Showing papers by "Maria Domenica Cappellini published in 2019"

Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia.

Abstract: s-thalassemia is caused by s-globin gene mutations resulting in reduced (β+) or absent (β0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express s-globin represents a potential therapeutic option. We treated three adults and six children with s0 or severe s+ mutations in a phase 1/2 trial ( NCT02453477 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6–76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10–1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome. In a phase 1/2 clinical trial, gene therapy with autologous hematopoietic stem cells significantly reduced transfusion requirement in adults and children with transfusion dependent s-thalassemia.

Sotatercept, a novel transforming growth factor β ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study.

Abstract: β-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin β globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. Sotatercept (ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor β superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent β -thalassemia and 30 patients with non-transfusion-dependent β-thalassemia were enrolled at seven centers in four countries between November 2012 and November 2014. Patients were treated with sotatercept at doses of 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to determine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent β-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion-dependent β-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life-threatening adverse events were observed. Thirteen percent of patients reported serious but manageable adverse events. The active dose of sotatercept was ≥0.3 mg/kg for patients with non-transfusion-dependent β-thalassemia and ≥0.5 mg/kg for those with transfusion-dependent β-thalassemia. Of 30 non-transfusion-dependent β-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent β-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with β-thalassemia. Most patients with non-transfusion-dependent β-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent β-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.

Current challenges in the management of patients with sickle cell disease - A report of the Italian experience.

Abstract: Sickle cell disease (SCD) is an inherited red blood cell disorder caused by a structural abnormality of hemoglobin called sickle hemoglobin (HbS). Clinical manifestations of SCD are mainly characterized by chronic hemolysis and acute vaso-occlusive crisis, which are responsible for severe acute and chronic organ damage. SCD is widespread in sub-Saharan Africa, in the Middle East, Indian subcontinent, and some Mediterranean regions. With voluntary population migrations, people harboring the HbS gene have spread globally. In 2006, the World Health Organization recognized hemoglobinopathies, including SCD, as a global public health problem and urged national health systems worldwide to design and establish programs for the prevention and management of SCD. Herein we describe the historical experience of the network of hemoglobinopathy centers and their approach to SCD in Italy, a country where hemoglobinopathies have a high prevalence and where SCD, associated with different genotypes including s-thalassemia, is present in the native population.

Quality of life in patients with β-thalassemia: A prospective study of transfusion-dependent and non-transfusion-dependent patients in Greece, Italy, Lebanon, and Thailand.

Abstract: REFERENCES 1. Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers. 2017;3:17020. 2. Jestin M, Benhamou Y, Schelpe AS, et al. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018;132(20):2143-2153. 3. Kasi PM, Tawbi HA, Oddis CV, Kulkarni HS. Clinical review: serious adverse events associated with the use of rituximab a critical care perspective. Crit Care. 2012;16(4):231. 4. Daly ME. Determinants of platelet count in humans. Haematologica. 2011;96(1):10-13. 5. Cartron G, Watier H. Obinutuzumab: what is there to learn from clinical trials? Blood. 2017;130(5):581-589. 6. CrowleyMP, McDonald V, Scully M. Ofatumumab for TTP in a patient with anaphylaxis associatedwith rituximab.N Engl J Med. 2018;378(1):92-93.

Red blood cell distribution width as a prognostic factor of mortality in elderly patients firstly hospitalized due to heart failure

Abstract: Background: Red blood cell distribution width (RDW) is a risk factor related to adverse outcome in patients with heart failure (HF). Less is known about its influence in patients in their first hospitalization by HF. Aims: Our objective was to investigate the prognostic role of RDW in elderly patients firstly hospitalized for acute HF. Methods: We reviewed all patients ≥ 65 years old admitted to a tertiary care university hospital with a main diagnosis of acute HF during a two year period (January 2013 to December 2014). Patients were divided in two different groups according to admission RDW values (< or ≥ 15%). Results: A total of 897 patients were included in the study. Mean age was 80.25 ± 7.6 years. Admission RDW was ≥ 15% in 474 (52.8%) patients, with a mean RDW of 15.5 % ± 2.3. Multivariate analysis confirmed the relationship between a higher admission RDW and a previous diagnostic history of diabetes and admission higher serum sodium concentrations. All-cause mortality was significantly higher among patients with RDW  15% at one year of follow-up (29.6% vs. 23.2%, p 0.026). Multivariate analysis confirmed the association between RDW and higher risk of one-year mortality, as well as with older age, higher Charlson comorbidity Index, higher potassium serum concentrations and no hypertension as a previous diagnosis. Conclusions: In elderly patients experiencing their first admission due to acute HF, a higher RDW at baseline might help identify patients at higher risk for one-year all-cause mortality.

EHA Research Roadmap on Hemoglobinopathies and Thalassemia: An Update.

Abstract: The inherited disorders of hemoglobin, which include sickle cell disease and thalassemias, are the most common and widespread distributed monogenic disorders. Due to a selective advantage in malaria regions, these hemoglobin defects are particularly frequent in Africa, Asia, or in the Mediterranean areas, where malaria was endemic until the last century. In recent decades, the globalization of migration has contributed to generate multiethnic European societies. Due to migration from countries or regions with high hemoglobinopathy frequencies such as Africa, Middle East, or Asia, large numbers of patients with these disorders are living in almost every European country today. Furthermore, the numbers are increasing because of increasing refugee flows toward Europe. Additional requirements are the development of European recommendations and guidelines for diagnosis and effective therapeutic approaches. These, together with the advancement of clinical trials using new drugs and therapeutic procedures could ameliorate the quality of life of patients affected with these diseases and increase their life expectancy. Lastly, coordinated efforts should be made to develop diagnostic pathways for thalassemias and hemoglobinopathies, in order to plan interventions, including prenatal diagnosis and cure. For these reasons, the development of new tools to reliably diagnose anemias is urgently needed and fits well with the needs of personalized medicine. In the last 15 years, hematology research has made many big leaps forward. Our general aim will be to solve several hematologic problems using these new approaches. We expect that the development of such a diagnostic tool will improve timely diagnosis throughout Europe, especially in those countries where it is difficult to gain access to "classical" diagnostic tests.

Risk factors for heart disease in transfusion-dependent thalassemia: serum ferritin revisited

Abstract: Heart disease remains a leading cause of morbidity and mortality in transfusion-dependent thalassemia (TDT), which can be attributed to several factors but primarily develops in the setting of iron overload. This was a retrospective cohort study utilizing Webthal® patient data from five major centers across Italy. Patients without heart disease were followed-up for 10 years (2000–2010) and data were collected for demographics, splenectomy status, serum ferritin and hemoglobin levels, and comorbidities associated with heart disease. Among 379 patients analyzed (mean age 22.9 ± 5.1 years, 47.8% men), 44 (cumulative incidence: 11.6%) developed heart disease during the period of observation. Splenectomy (p = 0.002) and serum ferritin level (p < 0.001) were the only risk factors with significant association with heart disease. A serum ferritin threshold of ≥ 3000 ng/mL was the best predictor for the development of heart disease (86.4% sensitivity and 92.8% specificity, AUC: 0.912, 95% CI 0.852–0.971, p < 0.001). On multivariate analysis, only a serum ferritin level ≥ 3000 ng/mL remained significantly and independently associated with increased risk of heart disease (HR: 44.85, 95% CI 18.85–106.74), with a 5- and 10-year heart disease-free survival of 58 and 39%. The association between iron overload and heart disease in patients with TDT is confirmed, yet a new serum ferritin level of 3000 ng/mL to flag increased risk is suggested.

Development of a patient-reported outcomes symptom measure for patients with nontransfusion-dependent thalassemia (NTDT-PRO©)

Abstract: This study demonstrates the quantitative characteristics of the first patient-reported outcome (PRO) tool developed for patients with nontransfusion-dependent β-thalassemia (NTDT), the NTDT-PRO© . A multicenter validation study was performed over 24 weeks, involving 48 patients from Italy, Lebanon, Greece, and Thailand. Most patients were female (68.8%), with a median age of 34.5 years (range, 18-52); 66.7% were diagnosed with β-thalassemia intermedia, and median time since diagnosis was 22 years (range, 0-43). The NTDT-PRO comprises 6 items across 2 domains (Tiredness/Weakness and Shortness of Breath [SoB]), and was valid and reliable, with good consistency. At baseline, most patients reported symptoms as present via the NTDT-PRO, and were highly compliant, ≥90% completing the NTDT-PRO tool. In a pairwise correlation analysis, all items were positively correlated. Correlations between NTDT-PRO and existing tools-36-Item Short Form Health Survey version 2 (SF-36v2) and Functional Assessment of Cancer Therapy-Anemia (FACT-An)-were assessed at weeks 1, 3, and 12; robust correlations were seen between SoB and SF-36v2-Vitality (rs = -0.53), and between SoB and Fact-An-Fatigue Experience (rs = -0.66) at week 1. Internal consistency was high for both Tiredness/Weakness (Cronbach alpha, 0.91) and SoB (Spearman-Brown coefficient, 0.78); intraclass correlation coefficients were high (Tiredness/Weakness, 0.88 and 0.97; SoB, 0.92 and 0.98), demonstrating stability. Further studies are required to fully support the validity of this tool, this study demonstrated the usefulness of the NTDT-PRO in the clinical setting and for longitudinal clinical research, particularly in trials where patient health-related quality of life is expected to change.

Oocyte quality in women with thalassaemia major: insights from IVF cycles.

Abstract: Background Women with thalassaemia major typically experience hypogonadotropic hypogonadism because of the toxic effects of iron overload on the anterior pituitary. Moreover, in affected women, serum anti-Mullerian hormone (AMH) and antral follicle count (AFC) are also shown to be reduced, suggesting that the peripheral excess of iron could also harm the ovarian reserve. To date, the detrimental effects of the disease on oocyte quality have not been investigated. Materials and methods Women with thalassaemia major who underwent in vitro fertilization (IVF) cycles were retrospectively identified over a 9 years period. They were matched (with a 1:5 ratio) by study period and age to a control group of infertile women undergoing IVF. Embriological variables were compared between the two groups. The primary outcome was the rate of top quality embryos. Results Twenty-one women with thalassaemia major (exposed group) and 105 controls (unexposed group) were ultimately included. Serum AMH was 0.6 [0.2-1.8] and 1.5 [0.7-3.5] ng/ml, respectively (p = 0.05). AFC was 4 (1-7.5) and 11 (5.5-16), respectively (p < 0.001). The total dose of gonadotropins used was higher in exposed women but the number of retrieved oocytes and oocytes used did not differ. The fertilization rate was higher in exposed compared to unexposed women, being 100% (76-100%) and 75% (50-100%). respectively (p = 0.03). The cleavage rate was also higher, being 75% (39-100%) and 50% (29-64%), respectively (p = 0.04). In contrast, the rate of top quality embryos did not differ, being 20% (0-76%) and 25% (5-50%), respectively (p = 0.98). Conclusions Despite lower ovarian reserve, oocyte quality is not significantly affected in women with thalassaemia major.

Iron overload in congenital haemolytic anaemias: role of hepcidin and cytokines and predictive value of ferritin and transferrin saturation.

Abstract: Iron overload (IO) is poorly investigated in the congenital haemolytic anaemias (CHAs), a heterogeneous group of rare inherited diseases encompassing abnormalities of the erythrocyte membrane and metabolism, and defects of the erythropoiesis. In this study we systematically evaluated routine iron parameters and cardiac and hepatic magnetic resonance imaging, together with erythropoietin, hepcidin, non-transferrin bound iron (NTBI), and cytokine serum levels in patients with different CHAs. We found that 40% of patients had a liver iron concentration (LIC) >4 mg Fe/g dry weight. Hepatic IO was associated with ferritin levels (P = 0·0025), transferrin saturation (TfSat, P = 0·002) and NTBI (P = 0·003). Moreover, ferritin >500 μg/l plus TfSat >60% was demonstrated as the best combination able to identify increased LIC, and TfSat alteration as more important in cases with discordant values. Possible confounding factors, such as transfusions, hepatic disease, metabolic syndrome and hereditary haemochromatosis-associated mutations, had negligible effects on IO. Erythropoietin and hepcidin levels were increased in CHAs compared with controls, correlating with LIC and ferritin, respectively. Regarding cytokines, γ-interferon (IFN-γ) was increased, and both interleukin 6 and IFN-γ levels positively correlated with ferritin and hepcidin levels. Overall, these findings suggest the existence of a vicious cycle between chronic haemolysis, inflammatory response and IO in CHAs.

Development of a thalassemia-related thrombosis risk scoring system

Abstract: REFERENCES 1. Neuwirth MG, Bartlett EK, Newton AD, et al. Morbidity and mortality after total splenectomy for lymphoid neoplasms. J Surg Res. 2016;205(1): 155-162. 2. Pata G, Damiani E, Tognali D, Solaini L, Watt J, Ragni F. Outcomes of open splenectomy for hematologic malignancy with splenomegaly: a contemporary perspective. Am Surg. 2015 Apr 1;81(4):414-420. 3. Rialon KL, Speicher PJ, Ceppa EP, et al. Outcomes following splenectomy in patients with myeloid neoplasms. J Surg Oncol. 2015 Apr;111(4): 389-395. 4. Santos FP, Tam CS, Kantarjian H, et al. Splenectomy in patients with myeloproliferative neoplasms: efficacy, complications and impact on survival and transformation. Leuk Lymphoma. 2014 Jan 1;55(1):121-127. 5. Bagrodia N, Button AM, Spanheimer PM, Belding-Schmitt ME, Rosenstein LJ, Mezhir JJ. Morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions: analysis of the American College of Surgeons National Surgical Quality Improvement Program data. JAMA Surg. 2014 Oct 1;149(10):1022-1029. 6. Zemlyak AY, Colavita PD, Augenstein VA, et al. Nationwide outcomes of nontrauma splenectomy. Surg Endosc. 2014 Apr 1;28(4):1063-1067.

UGT1A1 genotype does not affect tyrosine kinase inhibitors efficacy and safety in chronic myeloid leukemia.

Abstract: To the Editor: Gilbert's syndrome (GS) is a condition characterized by intermittent unconjugated hyperbilirubinemia without structural liver damage, affecting about 10% of the caucasian population. It is an autosomal recessive disorder, mainly associated with variations in uridine50-diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1). In Caucasians, the most common variation is the TATA box polymorphism, in which an insertion of an additional TA-repeat into the promoter region of the gene results in a A(TA) 7TAA sequence, that differs from the more prevalent A(TA) 6TAA. Gilbert's syndrome is a benign condition which does not lead to liver inflammation, cellular destruction, fibrosis, or cirrhosis but is merely clinically characterized by intermittent episodes of uncomplicated unconjugated hyperbilirubinemia. The effect of GS on liver complication and outcome of hematological malignancies has been scarcely investigated, with only a previous study in a series of children diagnosed with acute lymphoblastic leukemia, a series of adult patients with Hodgkin lymphoma and some anecdotal case reports in acute leukemia patients. Tyrosine-kinase inhibitors (TKIs) are currently used for the treatment of chronic myeloid leukemia (CML). Nilotinib inhibits bilirubin metabolism via UGT1A1, thereby increasing bilirubin levels; not surprisingly, GS has been associated with nilotinib-induced hyperbilirubinemia in patients affected by CML. Similar increases in bilirubin were also reported in patients with GS treated with imatinib or dasatinib. The aim of the present study is to assess if in CML-chronic phase (CML-CP) patients treated with either firstor second-generation TKIs, GS has an impact on clinical outcomes, assessed by cytogenetic/molecular response rates and progression-free survival (PFS), as well as on hematological or extra-hematological toxicities. We retrospectively collected data on CML-CP patients consecutively treated with TKIs at our institution between February 2002 and November 2018. All the following data were collected at baseline before TKI initiation: sociodemographic and hematological variables, disease risk scores (Sokal, Eutos, Hasford, and ELTS), and TKI starting dose. Monitoring and responses evaluation followed the current European LeukemiaNet recommendations. Progression-free survival was calculated from the start of first-line TKI to any of the following events: primary or secondary resistance, and/or discontinuation due to intolerance. Hematological and extra-hematological toxicities were graded according to the Common Toxicity Criteria Adverse Events (CTCAE) version 5.0. Gilbert's syndrome genotype was investigated by polymerase chain reaction (PCR) amplification of a region encompassing the TATA-box of the UGT1A1 gene (forward primer: 5’-GTC ACG TGA CAC AGT CAA AC-30: reverse primer: 50-TTT GCT CCT GCC AGA GGT-30; annealing temperature: 62°C. RefSeq UGT1A1 NG_033238.1). DNA fragment length analysiswas performed by 12%polyacrylamide gel electrophoresis (PAGE): a 98 bp fragment indicating the presence of the (TA)6TAA wildtype allele, while a 100 bp fragment accounts for the (TA)7TAA allele (c.-41_-40dupTA). The more rare (TA)8TAA allele (c.-43_-40dupTATA) could be as well evidenced by this technique as a 102 bp PCR product, but it was not detected in any of the patient studied. Clinical and sociodemographic characteristics were described using absolute and relative frequencies. We evaluated time to resistance (truncated at 10 years) according to GS genotype by calculating the Kaplan-Meier function and by fitting univariate and multivariable Cox models adjusted for gender, age, and line of therapy. P values were obtained from post-estimation global Wald tests. Statistical analysis was performed with Stata 15 (StataCorp. 2017). One hundred and five CML-CP patients consecutively treated with either firstor second-generation TKIs were evaluated. Clinicaldemographic data at diagnosis are showed in Table S1. In particular, concomitant drugs were reported in 49 patients (46.7%), with seven patients taking more than five medications. Gilbert's syndrome genotypes were distributed as follows: 17 (16.2%) patients were 7/7, 44 (41.9%) 6/7 and the remaining cases were wild-type. The majority of the patients were treated with imatinib (69.5%), following by nilotinib (17.1%) and dasatinib (13.3%). Complete cytogenetic response (CCyR) was obtained in 79 (75.2%) patients, of whom 55 (52.4%) were within 3 months of treatment. Among 7/7, 6/7 and 6/6 genotypes, CCyR was achieved by 12 (70.6%), 31 (70.4%) and 29 (65.9%) patients, respectively. Major molecular response (MMR) was obtained in 73 patients (69.5%); among them eight (47%) were 7/7, 23 (52.3%) 6/7 and 20 (45.4%) 6/6. Deep molecular response (DMR) was achieved in 51 (48.6%) patients, of whom 8 (47.1%), 23 (52.3%) and 20 (45.4%) showed a 7/7, 6/7, or 6/6 genotype, respectively. Interestingly, none of these differences was statistically significant. Forty-seven patients switched to second-line therapy, of whom 18 (38.3%) for primary resistance, 14 (29.8%) for secondary resistance and 15 (14.3%) for intolerance or unacceptable toxicity. Among patients who experienced primary resistance, two (22.2%) were 7/7, seven (36.8%) were 6/7 and nine (45%) wild-type. A similar distribution was also recorded among patients who switched for toxicity. Received: 4 July 2019 Revised: 23 July 2019 Accepted: 24 July 2019

Common fetal hemoglobin variants in Lebanese patients bearing the codon 29 beta gene mutation associated with different thalassemia phenotypes.

Abstract: Beta-thalassemia can present with a wide spectrum of phenotypes determined by the coinheritance of α-thalassemia, hereditary persistence of fetal hemoglobin, and polymorphic variants in the BCL11A, HMIP, and HBB clusters. The codon 29 (cd29) mutation in the beta gene has been associated with a broad diversity of thalassemia phenotypes, possibly through genetic modifiers determining the genotype-phenotype relationship. In this study, we evaluated the effect of 10 single nucleotide polymorphisms (SNPs) on β-thalassemia severity in a group of 21 Lebanese patients bearing the cd29 mutation. Hematological parameters and clinical characteristics were evaluated according to transfusion dependence. The proportions and absolute concentrations of HbF were found to be higher in non-transfusion-dependent (NTD) patients than in transfusion-dependent (TD) ones. Iron parameters were found to be higher in TD patients. The SNPs that were evaluated included the XmnI-158 polymorphism in the HBG gene and SNPs in the BCL11A and HMIP loci. It was noted that individuals homozygous or heterozygous for the effect allele in the BCL11A and HMIP SNPs had higher HbF levels, lower ferritin concentrations, and lower liver iron content and were less likely to be transfusion dependent. Our results showed that HbF production variants may have an important impact on the severity of β-thalassemia, which might provide a severity prediction tool that can help in the anticipation of patients' phenotypes and therefore in future therapeutic decision making.

Patterns of infections in older patients acutely admitted to medical wards: data from the REPOSI register

Abstract: In older adults infections are among the leading causes of emergency department visits, hospitalization, morbidity and mortality [1–3]. Infections also occur as adverse events during hospitalization, as highlighted by the large use of antibiotics in this setting, resulting in an increase of hospitalization length and mortality rate [4–6]. There is a paucity of studies, especially in European countries, that did offer a general pattern on all the types of infections occurring in acutely hospitalized older patients, being the literature mainly focused on single type of infections (i.e. pneumonia and urinary tract infections). To fill this gap of knowledge, we chose to observe and describe the prevalence and types of infections in a large cohort of older hospitalized patients in the frame of REPOSI (REgistro POliterapie SIMI) register. REPOSI is a collaborative register that involves a large number of Italian internal medicine and geriatric wards. Briefly, patients aged 65 years or more acutely hospitalized during four index periods lasting one week in each season were enrolled and signed an informed consent. The attending physicians were required to compile for each patient a web-based Case Report Form, including the main sociodemographic data, specific diagnoses and their severity according to the Cumulative Illness Rating Scale (CIRS), functional status at hospital admission (measured by Barthel index [BI]) [7] and drug therapies during the whole hospitalization period. This study was approved by the Ethical Committees of all participating hospitals. More details on REPOSI were provided elsewhere [5, 6]. Patients recruited in the register in 2008, 2010, 2012, 2014 and 2016 were considered for the purpose of this study. Infections were considered when they were the reason for hospitalization, when reported in the CIRS at admission and also when they occurred during the hospital stay, whether reported as a relevant adverse event or as the indication for antimicrobial therapy. Infections were categorized using the International Classification of Diseases-Ninth Edition (ICD9) according to the physiological system of origin, on the basis of a classification provided in other studies (Supplementary Table 1) [8]. Data were summarized as prevalence (%), or means and standard deviations when pertinent. The 95% confidence intervals (CI) were provided as well. The analysis was performed using the SAS/STAT software Version 9.2 (SAS Institute Inc., Cary, NC, USA). Among the 6047 patients enrolled in the REPOSI register, 2991 (49.5%, 95% CI 48.2–50.7%) were diagnosed with at least one infection, accounting for a total of 3554 infections. Overall 2522 patients (84.3%) had a single infection, The members of REPOSI Investigators are listed in “Acknowledgement” section.

Gaucher disease for the haematologist: An expert interview with Maria Domenica Cappellini

Abstract: