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1.
Cell ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33571429

RESUMO

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.

5.
J Clin Med ; 9(12)2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33260979

RESUMO

Evans' syndrome (ES) is defined as the concomitant or sequential association of warm auto-immune haemolytic anaemia (AIHA) with immune thrombocytopenia (ITP), and less frequently autoimmune neutropenia. ES is a rare situation that represents up to 7% of AIHA and around 2% of ITP. When AIHA and ITP occurred concomitantly, the diagnosis procedure must rule out differential diagnoses such as thrombotic microangiopathies, anaemia due to bleedings complicating ITP, vitamin deficiencies, myelodysplastic syndromes, paroxysmal nocturnal haemoglobinuria, or specific conditions like HELLP when occurring during pregnancy. As for isolated auto-immune cytopenia (AIC), the determination of the primary or secondary nature of ES is important. Indeed, the association of ES with other diseases such as haematological malignancies, systemic lupus erythematosus, infections, or primary immune deficiencies can interfere with its management or alter its prognosis. Due to the rarity of the disease, the treatment of ES is mostly extrapolated from what is recommended for isolated AIC and mostly relies on corticosteroids, rituximab, splenectomy, and supportive therapies. The place for thrombopoietin receptor agonists, erythropoietin, immunosuppressants, haematopoietic cell transplantation, and thromboprophylaxis is also discussed in this review. Despite continuous progress in the management of AIC and a gradual increase in ES survival, the mortality due to ES remains higher than the ones of isolated AIC, supporting the need for an improvement in ES management.

6.
Am J Hematol ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33170956

RESUMO

Immune thrombocytopenia (ITP) is now well-known to reduce patients' health-related-quality-of-life. However, data describing which signs and symptoms patients and physicians perceive as having the greatest impact are limited, as is understanding the full effects of ITP treatments. I-WISh (ITP World Impact Survey) was an exploratory, cross-sectional survey designed to establish the multifaceted impact of ITP, and its treatments, on patients' lives. It focused on perceptions of 1507 patients and 472 physicians from 13 countries regarding diagnostic pathway, frequency and severity of signs and symptoms, and treatment use. Twenty-two percent of patients experienced delayed diagnosis (caused by several factors), 73% of whom felt anxious as a result. Patients rated fatigue among the most frequent, severe symptom associated with ITP at diagnosis (58% most frequent; 73% most severe), although physicians assigned it lower priority (30%). Fatigue was one of the few symptoms persisting at survey completion (50% and 65%, respectively) and was the top symptom patients wanted resolved (46%). Participating physicians were experienced at treating ITP, thereby recognizing the need to limit corticosteroid use to newly-diagnosed or first-relapse patients and espoused increased use of thrombopoietin receptor agonists and anti-CD20 after relapse in patients with persistent/chronic disease. Patient and physicians were largely aligned on diagnosis, symptoms, and treatment use. I-WISh demonstrated that patients and physicians largely align on overall ITP symptom burden, with certain differences eg fatigue. Understanding the emotional and clinical toll of ITP on the patient will facilitate shared decision-management, setting and establishment of treatment goals and disease stage-appropriate treatment selection. This article is protected by copyright. All rights reserved.

7.
Am J Hematol ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33107998

RESUMO

Immune thrombocytopenia (ITP) has a substantial, multifaceted impact on patients' health-related quality of life (HRQoL). Data describing which aspects of ITP physicians and patients perceive as having the greatest impact are limited. ITP World Impact Survey (I-WISh) was a cross-sectional survey, including 1507 patients and 472 physicians, to establish the impact of ITP on HRQoL and productivity from patient and physician perspectives. Patients reported that ITP reduced their energy levels (85% of patients), capacity to exercise (77%), and limited their ability to perform daily tasks (75%). Eighty percent of physicians reported that ITP symptoms reduced patient HRQoL, with 66% reporting ITP-related fatigue substantially reduced patient HRQoL. Patients believed ITP had a substantial impact on emotional well-being (49%) and 63% worried their condition would worsen. Because of ITP, 49% of patients had already reduced, or seriously considered reducing their working hours, and 29% had considered terminating their employment. Thirty-six percent of patients employed at the time of the survey felt ITP decreased their work productivity, while 51% of patients with high/very high symptom burden reported that ITP affected their productivity. I-WISh demonstrated substantive impact of ITP on patients' HRQoL both directly for patients and from the viewpoint of their physicians. Patients reported reduced energy levels, expressed fears their condition might worsen, and those who worked experienced reduced productivity. Physicians should be aware not only of platelet counts and bleeding but also the multi-dimensional impact of ITP on patients' lives as an integral component of disease management. This article is protected by copyright. All rights reserved.

10.
Blood ; 136(20): 2290-2295, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32959052

RESUMO

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.


Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/patologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Soros Imunes/administração & dosagem , Linfopenia/terapia , Pneumonia Viral/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Transfusão de Componentes Sanguíneos , Infecções por Coronavirus/sangue , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Feminino , França , Neoplasias Hematológicas/complicações , Humanos , Imunização Passiva , Linfopenia/etiologia , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/terapia , Pneumonia Viral/virologia
11.
Haematologica ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32817288

RESUMO

B-cell activating factor may be involved in the failure of B-cell depleting therapy with rituximab in immune thrombocytopenia (ITP) by promoting the emergence of splenic long-lived plasma cells. From results obtained in mouse models, we hypothesized that combining rituximab with sequential injections of belimumab could increase the rate of response at one year in patients with persistent or chronic ITP by preventing the emergence of these long-lived plasma cells. The study was a single-center, single arm, prospective phase 2b trial (RITUX-PLUS, NCT03154385) investigating the safety and efficacy of rituximab given at a fixed dose of 1,000 mg, two weeks apart, combined with five infusions of belimumab, 10 mg/kg at week 0 (W0)+2 days, W2+2 days, W4, W8 and W12 for adults with primary persistent or chronic ITP. The primary endpoint was the total number of patients achieving an overall response (complete response + response) at W52 according to a standard definition. In total, 15 non-splenectomized adults, nine (60%) with persistent IPT and six (40%) with chronic ITP, were included. No severe adverse event, infection, or severe hypogammaglobulinemia was observed. Thirteen patients achieved an initial overall response. At W52, 12 (80%) patients achieved an overall response, including ten (66.7%) with complete response. When compared with a cohort of patients receiving rituximab alone, the kinetics of B-cell repopulation appeared similar, but the number of circulating T follicular helper cells was significantly decreased with belimumab combination therapy. Combining rituximab and belimumab seems a promising strategy in ITP, with high efficacy and acceptable safety.

12.
Blood ; 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814348

RESUMO

Management of immune thrombocytopenia (ITP) during pregnancy can be challenging since treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess safety and efficacy of off-label use of Tpo-RA during pregnancy, a multicenter observational and retrospective study was set up. Results from 15 pregnant women with ITP (17 pregnancies and 18 neonates) treated with either eltrombopag (N=8) or romiplostim (n=7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks [range: 1-39 weeks]; the indication for starting Tpo-RA was preparation for delivery in 10/17 (58%) pregnancies whereas 4 had chronic refractory symptomatic ITP and 3 were on eltrombopag when the pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed except for one case of neonatal thrombocytosis. Response to Tpo-RA was achieved in 77% of cases, mostly in combination (70% of responders) with concomitant ITP therapy. Based on these preliminary findings, temporary off-label use of a Tpo-RA for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and likely to be helpful especially prior to delivery.

13.
Orphanet J Rare Dis ; 15(1): 180, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641076

RESUMO

BACKGROUND: Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis. RESULTS: A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients. CONCLUSION: The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients' healthcare and probably has to be democratized notably for complex cases.

16.
BMJ ; 369: m1844, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409486

RESUMO

OBJECTIVE: To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen. DESIGN: Comparative observational study using data collected from routine care. SETTING: Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020. PARTICIPANTS: 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care. INTERVENTIONS: Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group). MAIN OUTCOME MEASURES: The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting. RESULTS: In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment. CONCLUSIONS: Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Pandemias , Adulto Jovem
19.
Br J Haematol ; 191(3): 460-465, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32342497

RESUMO

RITP was a double-blind randomized, 78-week follow-up trial in which 109 adults with immune thrombocytopenias (ITP) who failed to achieve adequate response to steroids, were randomized to receive rituximab or placebo. Here, we provide the duration of response, splenectomy and mortality rates based on extended follow-up after completion of the RITP study. Extended follow-up data were retrospectively collected for 72 (83%) patients out of the 84 patients who were not splenectomized during the initial RITP study. For the present analysis, median [interquartile range] duration of follow-up after randomization was 72 [62-82] months. Median duration of response among patients who achieved an initial response was significantly longer in patients who received rituximab (8·2 [5·5-16·7] months) as compared to placebo (1·8 [1·3-3·6] months), P = 0·036. Overall, 35 patients underwent splenectomy (13 in the rituximab, and 22 in the placebo arm, P = 0·12). Eleven patients (10%) died during the study: five in the rituximab and six in the placebo arms, including four deaths from severe bleeding. Although most rituximab-treated patients eventually relapsed, a longer duration of response and a trend towards lower splenectomy rate were observed in rituximab-treated patients.

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