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1.
Clinical Immunology ; Conference: 2023 Clinical Immunology Society Annual Meeting: Immune Deficiency and Dysregulation North American Conference. St. Louis United States. 250(Supplement) (no pagination), 2023.
Artigo em Inglês | EMBASE | ID: covidwho-20240620

RESUMO

RAG mutations cause various phenotypes: SCID, Omenn syndrome (OS), leaky SCID (LS) and combined immunodeficiency (CID). We had previously reported autoantibodies targeting IFN-alpha, IFN-omega in patients with RAG deficiency. However, how the presence of such antibodies correlated with the severity of the clinical phenotype and with the recombination activity of the mutant proteins was unknown. To address this, we have studied anti-cytokine antibodies in 118 patients with RAG defects (SCID, n = 28;OS, n = 29;LS, n = 29;CID, n = 32), and in 42 controls (protocols NCT03394053 and NCT03610802). RAG mutant proteins associated with CID and LS retained 35.6 +/- 4.3 (mean +/- SE) and 29.8 +/- 5.1% recombination activity respectively, compared to wildtype protein, which was significantly higher than the recombination activity of the mutant RAG proteins associated with OS (4.1 +/- 1.5%) and SCID (5.7 +/- 2.1%) (p < 0.0001). Among 32 CID patients, 24 tested positive for anti-IFN-alpha and 21 for anti-IFN-omega antibodies. Among 29 LS patients, 15 had high levels of anti-IFN-alpha and 13 of anti-IFN-omega antibodies. A minority of the CID and LS patients had also high levels of anti-IFN-beta and anti-IL-22 antibodies. By contrast, none of the OS patients tested positive for anti-cytokine antibodies. High levels of anti-IFN-alpha and anti-IFN-omega antibodies correlated with their neutralizing activity as demonstrated in vitro by analysis of STAT1 phosphorylation upon stimulation of healthy donor monocytes in the presence of the appropriate cytokine and patient's or control plasma. Severe viral infections were recorded in 26/41 patients with CID and LS who tested positive and in 7/20 who tested negative for anti-IFN-alpha and/or anti-IFN-omega antibodies (p <0.05). Among those with anti-IFN antibodies, EBV (n = 8), CMV (n = 6), HSV (n = 5), VZV (n = 4) and adenovirus (n = 4) infections were more common. Two patients had COVID-19, which was fatal in one. Presence of the rubella virus was documented in 5 patients with anti-type I IFN antibodies. These results demonstrate that high levels of neutralizing anti-IFN-alpha and anti-IFN-omega antibodies are common in patients with RAG mutations manifesting as CID and LS, but not in those with OS, and that their presence is associated with a high risk of serious viral infections.Copyright © 2023 Elsevier Inc.

2.
Journal of Psychosomatic Research ; Conference: 10th annual scientific conference of the European Association of Psychosomatic Medicine (EAPM). Wroclaw Poland. 169 (no pagination), 2023.
Artigo em Inglês | EMBASE | ID: covidwho-20236441

RESUMO

Background: Functional Somatic Disorders (FSDs) are characterized by persistent physical symptoms that cannot be explained by other somatic or psychiatric conditions. Multiple Chemical Sensitivity (MCS) is a non-allergic FSD characterized by odour intolerance and various somatic symptoms being attributed to the influence of toxic environmental chemicals in low, usually harmless doses. The pathophysiology of FSDs are still not clear. Smell and taste complaints were also among the notable symptoms characterizing the covid epidemic and the latest evidence suggests overlaps between long COVID and FSDs. Method(s): The study includes advanced analysis of MRI-derived functional and structural connectomes acquired on a 3 T MR scanner. Furthermore, it includes questionnaires and paraclinical tests, e.g. the Sniffin' Stick olfactory test, Mini-Mental State Examination, and Sino-Nasal Outcome test 22. The pilot part of the project included 6 MCS patients who were compared with 6 matched healthy participants. Later follow-up included analysis of 8 multiorgan FSD and 4 post-COVID patients. Result(s): The MCS group showed important brain structural connectivity differences in 34 tracts. Notably, for MCS patients, the olfactory cortex (especially in the right hemisphere) showed decreased connectivity with regions in the emotional system. Conclusion(s): We plan to extend these findings with whole-brain modelling of the functional connectivity in the patient groups. Long-term this could be used as a 'fingerprint' which could help with diagnosis and treatment monitoring in FSDs as well as with new diagnoses such as long-COVID.Copyright © 2023

3.
European Journal of Human Genetics ; 31(Supplement 1):708, 2023.
Artigo em Inglês | EMBASE | ID: covidwho-20233214

RESUMO

Background/Objectives: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease (COVID-19) enters the lung tissue through exocytosis, leading to the release of a large amount of pro-inflammatory cytokines called 'cytokine storm'. The aim was to provide more insight into relationship between plasma cytokines profile and fatal outcome of COVID-19. Method(s): Plasma cytokines (IL-17F,GM-CSF,IFNg,IL-10,CCL20/ MIP3a,IL-12P70,IL-13, IL-15,IL-17A,IL-22,IL-9,IL-1b,IL-33,IL-2,IL-21,IL-4,IL-23,IL-5,IL-6,IL-17E/IL-25,IL-27,IL-31,TNFa,TNFb,IL-28A) were detected in 30 patients with severe COVID-19 by a Luminex assay system with Milliplex Human Th17 Magnetic Premix 25 Plex Kit (HT17MG-14K-PX-25, Merk-Millipore, USA) according to the instructions. Patients were followed up for 30 days since admission to intensive care. 18 patients died and 12 patients survived during the period of observation. The control group comprised 10 individuals who had never been diagnosed with COVID-19. Result(s): IL-10 and CCL20/MIP3a plasma levels were elevated in non-survivors patients with COVID-19 compared to controls (p = 0.0027, p = 0.012, respectively). IL-15, IL-6, IL-27 plasma levels were higher in survivors with COVID-19 compared to controls (p = 0.049, p = 0.026, p = 0.00032, respectively). Interestingly, IL-15, IL-27 plasma levels were increased in non-survivors with COVID-19 compared to controls and survivors with severe COVID-19 (IL-15: p = 0.00098, p = 0.00014, respectively;IL-27: p = 0.011, p < 0.0001, respectively). Receiver operating characteristic (ROC) analysis has been conducted for IL-15 and IL-27. Cut-off value was estimated as 25.50 pg/ml for IL-15 and 1.51 pg/ml for IL-27. Conclusion(s): Our study demonstrated a more pronounced immune response in non-surviving patients with severe COVID-19. IL-15, IL-27 could be considered as a sensitive biomarker of the fatal outcome from COVID-19.

4.
Zeitschrift fur Gastroenterologie ; 61(1):e55, 2023.
Artigo em Inglês | EMBASE | ID: covidwho-2249981

RESUMO

Background and Aims Viral infections occur acutely but can also progress chronically, with the immune system having a central role in immunopathoge-nesis. The question arises whether all alterations in immune responses are reversible after viral elimination (spontaneously or by therapy). Therefore, the aim of this study is to compare soluble infammatory markers (SIM) during and after infection with SARS-CoV-2 and acute and chronic HCV-infections. Patients and Method Patients with acute HCV (n = 29), chronic HCV (n = 54), SARS-CoV-2 (n = 39) and 31 healthy-controls were included. Blood samples were tested at baseline, end of treatment/infection, and follow-up ( >= 9 months after baseline). IL-12p70, IL-1b, IL-4, IL-5, IL-6, IL-8, TNF, IFN-g, IL-10, IL-22, CXCL-10, MCP-1, MIP-1b, ITAC were quantified using the HD-SP-X Imaging and Analysis SystemTM. Results SIM profiles in patients with acute HCV were substantially elevated at baseline and the decrease during follow-up was considerably less compared to the SARS-CoV-2 cohort. In chronic HCV-patients, viral elimination by therapy resulted in a decrease in SIM, although not always to those of controls. Cirrhotic HCV patients had higher SIM levels after HCV elimination than non-cirrhotic chronic HCV-patients. In the SARS-CoV-2 cohort, most SIM returned to levels of controls 3 months after baseline. Conclusions SIM profiles and kinetics after viral elimination difer between blood-borne acute and chronic HCV- and respiratory SARS-CoV-2-infections. The immunologic imprint 9 months after cured HCV-infection (both acute and chronic) appears to be more pronounced than after SARS-CoV-2-infection. Further analysis is needed to correlate the SIM profle with the clinical pheno-type (long-HepC vs. long-COVID-19).

5.
Hematology, Transfusion and Cell Therapy ; 44(Supplement 2):S172, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2179125

RESUMO

Introducao: Com desafiador tratamento e de diagnostico criterioso, a leucemia aguda de fenotipo misto (LAFM) e uma entidade rara dentro do espectro das leucemias agudas. Requer a presenca imunofenotipica de marcadores de linhagem B (CD19, CD22, CD79a), T (CD3) em conjunto com a linhagem mieloide (mieloperoxidase e diferenciacao monocitica - CD11c, CD14, CD64 ou lisozima). Relato de caso: Paciente masculino, 30 anos, obeso e diabetico tipo 2, hipertrigliceridemia, inicia com febre (38C), dor abdominal em hipocondrio direito e fadiga. Com dois dias de sintomas procura atendimento sendo liberado com sintomaticos. No quarto dia de sintomas houve piora da febre (39degreeC) e da dor, surgindo maculas hiperemiadas pruriginosas pelo corpo, ictericia e coluria. Retornou ao hospital de sua cidade sendo prescrito azitromicina e liberado com suspeita de influenza. No sexto dia de sintomas notou piora da ictericia, procurando, novamente, atendimento. Encaminhado, entao ao servico de referencia da regiao. Interna inicialmente na equipe da gastroenterologia como suspeita de hepatite viral. Na chegada: Hb 14,9, leucocitos 6140 com 2793 neutrofilos, 442 monocitos e 2812 linfocitos, 53 mil plaquetas;AST 57, ALT 733, hiperbilirrubinemia as custas de bilirrubina direta. Com todos os marcadores virais negativos, prosseguiu a investigacao de hepatite. No dia em que realiza ressonancia magnetica, que indicava processo infiltrativo/inflamatorio em figado e rim esquerdo, alem de testar positivo para COVID-19, ha evolucao no hemograma: Hb 10,7, leucocitos 7450 com 1192 blastos, 60 neutrofilos, 2012 monocitos e 4187 linfocitos, 23 mil plaquetas. Com o aparecimento de blastos, piora dos niveis de bilirrubinas e das lesoes de pele, foi realizado imunofenotipagem de sangue periferico que indicava leucemia monocitica aguda. Transferido a equipe da hematologia, sendo realizada biopsia de medula e iniciado protocolo 7 + 3 com substituicao das antraciclinas em falta no mercado por doxorrubicina 45 mg/m2. No terceiro dia da inducao, foi liberado o resultado da imunofenotipagem que confirmava o diagnostico de leucemia aguda de fenotipo misto B/mieloide, marcando CD19, CD22 e CD79a, com diferenciacao monocitica (CD14 e CD64). Cariotipo nao houve crescimento e PCR BCR/ABL negativo. Optado por seguir tratamento com 7 + 3, apresentando medula no D14 aplasiada e medula no D28 com doenca residual minima (DRM) negativa. Realiza tres consolidacoes com altas doses de citarabina (3g/m2). Paciente sustenta DRM negativa, estando em remissao completa. Iniciado manutencao com vincristina, mercaptopurina, metotrexato e prednisona. Aguarda transplante de celulas tronco hematopoieticas (TCTH). Discussao: Com o diagnostico de LAFM, o tratamento requer o maior numero de quimioterapicos, sendo sugerido o uso de protocolos para leucemia linfoblastica aguda. Como ja havia sido instituido o tratamento com doxorrubicina e citarabina, foi optado por seguir protocolo e, na manutencao da remissao completa, terminar as consolidacoes e iniciar a manutencao prevista pelo protocolo HyperCVAD. Devido a ser uma leucemia de alto risco, a realizacao do TCTH e necessaria e, neste caso relatado, a manutencao sera mantida ate a realizacao do transplante. Conclusao: Contudo, por se tratar de doenca rara e com poucos estudos publicados, requer compartilhamento de conhecimentos e condutas para melhora da abordagem. Copyright © 2022

6.
Annals of the Rheumatic Diseases ; 81:927-928, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2008837

RESUMO

Background: Comorbidities, particularly cardio-metabolic disorders, are highly prevalent in patients with psoriatic arthritis (PsA) and they were associated with an increased risk of atherosclerotic cardiovascular disease, which have been associated with higher morbidity and mortality. Whether PsA enhances the risk of SARS-CoV-2 infection or affects the disease outcome remains to be ascertained. Objectives: To describe the sociodemographic, clinical and treatment characteristics of patients with PsA with confrmed SARS-CoV-2 infection from the SAR-COVID registry and to identify the variables associated with poor COVID-19 outcomes, comparing them with those with rheumatoid arthritis (RA). Methods: Cross-sectional observational study including patients ≥18 years old, with diagnosis of PsA (CASPAR criteria) and RA (ACR/EULAR 2010 criteria), who had confrmed SARS-CoV-2 infection (RT-PCR or serology) from the SAR-COVID registry. Recruitment period was between August 13, 2020 and July 31, 2021. Sociodemographic variables, comorbidities, and treatments were analyzed. To assess the severity of the infection, the ordinal scale of the National Institute of Allergy and Infectious Diseases (NIAID)1 was used, and it was considered that a patient met the primary outcome, if they presented criteria of categories 5 or higher on the severity scale. For this analysis, Chi2 test, Fisher's test, Student's test or Wilcoxon test, and binomial logistic regression using NIAID>=5 as dependent variable were performed. Results: A total of 129 PsA patients and 808 with RA were included. Clinical characteristics are shown in Table 1. Regarding PsA treatment, 12.4% of PsA were receiving IL-17 inhibitors, 5.4% IL12-23 inhibitors, one patient apremilast and one abatacept. The frequency of NIAID≥5 was comparable between groups (PsA 19.5% vs RA 20.1%;p=0.976). (Figure 1). PsA patients with NIAID≥5 in comparison with NIAID<5 were older (58.6±11.4 vs 50±12.5;p=0.002), had more frequently hypertension (52.2% vs 23%;p=0.011) and dyslipidemia (39.1% vs 15%;p=0.017). In the multivariate analysis, age (OR 1.06;95% CI 1.02-1.11) was associated with a worse outcome of the COVID-19 (NIAID≥5) in patients with PsA, while those who received methotrexate (OR 0.34;95% CI 0.11-0.92) and biological DMARDs (OR 0.28;95% CI 0.09-0.78) had a better outcome. Conclusion: Although PsA patients have a higher frequency of cardiovascular and metabolic comorbidities than those with RA, the COVID-19 severity was similar. Most of the patients had mild SARS-CoV-2 infection and a low death rate.

7.
Gut ; 71, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2002965

RESUMO

The proceedings contain 374 papers. The topics discussed include: optical biopsy with linked color imaging accurately predicts inflammation in ulcerative colitis;predicting use of opiates in patients with inoperable pancreatic cancer: a retrospective cohort study;unbiased clustering of breath signature in NAFLD identifies disease progression high-risk patient phenotype - 5 year study;prevalence of malnutrition screening;the association between IBD and mental ill health: a retrospective primary care cohort study;the interleukin 22//neutrophil axis is associated with treatment resistance in ulcerative colitis;neuromuscular dysfunction in patients with nausea and vomiting syndrome defined by body surface gastric mapping;two-tiered liver fibrosis assessment in primary care annual diabetic screening 3 year follow up;can an algorithm help in the difficult dilemma of upper gastrointestinal bleed and anticoagulant COVID-19 pandemic and alcohol-specific hospital admissions;and upper gastrointestinal hemorrhages and COVID-19: a nationwide cohort study of the pandemic's impact on hospitalizations.

8.
Journal of Hepatology ; 77:S889, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-1996651

RESUMO

Background and aims: The global pandemic has inevitably diverted resources away from management of chronic diseases, including cirrhosis, where up to 40% of patients are readmitted with new cirrhosis decompensation events. Whilst there is increasing knowledge on COVID-19 infection in liver cirrhosis, little is described on the impact of the pandemic on decompensated cirrhosis admissions and outcomes, which was the aim of this study. Method: A single-centre, retrospective study, evaluated decompensated cirrhosis admissions to a tertiary London hepatology and transplantation centre, from October 2018 to February 2021. Patients were included if they had an admission with cirrhosis decompensation defined as new onset jaundice or ascites, infection, encephalopathy, portal hypertensive bleeding or renal dysfunction. Admissions were excluded if they lasted <24 hours,were elective or occurred post liver-transplant. Results: Therewere 351 admissions in the pre-COVID period (October 2018 to February 2020) and 240 admissions during the COVID period (March 2020 to February 2021), with an average of 20.4 admissions per month throughout. Patients transferred in from secondary centres had consistently higher severity scores during the COVID period (UKELD 58 versus 54;p = 0.007, MELD Na 22 versus 18;p = 0.006, AD score 55.0 versus 51.0;p = 0.055). The proportion of ITU admissions pre versus during-COVID stayed constant (22.9% versus 19.2%), but there was a trend towards increased ICU admissions with acute-on-chronic liver failure (ACLF) (73.9% versus 63.8% prepandemic). Of those admitted to the intensive care without ACLF, there was a significant increase in EF-CLIF acute decompensation (AD) scores during the COVID period (58 versus 48, p = 0.009). In addition, there was a trend towards increased hospital re-admission rates during the COVID period (29.5% versus 21.5%, p = 0.067). When censored at 30 days, time to death post discharge was significantly reduced during the COVID period (p < 0.05) with a median time to death of 35 days compared to 62 days pre-COVID.(Figure Presented)Conclusion: This study provides a unique perspective on the impact that the global pandemic had on the clinical course and characteristics of decompensated cirrhosis admissions. The findings of increased early mortality and re-admissions, and higher AD scores, indicating increased disease morbidity, highlight the need to maintain resourcing on providing high-level hepatology care. Given that COVID-19 will likely be a chronic issue, alternative care pathways such as remote monitoring may need adoption to facilitate continuity of care post-discharge and to reduce readmission rates and morbidity in the future

9.
Topics in Antiviral Medicine ; 30(1 SUPPL):101, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-1880069

RESUMO

Background: Severe infection with SARS-CoV-2 induces systemic autoreactive antibodies with specificity to Type I IFN, phospholipids, nuclear or tissue specific targets. The wide breadth of targets suggests a system-wide defect in B cell tolerance during viral infection and that the source of autoreactive antibodies is likely a heterogenous subset of B cells. BND cells are mature naïve B cells that do not express IgM but do express IgD and are enriched in autoreactive specificities. BND cells are held in an anergic state in healthy humans as a mechanism of peripheral tolerance, although in vitro evidence suggests anergy can be broken with strong inflammation. We hypothesized that robust inflammation associated with viral infection from SARS-CoV2 may relax peripheral tolerance and promote breakage of BND cell anergy. Methods: Plasma and PBMCs were collected from healthy controls (N=10), subjects immunized with Pfizer BNT162b2-mRNA/Moderna mRNA-1273 (N=10), subjects with mild (N=11) or severe SARS-CoV-2 infection (N=14). BND cells were examined ex vivo for markers of activation by flow cytometry. Phosphorylation of signaling proteins downstream of the BCR were measured in vitro with or without BCR crosslinking. Inflammatory cytokines were measured in plasma by multiplex. For statistical analysis, unpaired t test between populations or paired t test between unstimulated and BCR stimulated conditions were performed. Results: BND cells from severe SARS-CoV-2 infection have lower expression of CD21, associated with loss of anergy, higher expression of activation markers CD68 and CD86 with lower expression of inhibitory receptors CD22 and CD72 when compared to BND cells from other subjects, suggesting a phenotypical breach of anergy. Upon BCR crosslinking, BND cells have higher levels of downstream signaling components of the BCR (pPLCγ2, pBlnk, and pSyk) when compared to healthy controls and immunized subjects, suggesting a functional breach in anergy with infection. Examination of plasma from severe SARS-CoV-2 infection showed higher levels of inflammatory cytokines (IFNγ, TNFα, IL-6 and CRP) where TNFα and CRP correlated with enhanced BCR signaling in BND cells. Conclusion: We demonstrate that SARS-CoV-2 viral infection relaxes peripheral tolerance of BND cells, likely through strong systemic inflammation produced during infection. These autoreactive cells overcome anergy and become activated with increased BCR signaling. Thus BND cells could be a source of autoreactive antibodies during viral infection.

10.
Hematology, Transfusion and Cell Therapy ; 43:S114-S115, 2021.
Artigo em Inglês | EMBASE | ID: covidwho-1859599

RESUMO

Introdução: A macroglobulinemia de Waldenstrom (MW) é uma patologia linfoproliferativa neoplásica maligna das células plasmáticas e linfócitos B, normalmente responsável pela síntese das cadeias pesadas de imunoglobulinas. Diferente da leucemia linfoblástica aguda, os linfócitos mantêm a capacidade de se diferenciar e amadurecer em células plasmáticas. A MW possui características que variam de células linfoides maduras a plasmócitos. Imunofenotipagem de células obtidas a partir da medula óssea, dos linfonodos ou do sangue periférico de pacientes com essa doença mostram IgM citoplasmática detectável em células plasmáticas e imunoglobulina superficial na maioria dos linfócitos. Objetivo: Apresentar um caso de MW. Material e métodos: Revisão de prontuáriros médicos e literatura. Descrição do caso: Paciente do sexo masculino, 61 anos, apresentou epistaxe de grande volume com repetição, fadiga e astenia, além de perda de 15 quilos em 6 meses. Na admissão hospitalar apresentava os seguintes exames: anemia com hemoglobina 5,4 g/dL, hemácias de 1,45 milhão/mm3, plaquetopenia (87.000/mm3), presença de esplenomegalia importante, roleaux eritrocitário, esplenomegalia e linfonodomegalia abdominal. Solicitada avaliação com hematologista por paciente referir repetidas anemias ao longo da vida e histórico de transfusões de repetição. Seguem os resultados da investigação com especialisgta: Mielograma apresentou células linfoides de tamanho pequeno e aspecto maduro, algumas apresentando aspecto plasmocitoide. Imunofenotipagem de sangue periférico com CD20/CD38, CD38, CD200, CD19/CD200 positivo fraco;CD19, CD45, CD45/CD22, KAPPA, CD20: positivo de alta intensidade;KAPPA cito- plasmático e CD43 positivo. Dosagem de Imunoglobulinas: IgM 10.100 mg/dL, IgG 242 mg/dL e IgA 91,5 mg/dL. Pico monoclonal IgM/Lambda na imunofixação sérica. Exame de Coombs direto negativo. Como terapêutica, iniciou-se Ciclofosfamida associado a Rituximabe. O paciente evoluiu ao óbito devido ao Covid-19 durante a internação. Discussão: A MW é uma neoplasia rara, sendo que o paciente deste relato enquadra-se na idade média do diagnóstico de MW, que ocorre em torno dos 60 anos, maioria do sexo masculino. Grande parte dos pacientes apresenta sintomas como fadiga, fraqueza e sangramento (principalmente epistaxe). Outras manifestações como perda de peso, distúrbios visuais e fenômeno de Raynaud são menos comuns. Ao exame físico, encontra-se rotineiramente hepatoesplenomegalia e linfadenopatia. Proteinúria de Bence Jones está presente em um quarto de todos os pacientes com MW, devido a uma lesão predominantemente glomerular com depósitos de IgM e material amiloide. A função plaquetária está prejudicada pelo revestimento de plaquetas com IgM, e alguns pacientes podem apresentar defeitos da cascata de coagulação. Os níveis de IgM são marcadamente aumentados, e a crioglobulina pode ser detectada em alguns pacientes. O tratamento deve ser individualizado de acordo com as manifestações clínicas de cada paciente e seu curso clínico é variável. Causas de morte relacionam-se geralmente a hiperviscosidade, anemia, hemorragia, trombose e infecções, sendo que neste caso a infecção por Covid-19 atuou como fator definidor. Conclusão: É oportuno o relato de um caso de MW devido a raridade de seu diagnóstico e importância de estabelecer diagnóstico diferencial com doenças de maior prevalência.

11.
Endocrine Practice ; 28(5):S51, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-1851059

RESUMO

Objective: Uncontrolled hyperglycaemia is associated with poor clinical outcomes among patients with COVID-19. Diabetes mellitus and hyperglycemia at presentation, are independent risk factors for disease severity and worse outcome of COVID-19 infection. Methods: We evaluated the association of biomarkers of COVID-19 (CRP, D-Dimer and Ferritin) with the random blood sugar (RBS) as reported through SMBG by the patients who were already under regular care, across two dedicated diabetes centres. We compared the levels of CRP, D-Dimer and Ferritin across the groups with RBS < 200 and with RBS ≥ 200, Normal values: CRP 0-5 mg/L, D-Dimer < 0.5 mg/dl, Ferritin 30-400 ng/mL Results: The mean age of the patients was 59 years (SD±13, 95% CI 58 to 60). 256 were male. In our cohort, 378 (87%) were mild cases and 56 (12.9%) were moderate cases. The mean RBS in mild cases at the first consultation was 198 mg/dL (SD±45, 95% CI 170 to 231). The mean CRP (mg/dl), D-Dimer (mg/L) and Ferritin (mg/L) in mild cases were 6.7 (SD±3, 95% CI 5.5 to 7.3), 0.62 (SD±2, 95% CI 0.57 to 6.6) and 485 (SD±34, 95% CI 455 to 516), respectively. The mean RBS in moderate cases at the first consultation was 225 mg/dL (SD±32, 95% CI 196 to 259). The mean CRP (mg/dl), D-Dimer (mg/L) and Ferritin (mg/L) in moderate cases cases were 12.1 (SD±4, 95% CI 6.2 to 13.9), 1.3 (SD±2, 95% CI 0.9 to 1.7) and 655 (SD±42, 95% CI 588 to 691), respectively. There were 92 patients (21.1%) who were initiated on Premixed Analog insulin regimen to achieve glycemic control. Mild cases were managed by standard care approach for diabetes care, including oral drugs. 58 patients (63%) needed uptitration of insulin regimen as the RBS was over 300mg/dL, as a predefined threshold. Discussion/Conclusion: We observed that the T2DM patients with higher grade of hyperglycemia had higher concentrations of prognostic biomarkers. This might have happened due to inflammatory reactions and related tissue destruction. COVID-19 vaccination program should also target those populations with higher RBS to improve their outcomes. We could not quantify the grade of insulin resistance and obesity that would have independently deteriorated the glycemic control with accelerated transition of mild to moderate COVID-19. Our study highlights the need to evaluate COVID-19 biomarkers guided by higher RBS and accordingly predict the progress of mild to moderate cases and timely intervene to manage these patients, while optimally utilising the resources for management of COVID-19.

12.
Blood ; 138:511, 2021.
Artigo em Inglês | EMBASE | ID: covidwho-1582347

RESUMO

On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group. Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL. Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets < 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4;Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5;CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870. Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation. Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL. [Formula presented] Disclosures: Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor;Jazz Pharmaceuticals: Other: Advisor;Celgene: Other: Advisor;BMS: Other: Advisor;Amgen: Other: Advisor;Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy;PFIZER: Consultancy;CELGENE/BMS: Consultancy;ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria;Servier: Consultancy, Honoraria;Incyte: Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Bristol-Myers Squibb: Honoraria, Research Funding;PFIZER: Consultancy, Honoraria;JAZZ Pharma: Honoraria, Research Funding;SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding;Incyte: Honoraria, Research Funding;Jazz Pharmaceuticals: Honoraria, Research Funding;Novartis: Research Funding;Pfizer: Honoraria, Research Funding;Servier: Research Funding;Abbvie: Honoraria;BMS-Celgene: Honoraria;Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia

13.
Blood ; 138:1757, 2021.
Artigo em Inglês | EMBASE | ID: covidwho-1582174

RESUMO

Background: The two FDA approved mRNA-based SARS-CoV2 vaccines have shown >90% efficacy at preventing COVID and eliciting protective immunity in nearly all healthy individuals. However, the extent of vaccine induced antibody and T cell immunity in immunocompromised patients is not well known. Our study objective is to determine if patients with hematologic malignancies treated with B-cell targeting chimeric antigen receptor (CAR) T cell therapies can mount antibody and T cell immune responses to SARS-CoV2 vaccines. A prospective single-center study to evaluate the SARS-CoV2 immune responses in immunocompromised individuals (COVAX Study) was initiated at University of Pennsylvania following the IRB guidelines. The study enrolled 8 healthy adults,12 patients are in remission after treatment (average of 40.6 months) with CART cells targeting either CD19 or CD19+CD22 and received both doses of SARS-CoV2 vaccine. Methods and Results: Serology to SARS-CoV2 spike-receptor binding domain (RBD) IgG, RBD-IgA, RBD-IgM and spike-specific T cell responses were measured prior to vaccination and serially up to 28 days after booster vaccination. RBD-IgG and RBD-IgA were detected in 8/8 and 7/8 healthy subjects compared to 5/12 and 2/12 CART patients, respectively (Figure A). In the CART cohort, several patients who demonstrated an induction of RBD-IgG (57.2/uL +/- 20.2) compared to those who were RBD-IgG-negative (9/uL +/- 10.1, ANOVA with multiple comparisons test p=0.017) have higher level of circulating B cells. No association was found with time since CART infusion, age, disease type, or vaccine manufacturer. All 8 healthy subjects demonstrated induction of SARS-Cov2 spike-specific CD4 + T cell immunity compared to 7 out of 11 CART patients (Figure B). RBD-IgG responses were not correlated with CD4 + T cell activation (Pearson correlation, R=0.21, p=0.53). Indeed, 3 CART patients demonstrated robust CD4 + T cell activation despite absence of antibody induction. Overall, 8/12 CART patients demonstrated induction of either or both humoral and T cell immune responses. Conclusions: We show that immune responses to SARS-CoV2 mRNA vaccines are induced in majority of patients who have been treated with CART therapies targeting B-cell lineage antigens. Induction of vaccine-specific antibody was strongly associated with the level of circulating B cells. However, in CART cohort patients despite severe humoral immune deficiency, strong CD4 + T cell responses were observed suggestive of a sufficient protective immunity. [Formula presented] Disclosures: Frey: Novartis: Research Funding;Sana Biotechnology: Consultancy;Kite Pharma: Consultancy;Syndax Pharmaceuticals: Consultancy. Garfall: Amgen: Honoraria;CRISPR Therapeutics: Research Funding;GlaxoSmithKline: Honoraria;Janssen: Honoraria, Research Funding;Novartis: Research Funding;Tmunity: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria;Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months;ASH: Membership on an entity's Board of Directors or advisory committees;DeCart: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees;National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;Tmunity: Patents & Royalties;Wiley and Sons Publishing: Honoraria. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy;Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company;Novartis: Patents & Royalties.

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