RESUMEN
Data on mTOR inhibitors (mTORi) in autoimmune cytopenia (AIC), in adults are scarce. We retrospectively analysed 30 cases of refractory or relapsing AIC treated with an mTORi-based therapy. Eleven warm autoimmune hemolytic anaemia, 10 autoimmune thrombocytopenia, 6 acquired pure red cell aplasia, 3 autoimmune neutropenia were included. Twenty were multilineage AIC (67%) and 21 were secondary AIC (70%). mTORi were associated with other therapies in 23 AIC (77%). Twenty-two AIC (73%) responded to mTORi-based therapy: 5 reached a partial response (17%) and 17 a complete response (57%). Survival without unfavourable outcome (failure, requirement of a new therapy, or death) was longer in multilineage AIC compared to single-lineage AIC (p = 0.049) with a median event-free survival of 48 versus 12 months. Median event-free survival was 48 months in secondary AIC and 33 months in primary AIC (p = 0.79). mTORi were discontinued in 4 patients (15%) for safety reasons and in 3 patients for patient's choice (12%). In conclusion, mTORi could be considered as an alternative or an add-on therapy in refractory or relapsing AIC in adult patients, especially in multilineage AIC.
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Anemia Hemolítica Autoinmune , Trombocitopenia , Humanos , Adulto , Inhibidores mTOR , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Trombocitopenia/tratamiento farmacológicoRESUMEN
Rituximab has revolutionized the treatment of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8-associated multicentric Castleman disease (HHV8+ MCD), converting a rapidly fatal illness into a relapsing disease. HHV8+ MCD mainly affects patients with HIV infection but can also be observed in patients without HIV infection. We retrospectively analyzed a cohort of 99 patients (73 who tested HIV+ and 26 who tested HIV-), with HHV8+ MCD treated with rituximab-based therapy. Baseline characteristics were similar in patients who had HIV- and HIV+ results, although those who tested HIV- were older (65 vs 42 years) and presented less frequently with Kaposi sarcoma (15% vs 40%). Ninety-five patients (70 HIV+ and 25 HIV-) achieved complete remission (CR) after rituximab-based therapy. After a median follow-up of 51 months, 36 patients (12 HIV- and 24 HIV+) experienced disease progression. The 5-year progression-free survival (PFS) was 54%. The 5-year PFS was lower in HIV- patients than in HIV+ patients : 26% and 62%, respectively (P = .02). A multivariate prognostic factors analysis including time-dependent covariates revealed that HIV- status, reoccurrence of HHV8 DNA >3 log copies per mL, and serum C-reactive protein (CRP) >20 mg/mL were independently associated with an increased risk of progression after rituximab-induced CR (P = .001; P = .01; and P = .01, respectively). The lower rate of progression observed in the population with HIV+ results despite a longer follow-up period might have resulted from the possible immune restoration upon antiretroviral therapy. HHV8 viral load and serum CRP monitoring after rituximab therapy provide information on the progression risk and may help in the decision to resume specific therapy.
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Enfermedad de Castleman , Infecciones por VIH , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Rituximab/efectos adversos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Estudios Retrospectivos , Enfermedad de Castleman/tratamiento farmacológico , Enfermedad de Castleman/complicaciones , Recurrencia Local de Neoplasia , Sarcoma de Kaposi/complicaciones , Herpesvirus Humano 8/genéticaRESUMEN
BACKGROUND: Secretory IgA interacts with commensal bacteria, but its impact on human mycobiota ecology has not been widely explored. In particular, whether human IgA-deficiency is associated with gut fungal dysbiosis remains unknown. OBJECTIVES: Our goal was to study the impact of IgA on gut mycobiota ecology. METHODS: The Fungi-Flow method was used to characterize fecal, systemic, and maternal IgA, IgM, and IgG responses against 14 representative fungal strains (yeast/spores or hyphae forms) in healthy donors (HDs) (n = 34, 31, and 20, respectively) and to also compare gut mycobiota opsonization by secretory antibodies in HDs (n = 28) and patients with selective IgA deficiency (SIgAd) (n = 12). Stool mycobiota composition was determined by internal transcribed spacer gene sequencing in HDs (n = 23) and patients with SIgAd (n = 17). Circulating CD4+ T-cell cytokine secretion profiles were determined by intracellular staining. The impact of secretory IgA, purified from breast milk (n = 9), on Candidaalbicans growth and intestinal Caco-2 cell invasion was tested in vitro. RESULTS: Homeostatic IgA binds commensal fungi with a body fluid-selective pattern of recognition. In patients with SIgAd, fungal gut ecology is preserved by compensatory IgM binding to commensal fungi. Gut Calbicans overgrowth nevertheless occurs in this condition but only in clinically symptomatic patients with decreased TH17/TH22 T-cell responses. Indeed, secretory IgA can reduce in vitro budding and invasion of intestinal cells by Calbicans and therefore exert control on this pathobiont. CONCLUSION: IgA has a selective impact on Calbicans ecology to preserve fungal-host mutualism.
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Candida albicans , Deficiencia de IgA , Femenino , Humanos , Células CACO-2 , Inmunoglobulina A , Inmunoglobulina A Secretora , Inmunoglobulina MRESUMEN
Here, we report on a heterozygous interferon regulatory factor 4 (IRF4) missense variant identified in three patients from a multigeneration family with hypogammaglobulinemia. Patients' low blood plasmablast/plasma cell and naïve CD4 and CD8 T cell counts contrasted with high terminal effector CD4 and CD8 T cell counts. Expression of the mutant IRF4 protein in control lymphoblastoid B cell lines reduced the expression of BLIMP-1 and XBP1 (key transcription factors in plasma cell differentiation). In B cell lines, the mutant IRF4 protein as wildtype was found to bind to known IRF4 binding motifs. The mutant IRF4 failed to efficiently regulate the transcriptional activity of interferon-stimulated response elements (ISREs). Rapid immunoprecipitation mass spectrometry of endogenous proteins indicated that the mutant and wildtype IRF4 proteins differed with regard to their respective sets of binding partners. Our findings highlight a novel mechanism for autosomal-dominant primary immunodeficiency through altered protein binding by mutant IRF4 at ISRE, leading to defective plasma cell differentiation.
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Linfocitos B , Factores Reguladores del Interferón , Humanos , Linfocitos B/metabolismo , Diferenciación Celular , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Mutación/genética , Células Plasmáticas/metabolismoRESUMEN
Thrombotic thrombocytopenic purpura (iTTP) and atypical hemolytic-uremic syndrome (aHUS), once in remission, may cause long-term symptoms, among which mental-health impairments may be difficult to detect. We conducted telephone interviews 72 [48-84] months after ICU discharge to assess symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD) and the 36-item Short Form questionnaire (SF-36). Of 103 included patients, 52 had iTTP and 51 aHUS; 74% were female, median age was 39 y (31-54), and 39 (38%) patients were still taking treatment. Symptoms of anxiety, PTSD and depression were present in 50%, 27% and 14% of patients, respectively, with no significant difference between the iTTP and aHUS groups. Patients with PTSD symptoms had significantly greater weight gain and significantly worse perceived physical and/or emotional wellbeing, anxiety symptoms, and depression symptoms. The SF-36 physical and mental components indicated significantly greater quality-of-life impairments in patients with vs. without PTSD symptoms and in those with aHUS and PTSD vs. iTTP with or without PTSD. In the aHUS group, quality of life was significantly better in patients with vs. without eculizumab treatment. Factors independently associated with PTSD symptoms were male sex (odds ratio [OR], 0.11; 95%CI, 0.02-0.53), platelet count ≤20 G/L at acute-episode presentation (OR, 2.68; 1.01-7.38), and current treatment (OR, 2.69; 95%CI, 1.01-7.36). Mental-health screening should be routine in patients with iTTP and aHUS to ensure appropriate care.
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Síndrome Hemolítico Urémico Atípico , Púrpura Trombocitopénica Trombótica , Trastornos por Estrés Postraumático , Humanos , Masculino , Femenino , Adulto , Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/diagnóstico , Trastornos por Estrés Postraumático/epidemiología , Calidad de Vida , Síndrome Hemolítico Urémico Atípico/diagnóstico , Síndrome Hemolítico Urémico Atípico/etiología , Síndrome Hemolítico Urémico Atípico/terapia , SobrevivientesRESUMEN
BACKGROUND: Etoposide remains the cornerstone of symptomatic management of critically ill patients with secondary hemophagocytic syndrome (sHS). Risk of healthcare-associated infections (HAIs) in this setting with etoposide has never been assessed. We sought to evaluate the association between etoposide administration, HAIs occurrence and survival in critically ill adult patients with sHS. In this retrospective single-center study conducted in a university hospital ICU between January 2007 and March 2020, all consecutive patients with sHS were included. HAIs were defined as any microbiologically documented infection throughout ICU stay. Competing risk survival analysis was performed to determine factors associated with HAIs. Propensity score-based overlap weighting was performed to adjust for factors associated with etoposide use. RESULTS: 168 patients with a median age of 49 [38, 59] were included. Forty-three (25.6%) patients presented with at least 1 microbiologically documented HAI throughout ICU stay. After adjustment, cumulative incidence of HAI was higher in patients receiving etoposide (p = 0.007), while survival was unaffected by etoposide status (p = 0.824). By multivariable analysis, etoposide treatment was associated with a higher incidence of HAIs (sHR 3.75 [1.05, 6.67]), whereas no association with survival (sHR 0.53 [0.20, 1.98]) was found. Other factors associated with increased mortality after adjustment included age, immunodepression, male sex, SOFA score > 13, and occurrence of HAI. CONCLUSIONS: In patients with sHS, etoposide treatment is independently associated with increased occurrence of HAIs, whereas no association with survival was found. Intensivists should be aware of increased infectious risk, to promptly detect and treat infections in this specific setting. Studies to assess benefits from prophylactic anti-infectious agents in this setting are warranted and the lack of benefit of etoposide on survival needs to be interpreted cautiously.
RESUMEN
Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disease of unknown etiology. Deciphering mechanisms involved in CD pathogenesis may help improving patients' care. Six cases of stereotyped sub-diaphragmatic iMCD affecting lower limb-draining areas and associated with severe and often ulcerative lower extremity chronic dermatological condition were identified in our cohort. Pathological examination revealed mixed or plasma-cell type MCD. In three patients, shotgun metagenomics failed to identify any pathogen in involved lymph nodes. Antibiotics had a suspensive effect while rituximab and tocilizumab failed to improve the condition. This novel entity requires a specific approach and exclusion of potentially harmful immunomodulation.
RESUMEN
Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor used in B-cell lymphoproliferative disorders. Patients with genetic BTK deficiency are susceptible to recurrent and severe Campylobacter infections. We report 4 patients treated with ibrutinib who developed chronic or extra-digestive campylobacteriosis resembling ibrutinib-related adverse events including diarrhea (n = 4), panniculitis (n = 2), and arthritis (n = 1). Microbiological explorations identified Campylobacter jejuni (n = 3) or Campylobacter coli (n = 1). All the patients completely recovered after a short course of oral antibiotic therapy. In patients treated with ibrutinib presenting with chronic diarrhea, dermatological, or rheumatological manifestations, campylobacteriosis should be ruled out before attributing the symptoms to ibrutinib and discuss its discontinuation.
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Infecciones por Campylobacter , Leucemia Linfocítica Crónica de Células B , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Infecciones por Campylobacter/tratamiento farmacológico , Diarrea/tratamiento farmacológico , Humanos , Leucemia Linfocítica Crónica de Células B/inducido químicamente , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Piperidinas , Inhibidores de Proteínas Quinasas , Pirazoles/efectos adversos , Pirimidinas/efectos adversosRESUMEN
The capacity of pre-existing immunity to human common coronaviruses (HCoV) to cross-protect against de novo COVID-19is yet unknown. In this work, we studied the sera of 175 COVID-19 patients, 76 healthy donors and 3 intravenous immunoglobulins (IVIG) batches. We found that most COVID-19 patients developed anti-SARS-CoV-2 IgG antibodies before IgM. Moreover, the capacity of their IgGs to react to beta-HCoV, was present in the early sera of most patients before the appearance of anti-SARS-CoV-2 IgG. This implied that a recall-type antibody response was generated. In comparison, the patients that mounted an anti-SARS-COV2 IgM response, prior to IgG responses had lower titres of anti-beta-HCoV IgG antibodies. This indicated that pre-existing immunity to beta-HCoV was conducive to the generation of memory type responses to SARS-COV-2. Finally, we also found that pre-COVID-19-era sera and IVIG cross-reacted with SARS-CoV-2 antigens without neutralising SARS-CoV-2 infectivity in vitro. Put together, these results indicate that whilst pre-existing immunity to HCoV is responsible for recall-type IgG responses to SARS-CoV-2, it does not lead to cross-protection against COVID-19.
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Betacoronavirus/fisiología , COVID-19/inmunología , Resfriado Común/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , SARS-CoV-2/fisiología , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Antígenos Virales/inmunología , COVID-19/mortalidad , COVID-19/terapia , Reacciones Cruzadas , Femenino , Humanos , Inmunidad Heteróloga , Inmunoglobulina G/metabolismo , Inmunoglobulina M/metabolismo , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
Primary effusion lymphoma (PEL) is associated with human herpesvirus 8 and frequently with Epstein-Barr virus (EBV). We report here a single-center series of 19 human immunodeficiency virus-associated PELs, including 14 EBV+ and 5 EBV- PELs. The objectives were to describe the clinicopathologic features of PELs, with a focus on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, to search for genetic alterations by targeted deep sequencing analysis, and to compare the features between EBV+ and EBV- cases. All the patients were male, and the median age at diagnosis was 47 years old (interquartile range: 40 to 56 y). Reflecting the terminal B-cell differentiation, immunophenotypic profiles showed low expression levels of B-cell markers, including CD19 (0/19), CD20 (1/19), CD79a (0/19), PAX5 (1/19), BOB1 (3/19), and OCT2 (4/19), contrasting with a common expression of CD38 (10/19), CD138 (7/19), and IRF4/MUM1 (18/19). We observed a frequent aberrant expression of T-cell markers, especially CD3 (10/19), and less frequently CD2 (2/19), CD4 (3/19), CD5 (1/19), and CD8 (0/19). Only 2 cases were PD-L1 positive on tumor cells and none PD-1 positive. With respect to immune cells, 3 samples tested positive for PD-L1 and 5 for PD-1. Our 36-gene lymphopanel revealed 7 distinct variants in 5/10 PELs, with either a single or 2 mutations per sample: B2M (n=2), CD58 (n=1), EP300 (n=1), TNFAIP3 (n=1), ARID1A (n=1), and TP53 (n=1). Finally, we did not observe any major clinical, pathologic, or immunohistochemical differences between EBV+ and EBV- PELs and the outcome was similar (2-y overall survival probability of 61.9% [95% confidence interval, 31.2-82.1] vs. 60.0% [95% confidence interval, 12.6-88.2], respectively, P=0.62).
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Infecciones por VIH/complicaciones , Linfoma de Efusión Primaria/diagnóstico , Adulto , Biomarcadores de Tumor/metabolismo , Humanos , Inmunohistoquímica , Linfoma de Efusión Primaria/metabolismo , Linfoma de Efusión Primaria/patología , Linfoma de Efusión Primaria/virología , Masculino , Persona de Mediana EdadRESUMEN
Idiopathic multicentric Castleman disease (iMCD) is a non-clonal inflammatory lymphoproliferative disorder of unknown origin. Recently, TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) emerged as a singular variant of iMCD in Asia and was associated with a severe course and a poor outcome. The present study describes the first large Western cohort of TAFRO syndrome patients (n = 25) meeting the All Japan TAFRO Syndrome Research Group diagnostic criteria. Characteristics of TAFRO patients were compared to iMCD-not otherwise specified (iMCD-NOS) patients used as a control group (n = 43). Our results show that despite baseline characteristics in accordance with previously reported series, Western TAFRO syndrome patients do not appear to present with a worse outcome than iMCD-NOS patients. There were no significant differences between the two groups regarding treatment choice, response to rituximab (71% vs. 67%) or tocilizumab (69% vs. 91%) in TAFRO and iMCD-NOS, respectively. The two-year overall survival was above 95% in both groups. Limits of inclusion and exclusion criteria for TAFRO definition are also discussed. Our findings raise the question of the singularity of the TAFRO entity in Western countries. The data should promote further research using unsupervised models to identify markers of disease severity in Western cohorts of iMCD patients.
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Enfermedad de Castleman/diagnóstico , Fenotipo , Adulto , Biopsia , Enfermedad de Castleman/etiología , Enfermedad de Castleman/mortalidad , Enfermedad de Castleman/terapia , Toma de Decisiones Clínicas , Terapia Combinada , Diagnóstico Diferencial , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Estudios Retrospectivos , Síndrome , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Coagulation disorders are common in patients with hemophagocytic lymphohistiocytosis (HLH), associated with an increased risk of bleeding and death. We aim to investigate coagulation disorders and their outcome implications in critically ill patients with HLH. METHODS: We prospectively evaluated 47 critically ill patients with HLH (median age of 54 years [42-67]) between April 2015 and December 2018. Coagulation assessments were performed at day 1. Abnormal standard coagulation was defined as prothrombin time (PT) <50% and/or fibrinogen <2g/L. HLH aetiology was mostly ascribed to haematological malignancies (74% of patients). RESULTS: Coagulation disorders and severe bleeding events were frequent, occurring in 30 (64%) and 11 (23%) patients respectively. At day 1, median fibrinogen level was 2â65g/L [1.61-5.66]. Fibrinolytic activity was high as suggested by increased median levels of D-dimers, fibrin monomers, PAI-1 (plasminogen activator inhibitor) and tPA (tissue plasminogen activator). Forty-one (91%) patients had a decreased ADAMTS13 activity (A Disintegrin-like And Metalloproteinase with ThromboSpondin type 1 repeats, member 13). By multivariable analysis, the occurrence of a severe bleeding (OR 3.215 [1.194-8.653], p = 0â021) and SOFA score (Sepsis-Related Organ Failure Assessment) at day 1 (OR 1.305 per point [1.146-1.485], p<0â001) were independently associated with hospital mortality. No early biological marker was associated with severe bleeding. CONCLUSIONS: Hyperfibrinolysis may be the primary mechanism responsible for hypofibrinogenemia and may also participate in ADAMTS13 degradation. Targeting the plasmin system appears as a promising approach in severe HLH-related coagulation disorders.
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Trastornos de la Coagulación Sanguínea , Hemorragia , Mortalidad Hospitalaria , Linfohistiocitosis Hemofagocítica , Proteína ADAMTS13/sangre , Adulto , Anciano , Biomarcadores/sangre , Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/etiología , Trastornos de la Coagulación Sanguínea/mortalidad , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Francia/epidemiología , Hemorragia/sangre , Hemorragia/etiología , Hemorragia/mortalidad , Humanos , Linfohistiocitosis Hemofagocítica/sangre , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/mortalidad , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/sangre , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Activador de Tejido Plasminógeno/sangreRESUMEN
Background & Aims: SARS-CoV2 infection is associated with an increased risk of malnutrition. Although there are numerous screening and nutritional management protocols for malnutrition, only few studies have reported nutritional evolution after COVID-19. The objectives of this study were to describe the evolution of nutritional parameters between admission and 30 days after hospital discharge, and to determine predictive factors of poor nutritional outcome after recovery in adult COVID-19 patients. Methods: In this observational longitudinal study, we report findings after discharge in 91 out of 114 patients initially admitted for COVID-19 who received early nutritional management. Nutritional status was defined using GLIM criteria and compared between admission and day 30 after discharge. Baseline predictors of nutritional status at day 30 were assessed using logistic regression. Results: Thirty days after discharge, 28.6% of patients hospitalized for COVID-19 were malnourished, compared to 42.3% at admission. Half of malnourished patients (53%) at admission recovered a normal nutritional status after discharge. Weight trajectories were heterogeneous and differed if patients had been transferred to an intensive care unit (ICU) during hospitalization (p = 0.025). High oxygen requirement during hospitalization (invasive ventilation p = 0.016 (OR 8.3 [1.6-61.2]) and/or oxygen therapy over 5 L/min p = 0.021 (OR 3.2 [1.2-8.9]) were strong predictors of malnutrition one month after discharge. Conclusions: With early nutritional management, most patients hospitalized for COVID-19 improved nutritional parameters after discharge. These findings emphasize the importance of nutritional care in COVID-19 patients hospitalized in medicine departments, especially in those transferred from ICU.
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COVID-19/dietoterapia , Hospitalización , Desnutrición/epidemiología , Estado Nutricional , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Unidades de Cuidados Intensivos , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Evaluación Nutricional , Terapia Nutricional/métodos , Terapia por Inhalación de Oxígeno/estadística & datos numéricos , Alta del Paciente , Factores de Riesgo , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Based on animal models and human studies, there is now strong suspicion that host/microbiota mutualism in the context of gut microbial dysbiosis could influence immunity and multiple sclerosis (MS) evolution. Our goal was to seek evidence of deregulated microbiota-induced systemic immune responses in patients with MS. METHODS: We investigated gut and systemic commensal-specific antibody responses in healthy controls (n = 32), patients with relapsing-remitting MS (n = 30), and individuals with clinically isolated syndromes (CISs) (n = 15). Gut microbiota composition and diversity were compared between controls and patients by analysis of 16S ribosomal ribonucleic acid (rRNA) sequencing. Autologous microbiota and cultivable bacterial strains were used in bacterial flow cytometry assays to quantify autologous serum IgG and secretory IgA responses to microbiota. IgG-bound bacteria were sorted by flow cytometry and identified using 16S rRNA sequencing. RESULTS: We show that commensal-specific gut IgA responses are drastically reduced in patients with severe MS, disease severity being correlated with the IgA-coated fecal microbiota fraction (r = -0.647, p < 0.0001). At the same time, IgA-unbound bacteria elicit qualitatively broad and quantitatively increased serum IgG responses in patients with MS and CIS compared with controls (4.1% and 2.5% vs 1.9%, respectively, p < 0.001). CONCLUSIONS: Gut and systemic microbiota/immune homeostasis are perturbed in MS. Our results argue that defective IgA responses in MS are linked to a breakdown of systemic tolerance to gut microbiota leading to an enhanced triggering of systemic IgG immunity against gut commensals occurring early in MS.
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Microbioma Gastrointestinal/inmunología , Homeostasis/inmunología , Microbiota/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/microbiología , Adolescente , Adulto , Femenino , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/microbiología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Gravedad del Paciente , ARN Ribosómico 16S , Adulto JovenRESUMEN
Rituximab (RTX), an antibody targeting CD20, is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Here, we characterize the cellular basis responsible for disease relapse in secondary lymphoid organs in humans, taking advantage of the opportunity offered by therapeutic splenectomy in patients with relapsing immune thrombocytopenia. By analyzing the B and plasma cell immunoglobulin gene repertoire at bulk and antigen-specific single-cell level, we demonstrate that relapses are associated with two responses coexisting in germinal centers and involving preexisting mutated memory B cells that survived RTX treatment and naive B cells generated upon reconstitution of the B cell compartment. To identify distinctive characteristics of the memory B cells that escaped RTX-mediated depletion, we analyzed RTX refractory patients who did not respond to treatment at the time of B cell depletion. We identified, by single-cell RNA sequencing (scRNA-seq) analysis, a population of quiescent splenic memory B cells that present a unique, yet reversible, RTX-shaped phenotype characterized by down-modulation of B cell-specific factors and expression of prosurvival genes. Our results clearly demonstrate that these RTX-resistant autoreactive memory B cells reactivate as RTX is cleared and give rise to plasma cells and further germinal center reactions. Their continued surface expression of CD19 makes them efficient targets for current anti-CD19 therapies. This study thus identifies a pathogenic contributor to autoimmune diseases that can be targeted by available therapeutic agents.
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Púrpura Trombocitopénica Idiopática , Anticuerpos Monoclonales de Origen Murino , Linfocitos B , Humanos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Recurrencia , Rituximab/farmacología , Rituximab/uso terapéuticoRESUMEN
Early thrombotic thrombocytopenic purpura (TTP) recognition is critical as this disease is almost always lethal if not treated promptly with therapeutic plasma exchanges. Currently, as ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity is not widely available in emergency, scores have been developed to help differentiating TTP from other thrombotic microangiopathies (TMAs). The aim of this work was to study the accuracy of these diagnostic scores in the intensive care unit (ICU) setting. Performance of both Coppo and PLASMIC scores was studied in a cohort of adult TMA patients requiring admission to one university hospital ICU from 2006 to 2017. Receiver operating characteristic (ROC) curves were established, and confidence intervals of the area under the curve (AUC) were determined. Multivariate logistic regression analysis was performed to identify parameters specifically associated with TTP, to compare diagnostic scores and to elaborate more accurate diagnostic models. During the study period, 154 TMA patients required ICU admission, including 99 (64.2%) TTP and 55 (35.7%) non-TTP patients. AUC under the ROC curve in predicting TTP was 0.86 (95% confidence interval [CI]: 0.81-0.92) for the Coppo score, 0.67 (95% CI: 0.58-0.76) for the PLASMIC score, and 0.86 (95% CI: 0.81-0.92) for platelet count alone. Platelet count ≤20 G/L, determined as the best cut-off rate for thrombocytopenia, performed similarly to the Coppo score and better than the PLASMIC score to differentiate TTP from non-TTP patients, both using AUC ROC curve and logistic regression. In a monocentric cohort of TMA patients requiring ICU admission, the PLASMIC score had limited performance for the diagnosis of TTP. The performance of the Coppo score was good but similar to a single highly discriminant item: platelet count ≤20 G/L at admission.
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Técnicas de Apoyo para la Decisión , Unidades de Cuidados Intensivos , Microangiopatías Trombóticas/diagnóstico , Adulto , Anticuerpos Antinucleares/sangre , Biomarcadores/sangre , Creatinina/sangre , Índices de Eritrocitos , Femenino , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Paris , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Microangiopatías Trombóticas/sangre , Microangiopatías Trombóticas/terapiaRESUMEN
Humoral immune responses are typically characterized by primary IgM antibody responses followed by secondary antibody responses associated with immune memory and composed of IgG, IgA, and IgE. Here, we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of SARS-CoV-2-specific neutralizing antibodies in the serum, saliva, and bronchoalveolar fluid of 159 patients with COVID-19. Early SARS-CoV-2-specific humoral responses were dominated by IgA antibodies. Peripheral expansion of IgA plasmablasts with mucosal homing potential was detected shortly after the onset of symptoms and peaked during the third week of the disease. The virus-specific antibody responses included IgG, IgM, and IgA, but IgA contributed to virus neutralization to a greater extent compared with IgG. Specific IgA serum concentrations decreased notably 1 month after the onset of symptoms, but neutralizing IgA remained detectable in saliva for a longer time (days 49 to 73 post-symptoms). These results represent a critical observation given the emerging information as to the types of antibodies associated with optimal protection against reinfection and whether vaccine regimens should consider targeting a potent but potentially short-lived IgA response.
Asunto(s)
Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/diagnóstico , Inmunidad Humoral , Inmunoglobulina A/sangre , SARS-CoV-2/inmunología , Biomarcadores/sangre , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/virología , COVID-19/sangre , COVID-19/inmunología , COVID-19/virología , Estudios de Casos y Controles , Interacciones Huésped-Patógeno , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Estudios Longitudinales , Saliva/inmunología , Saliva/virología , Factores de TiempoRESUMEN
BACKGROUND & AIMS: Nutritional knowledge in patients with SARS-Cov2 infection (COVID-19) is limited. Our objectives were: i) to assess malnutrition in hospitalized COVID-19 patients, ii) to investigate the links between malnutrition and disease severity at admission, iii) to study the impact of malnutrition on clinical outcomes such as transfer to an intensive care unit (ICU) or death. METHODS: Consecutive patients hospitalized in a medicine ward at a university hospital were included from March 21st to April 24th 2020 (n = 114, 60.5% males, age: 59.9 ± 15.9 years). Nutritional status was defined using Global Leadership Initiative on Malnutrition (GLIM) criteria. Clinical, radiological and biological characteristics of COVID-19 patients were compared according to the presence of malnutrition. Logistic regression was used to assess associations between nutritional parameters and unfavourable outcomes such as transfer to intensive care unit (ICU) or death. RESULTS: The overall prevalence of malnutrition was 42.1% (moderate: 23.7%, severe: 18.4%). The prevalence of malnutrition reached 66.7% in patients admitted from ICU. No significant association was found between nutritional status and clinical signs of COVID-19. Lower albumin levels were associated with a higher risk of transfer to ICU (for 10 g/l of albumin, OR [95%CI]: 0.31 [0.1; 0.7]; p < 0.01) and this association was independent of age and CRP levels. CONCLUSIONS: COVID-19 in medical units dedicated to non-intensive care is associated with a high prevalence of malnutrition, especially for patients transferred from ICU. These data emphasize the importance of early nutritional screening in these patients to adapt management accordingly.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Hospitalización , Desnutrición/epidemiología , Neumonía Viral/complicaciones , Adulto , Anciano , COVID-19 , Femenino , Francia/epidemiología , Mortalidad Hospitalaria , Humanos , Estudios Longitudinales , Masculino , Desnutrición/complicaciones , Persona de Mediana Edad , Evaluación Nutricional , Pandemias , Prevalencia , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
The genetic investigation of a family presenting with a dominant form of hyper IgM syndrome published in 1963 and 1975 revealed a R190X nonsense mutation in activation-induced cytidine deaminase. This report illustrates the progress made over 6 decades in the characterization of primary immunodeficiencies, from immunochemistry to whole-exome sequencing.