulation tissue with abscesses, a granuloma of giant plurinucleated cells and the presence of septate hyphae compatible with the morphology of the isolated A. nidulans. The presence of precipitating antibodies against somatic and metabolic A. fumigatus antigens (Microgen Bioproducts, Camberley, UK; Bio-Rad, Marnes-la Coquette, France) agreed with the isolation of Aspergillus in culture. On the contrary, no galactomannan antigen was detected using Platelia Aspergillus (Bio-Rad) in repeated serum samples. The level of total serum IgE was 8910 kIU l and anti A. fumigatus IgE Correspondence: Prof. Maria Cristina Pietrogrande, Department of Pediatrics, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Via Commenda 9, Milan 20122, Italy. Tel.: +39 2 5503 2496. Fax: +39 2 5032 0210. E-mail: mariacristina.pietrogrande@unimi.it

The decision-making process in antibacterial treatment of pediatric upper respiratory infections: a national prospective office-based observational study

BACKGROUND The identification of patient management practices and the sources of medical information is crucial for rationalizing the treatment of respiratory tract infections, whose high incidence, especially in children, makes them one of the maior areas of unnecessary health expenditure. MATERIALS AND METHODS This national prospective study was designed to investigate the diagnostic and prescribing habits of 100 office-based pediatricians managing upper respiratory tract infections in 1111 pediatric patients (604 males, mean age 6.7962.77 years; 507 females, mean age 6.7362.8 years) sequentially enrolled when an antibiotic treatment was deemed necessary. RESULTS The most frequently diagnosed diseases were acute tonsillopharyngitis (56.2%) and acute otitis media (18.1%). Penicillins were prescribed in 34.3% of the cases, cephalosporins in 38.1%, and macrolides in 26.1%: oral drugs accounted for 92.2% of the prescriptions. The treatments were administered once or twice daily in 75.8% of the patients, and prescribed for 8 days in more than 80%; 76.7% also received supportive or symptomatic treatment (antipyretics, corticosteroids, cough suppressants and non-steroidal anti-inflammatory drugs). Laboratory or radiologic investigations were rarely requested. The main sources of medical information indicated by the participating pediatricians were pharmaceutical companies (35.6%) and meeting or congress reports (27.3%). CONCLUSIONS The results indicate that more active education is still needed to improve the decision-making processes of office-based pediatricians.