Patients suffering from Sickle Cell Disease (SCD) are at increased risk for complications due to influenza virus. Annual influenza vaccination is strongly recommended but few clinical studies have ...assessed its immunogenicity in individuals with SCD. The aim of this study was to explore the biological efficacy of annual influenza vaccination in SCD patients by characterizing both their humoral and cell-mediated immunity against influenza antigen. We also aimed to investigate these immunological responses among SCD individuals according to their treatment (hydroxyurea (HU), chronic blood transfusions (CT), both HU and CT or none of them).
Seventy-two SCD patients (49 receiving HU, 9 on CT, 7 with both and 7 without treatment) and 30 healthy controls were included in the study. All subjects received the tetravalent influenza α-RIX-Tetra® vaccine from the 2016-2017 or 2017-2018 season.
Protective anti-influenza HAI titers were obtained for the majority of SCD patients one month after vaccination but seroconversion rates in patient groups were strongly decreased compared to controls. Immune cell counts, particularly cellular memory including memory T and memory B cells, were greatly reduced in SCD individuals. Functional activation assays confirmed a poorer CD8+ T cell memory. We also document an imbalance of cytokines after influenza vaccination in SCD individuals with an INFγ/IL-10 ratio (Th1-type/Treg-type response) significantly lower in the SCD cohort.
SCD patients undergoing CT showed altered immune regulation as compared to other treatment subgroups. Altogether, the cytokine imbalance, the high regulatory T cell levels and the low memory lymphocyte subset levels observed in the SCD cohort, namely for those on CT, suggest a poor ability of SCD patients to fight against influenza infection. Nevertheless, our serological data support current clinical practice for annual influenza vaccination, though immunogenicity to other vaccines involving immunological memory might be hampered in SCD patients and should be further investigated.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, ...IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21.
We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.
Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (
< 0.0001) as well as MYC target genes (
= 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (
< 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements-similar to UM IgHV status-conferred poor prognosis compared with mutated IgHV (
< 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (
< 0.0001).
We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV3-21 light chain usage defines a new subgroup of CLL patients with poor prognosis.
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This retrospective multicenter study in patients with chronic myeloid leukemia in chronic phase was undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily ...practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p=0.02, R2=0.1). More interestingly, patients with poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822ng/mL vs 1099ng/mL; Student's t-test, p=0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p=0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and major molecular response. In conclusion: in patients treated with imatinib at a fixed daily dose of 400mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients.
•In patients treated with a fixed daily dose of imatinib, imatinib plasma concentrations are lower in overweight patients•Lower imatinib concentrations are associated with treatment failure•Imatinib plasma concentration assessment during the chronic phase of chronic myelocytic leukemia should be encouraged
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron ...chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1). Methods Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (≥6 versus <6 months) and quality of chelation (adequate versus weak). Results Crude chelation rate was 63% but 88% among patients with serum ferritin ≥1000 μg/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated ≥6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients ( p < 0.001). For patients chelated ≥6 m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR = 1.08, p = 0.04) but was lower in patients receiving adequate chelation or chelation ≥6 m (HR = 0.24, p < 0.001). Conclusion Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Conventional pretransfusion testing based on hemagglutination assays can be challenging for patients with autoimmune hemolytic anemia (AIHA) because of the presence of auto-antibodies. It has been ...suggested that deoxyribonucleic acid-based methods could be more efficient in the selection of antigen-matched red blood cell units in those settings. Because of the high risk of alloimmunization of these patients and the labor-intensive nature of adsorption techniques, we decided to evaluate the feasibility of selecting antigen-matched units on the basis of RBC genotyping. We included in our routine RBC genotyping program samples from 7 patients with AIHA presenting a strongly positive direct antiglobulin test. This made the routine compatibility tests difficult. Most patients had previously received transfusions because of warm AIHA. Matched donor units were selected according to the genotype. For all but 1 patient, blood group genotyping could be done on time to allow antigen-matched transfusion. Four patients received antigen-matched red blood cell units based on RBC genotyping and for 1 patient the fact that no matched units were available led us to postpone the transfusion. After each transfusion, the recovery was recorded and considered satisfactory for all transfused patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Introduction Circulating microparticles are reported to play a role in cancer hypercoagulability. The procoagulant properties of microparticles derive from the amount of tissue factor and/or ...phosphatidylserine that they can expose. The aim of our study is to assess the procoagulant activity, including microparticles’ activity, in the plasma of newly diagnosed cancer patients with a simple assay, easy to implement in the laboratory. Material and methods Newly diagnosed cancer patients (n = 31) before the start of anticoagulant or chemotherapy were compared to matched controls. We used a thrombin generation assay in four conditions: 1: addition of 1pM tissue factor and 4 μM procoagulant phospholipids, 2: without any trigger, 3 and 4: addition of tissue factor or procoagulant phospholipids alone respectively. Results When we added only phospholipids, so that thrombin generation is dependent upon endogenous tissue factor, the lag time was significantly shorter in cancer patients. When we added only tissue factor, i.e. made the results dependent upon phospholipids, the endogenous thrombin potential, the peak, and the velocity index were significantly higher and the time-to-peak was significantly shorter. This suggests that the plasma of cancer patients contained a higher activity of endogenous phospholipids and/or tissue factor which may be borne by microparticles. Conclusion This new simple methodology can demonstrate a procoagulant activity in the plasma of newly diagnosed cancer patients which can be explained by higher procoagulant phospholipids and tissue factor activity and thus, brings potentially useful information that current coagulation tests cannot provide.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract 2659
Sickle cell disease (SCD) has polymorphic manifestations, it is not well known by many physicians, and patients have often a precarious status. So despite enormous improvements in the ...understanding of the pathogenesis of SCD, patient care remains difficult.The objectives of this work were to create a clinical data base in order to learn the characteristics of this population, to create a network between practitioners (general, emergency and specialist practitioners), to provide state-of-the art and guidelines, it could be a tool to disseminate information, for education projects and for research; it could also represent a pilot project for other chronic diseases. A practical aspect of this data base is to improve follow-up and treatment of SCD patients by “online access from everywhere”. The SCD clinical data base was a national project and was approved by each local ethic committee; informed consent of each patient was obtained. The first step was to create the electronic database with several security measures (i.e. login, password, and separate administrators). The second step was to introduce patient's data. Patients were followed in different Academic and Secondary Care Centers. Data were collected from the initial contact until December 31, 2007. The data collection included parents' origin, hemoglobin phenotype, origin of diagnosis, clinical events, biological and radiological data, hospitalizations, and types of treatment.
Up to date, we introduced 280 medical records (146 diagnosed by neonatal screening). The median age and follow-up of the cohort was 9.3 year (range, 0–44) and 6.5 year (range, 0–32), respectively. The first information provided was the predominance of patients from DR Congo (67.5 %), the occurence of severe events in 84 % of patients (Table 1), the predominance of Hb SS phenotype (90 %) and its severity, the report of septicemia which remain still very worrying (8.2 %), but also that clinical and radiological neurological events are sizeable, and that there is a good response to treatment intensification, particularly to bone marrow transplantation (BMT) and hydroxyurea.
Table 1:SCD related events reported in the Belgian data baseSCD related eventsPatients,%(n)Dactilytis24.3 (68/280)Acute Chest Syndrome18.9 (53/280)Recurrent Vaso-occlusive Crisis61.8 (173/280)Anemia ≤ 6 g/dl51.8 (145/280)Septicemia8.2 (23/280)Splenic sequestration7.9 (22/280)Stroke/TIA3.9 (11/280)Osteonecrosis5.0 (14/280)Osteomyelitis2.5 (7/280)
The main pathogen remained Streptococcus pneumoniae with no resistant strain despite regular prophylaxis. The second most common germ was Salmonella. Haemophilus influenza concerned older patients and disappeared since the introduction of the vaccination. The incidence of death was 2.86% (8/280). All of them were homozygous for Hb S. Two deaths occurred in the very early childhood due to the no compliance to antibio-prophylaxis in the first patient and poor follow-up in the second one. One death was very sudden after meningeal hemorrhage. Two other deaths happened in the adulthood, one after cerebral hemorrhage and the other one of unknown cause after going back to native country. The last three deaths were due to BMT complications (Table 2).
In conclusion, the preliminary results confirmed the still high morbidity and mortality of SCD. It is not only a precious practical tool, but it also helps to improve clinical management of patients with SCD, it is a tool to identify risk factors and to tailor treatments. In this perspective, it constitutes a basis for prospective studies in view to validate criteria of disease severity and to adopt guidelines for adequate treatment.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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