Raffaella Colombatti

The Guinea-Bissau family of Mycobacterium tuberculosis complex revisited.

The Guinea-Bissau family of strains is a unique group of the Mycobacterium tuberculosis complex that, although genotypically closely related, phenotypically demonstrates considerable heterogeneity. We have investigated 414 M. tuberculosis complex strains collected in Guinea-Bissau between 1989 and 2008 in order to further characterize the Guinea-Bissau family of strains. To determine the strain lineages present in the study sample, binary outcomes of spoligotyping were compared with spoligotypes existing in the international database SITVIT2. The major circulating M. tuberculosis clades ranked in the following order: AFRI (n = 195, 47.10%), Latin-American-Mediterranean (LAM) (n = 75, 18.12%), ill-defined T clade (n = 53, 12.8%), Haarlem (n = 37, 8.85%), East-African-Indian (EAI) (n = 25, 6.04%), Unknown (n = 12, 2.87%), Beijing (n = 7, 1.68%), X clade (n = 4, 0.96%), Manu (n = 4, 0.97%), CAS (n = 2, 0.48%). Two strains of the LAM clade isolated in 2007 belonged to the Cameroon family (SIT61). All AFRI isolates except one belonged to the Guinea-Bissau family, i.e. they have an AFRI_1 spoligotype pattern, they have a distinct RFLP pattern with low numbers of IS6110 insertions, and they lack the regions of difference RD7, RD8, RD9 and RD10, RD701 and RD702. This profile classifies the Guinea-Bissau family, irrespective of phenotypic biovar, as part of the M. africanum West African 2 lineage, or the AFRI_1 sublineage according to the spoligtyping nomenclature. Guinea-Bissau family strains display a variation of biochemical traits classically used to differentiate M. tuberculosis from M. bovis. Yet, the differential expression of these biochemical traits was not related to any genes so far investigated (narGHJI and pncA). Guinea-Bissau has the highest prevalence of M. africanum recorded in the African continent, and the Guinea-Bissau family shows a high phylogeographical specificity for Western Africa, with Guinea-Bissau being the epicenter. Trends over time however indicate that this family of strains is waning in most parts of Western Africa, including Guinea-Bissau (p = 0.048).

A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events

BACKGROUND Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

Pulmonary hypertension in sickle cell disease children under 10 years of age.

Despite the finding of elevated Tricuspid Regurgitant Velocity (TRV) in children below 5 years of age, the prevalence and evolution of Pulmonary Hypertension (PH) in young children with sickle cell disease (SCD) are unclear. In order to identify predictive factors of precocious PH development, SCD children ≥3 years old, at steady state, underwent annual echocardiography and Tissue Doppler Imaging (TDI). Patients receiving chronic transfusion were excluded. Thirty‐seven of seventy‐five patients were ≥3 years, with measurable TRV. In our young population (mean age 6·2 years) of mainly African, HbS/HbS patients, 8/37 (21·6%) had TRV ≥2·5 m/s, 8% being only 3 years old. Significant correlation was found between precocious TRV elevation and high platelet and reticulocyte counts and frequent acute chest syndromes (ACS). In multivariate analysis, ACS was the only variable predicting TRV ≥2·5 m/s. TDI of the 37 patients showed signs of diastolic dysfunction of the left ventricle. At follow‐up all eight patients with high TRV displayed further increase and seven more developed TRV ≥2·5 m/s. PH seems to begin in children earlier than expected. Factors involved in its early onset might be different from the ones causing its development in older children or adults. African children might benefit from early screening and re‐assessment once a year.

Hospitalization of children with sickle cell disease in a region with increasing immigration rates

Sickle cell disease (SCD) has become a paradigm of immigration hematology in Europe. Accurate up-to date information is needed to determine SCD prevalence, define real burden of disease and develop appropriate clinical networks of care, especially in regions lacking screening programs. We used two independent sources of data (Regional Register of Rare Disorders and Regional Register of Hospital Discharge Records) to determine extent of SCD and pattern of hospitalization of pediatric patients in the Veneto Region of NorthEast Italy. A steady increase of case notifications and hospitalizations has been observed in the past five years. Ninety-five percent of patients are immigrants with HbS/HbS SCD. Specialized regional registers can be used to define disease extent and guide targeted interventions in regions still lacking comprehensive care screening programs.

Coagulation Activation in Children with Sickle Cell Disease Is Associated with Cerebral Small Vessel Vasculopathy

Background Thrombotic complications in Sickle Cell Disease (SCD) arise since infancy, but the role of the coagulation system in children has been poorly explored. To determine its role in the development of clinical complications in childhood we measured coagulation and endothelial parameters in children with SCD at steady state. Methods Markers of thrombin generation, fibrin dissolution and endothelial activation were evaluated in 38 children with SS-Sβ°, 6 with SC disease and 50 age and blood group matched controls. Coagulation variables were correlated with markers of hemolysis and inflammation, with the presence of cerebral and lung vasculopathy and with the frequency of clinical complications. Results SS-Sβ° patients presented higher levels of factor VIII, von Willebrand factor antigen (VWF:Ag) and collagen binding activity, tissue plasminogen activator antigen (t-PA:Ag), D-dimer, p-selectin, prothrombin fragment1+2 (F1+2) and lower ADAMTS-13:activity/VWF:Ag (p<0.05) compared to controls and SC patients. In SS-Sβ° patients coagulation variables correlated positively with markers of inflammation, hemolysis, and negatively with HbF (p<0.05). Patients with cerebral silent infarcts showed significant decrease in t-PA:Ag and ADAMTS-13 Antigen and a tendency toward higher D-dimer, F1+2, TAT compared to patients without them. D-dimer was associated with a six fold increased risk of cerebral silent infarcts. No correlation was found between coagulation activation and large vessel vasculopathy or other clinical events except for decreased t-PA:Ag in patients with tricuspid Rigurgitant Velocity >2.5m/sec. Conclusions SS-Sβ° disease is associated with extensive activation of the coagulation system at steady state since young age. ADAMTS-13 and t-PA:Ag are involved in the development of cerebral silent infarcts.

Anemia and transfusion in the neonate.

Neonatal anemia is a frequent occurrence in neonatal intensive care units. Red blood cell transfusion criteria in case of blood loss are clearly defined but optimal hemoglobin or hematocrit thresholds of transfusion for anemia due to decreased production or increased destruction are less evident. This review focuses on the causes of anemia in the newborn period and the most recent evidence-based treatment options, including transfusion and erythropoiesis-stimulating agents.

Comprehensive care for sickle cell disease immigrant patients: a reproducible model achieving high adherence to minimum standards of care.

Comprehensive care and advances in clinical investigations have reduced morbidity and mortality in sickle cell disease (SCD), but only a minority of children with SCD has access to comprehensive care. In Europe the majority of patients with SCD are immigrants who present barriers in accessing the health system; therefore, new evidence‐based models of comprehensive care are needed to ensure that all SCD patients receive high‐quality care, overcoming patient‐ and health system‐related barriers. We wanted to verify if addressing the specific needs of immigrant patients contributes to improving adherence.

Malaria prevention reduces in-hospital mortality among severely ill tuberculosis patients: a three-step intervention in Bissau, Guinea-Bissau

BackgroundMalaria and Tuberculosis (TB) are important causes of morbidity and mortality in Africa. Malaria prevention reduces mortality among HIV patients, pregnant women and children, but its role in TB patients is not clear. In the TB National Reference Center in Guinea-Bissau, admitted patients are in severe clinical conditions and mortality during the rainy season is high. We performed a three-step malaria prevention program to reduce mortality in TB patients during the rainy season.MethodsSince 2005 Permethrin treated bed nets were given to every patient. Since 2006 environmental prevention with permethrin derivates was performed both indoor and outdoor during the rainy season. In 2007 cotrimoxazole prophylaxis was added during the rainy season. Care was without charge; health education on malaria prevention was performed weekly. Primary outcomes were death, discharge, drop-out.Results427, 346, 549 patients were admitted in 2005, 2006, 2007, respectively. Mortality dropped from 26.46% in 2005 to 18.76% in 2007 (p-value 0.003), due to the significant reduction in rainy season mortality (death/discharge ratio: 0.79, 0.55 and 0.26 in 2005, 2006 and 2007 respectively; p-value 0.001) while dry season mortality remained constant (0.39, 0.37 and 0.32; p-value 0.647). Costs of malaria prevention were limited: 2€/person. No drop-outs were observed. Health education attendance was 96-99%.ConclusionsMalaria prevention in African tertiary care hospitals seems feasible with limited costs. Vector control, personal protection and cotrimoxazole prophylaxis seem to reduce mortality in severely ill TB patients. Prospective randomized trials are needed to confirm our findings in similar settings.Trial registration numberCurrent Controlled Trials: ISRCTN83944306

Intellectual function evaluation of first generation immigrant children with sickle cell disease: the role of language and sociodemographic factors

BackgroundSickle Cell Disease (SCD) is the most common genetic disease worldwide. Neurological events are among the most worrisome clinical complications of SCD and are frequently accompanied by cognitive impairment. Intellectual function in SCD may vary according to genetic and environmental factors. Immigrant children with SCD are increasing at a global level and display specific health care needs. The aim of our multicenter study was to describe the intellectual function of first generation African immigrants with SCD and the influence of sociodemographic factors on its characteristics.MethodsThe Wechsler Intelligence Scales were administered to evaluate broad intellectual functions in children with SCD and in age-matched healthy siblings. Patients’ clinical, socio-demographic, Magnetic Resonance Imaging (MRI) and Angiography (MRA) data were correlated to intellectual function scores.Results68 children, mean age 8.95 years were evaluated. 72% spoke three languages, 21% two. FSIQ was <75 in 25% of the children. Mean VIQ was lower than PIQ in 75%. Mean verbal subtest scores were lower than performance scores. Female gender, number of languages spoken at home and mother’s employment were associated with single subtest performances (p < 0.05). MRA was abnormal in 73.4% and MRI in 35.9%. No significant correlation was established between silent lesions and intellectual function, even if patients with lesions performed worse. Fifteen siblings performed better than patients on cognitive domains, including language (p < 0.05).ConclusionsImmigrant bilingual children with SCD seem to display a rate of cognitive impairment similar to their monolingual counterparts but a more pronounced and precocious onset of language difficulties. Adjunctive tests need to be considered in this group of patients to better define their specific deficits.

Cognitive evoked potentials and neural networks are abnormal in children with sickle cell disease and not related to the degree of anaemia, pain and silent infarcts

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