Abstract: Introduction: The incidence of immune thrombocytopenia (ITP) is high in the elderly. Observational studies demonstrated that age above 65 years impacts ITP presentation and management. However, data are lacking in very elderly patients (VEP) with ITP. The aim of this study was to describe the presentation and the management of primary ITP that occurs in VEP (≥80 year-old) in comparison with elderly patients (EP; ≥65-79 year-old). Methods: Data source was the CARMEN-France registry. The CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adult patients in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) newly diagnosed for ITP in routine visit or hospital stay and detailed information on patients' characteristics and management of ITP are prospectively recorded. This registry has been implemented in the French referral center for ITP (Créteil) since October 2015, taking the name of CARMEN-France. Inclusion criteria in the present study were: inclusion in the CARMEN-France registry between June 2013 and December 2018; age ≥65 years at ITP onset; primary ITP defined by international criteria (platelets count 〈 100 x 109/L and exclusion of other causes of thrombocytopenia) and with normal bone marrow examination. Patients were then categorized by age groups (VEP vs EP). We compared patients' characteristics, ITP presentation including bleeding by platelet counts, exposure to first and second-line treatments. We also assessed the factors associated to any and severe (hematuria, gastro-intestinal tract or intracranial) bleeding at ITP onset in the VEP group using logistic regression models. Results: Out of 541 patients included in the CARMEN-France registry, 184 fulfilled inclusion criteria: 87 in the VEP group and 97 in the EP group. Mean age was 85.7 years in the VEP group versus 71.8 in the EP group. Male:female sex-ratio was similar (63.2% vs. 60.8%). Patients in the VEP group had more frequently comorbidities of the Charlson's Index (67.4% versus 47.9%) and polypharmacy (≥4 drugs; 63.3% versus 45.4%); they were more frequently exposed to antiplatelet drugs (37.9% versus 23.7%) and to anticoagulant (18.4% versus 10.3%). Median platelet counts at ITP onset were similar (22.0 versus 18.0 x 109/L). The frequencies of any bleeding were similar (58.6% versus 54.6%) as well as mucosal bleeding (25.3% versus 26.8%), but severe bleeding was more frequent in the VEP group (10.3% versus 4.1%). The frequencies of any bleeding and mucosal bleeding were higher in case of platelet count 〈 20 x 109/L in both groups. Severe bleeding occurred with platelet count 〈 20 x 109/L in all EP cases (n=4) while they occurred at any platelet count in the VEP group. In the VEP group, 85.1% of the patients were treated for ITP, versus 80.4% in the EP group. Among treated patients, 36.5% in the VEP group had steroids alone and 60.3% steroids plus intravenous immunoglobulin (IVIg), in comparison with 50.0% and 48.7% in the EP group, respectively. Second-line treatment was prescribed in 39.1% of VEP versus 37.5% of EP: thrombopoietin receptor agonists (13.8% versus 13.4%), dapsone (8.1% versus 8.2%), rituximab (6.9% versus 6.2%), and danazol (6.9% versus 4.1%). In univariate analysis, the factors associated with any bleeding in the VEP group were: female sex (odds ratio - OR: 1.97; 95% confidence interval - CI: 0.79-4.93), polypharmacy (OR: 2.64; 95% CI: 1.08-6.48); infection within the six weeks before ITP onset (OR: 2.60; 95% CI: 0.66-10.4) and platelet count 〈 20 x 109/L (OR: 10.0; 95% CI: 3.49-28.63). In univariate analysis, the main factors associated with severe bleeding were exposure to anticoagulant (OR: 7.61; 95% CI: 1.77-32.83), polypharmacy (OR: 5.28; 95% CI: 0.63-44.30), a Charlson's Comorbidity Index score ≥1 (OR: 4.32; 95% CI: 0.51-36.38); the OR for a platelet count 〈 20 x 109/L was 1.54 (95% CI: 0.38-6.16). Conclusion: VEP had more frequently severe bleeding at ITP onset. They were more frequently exposed to IVIg but did not require more frequently a second-line treatment. The pattern of second-line treatment was similar between VEP and EP. Platelet count 〈 20 x 109/L was a major risk factor for any bleeding in VEP. In contrast, exposure to anticoagulant, and not platelet count 〈 20 x 109/L, was highly associated with severe bleeding in VEP. Introduction: The incidence of immune thrombocytopenia (ITP) is high in the elderly. Observational studies demonstrated that age above 65 years impacts ITP presentation and management. However, data are lacking in very elderly patients (VEP) with ITP. The aim of this study was to describe the presentation and the management of primary ITP that occurs in VEP (≥80 year-old) in comparison with elderly patients (EP; ≥65-79 year-old). Methods: Data source was the CARMEN-France registry. The CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adult patients in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ³18 years) newly diagnosed for ITP in routine visit or hospital stay and detailed information on patients' characteristics and management of ITP are prospectively recorded. This registry has been implemented in the French referral center for ITP (Créteil) since October 2015, taking the name of CARMEN-France. Inclusion criteria in the present study were: inclusion in the CARMEN-France registry between June 2013 and December 2018; age ≥65 years at ITP onset; primary ITP defined by international criteria (platelets count 〈 100 x 109/L and exclusion of other causes of thrombocytopenia) and with normal bone marrow examination. Patients were then categorized by age groups (VEP vs EP). We compared patients' characteristics, ITP presentation including bleeding by platelet counts, exposure to first and second-line treatments. We also assessed the factors associated to any and severe (hematuria, gastro-intestinal tract or intracranial) bleeding at ITP onset in the VEP group using logistic regression models. Results: Out of 541 patients included in the CARMEN-France registry, 184 fulfilled inclusion criteria: 87 in the VEP group and 97 in the EP group. Mean age was 85.7 years in the VEP group versus 71.8 in the EP group. Male:female sex-ratio was similar (63.2% vs. 60.8%). Patients in the VEP group had more frequently comorbidities of the Charlson's Index (67.4% versus 47.9%) and polypharmacy (³4 drugs; 63.3% versus 45.4%); they were more frequently exposed to antiplatelet drugs (37.9% versus 23.7%) and to anticoagulant (18.4% versus 10.3%). Median platelet counts at ITP onset were similar (22.0 versus 18.0 x 109/L). The frequencies of any bleeding were similar (58.6% versus 54.6%) as well as mucosal bleeding (25.3% versus 26.8%), but severe bleeding was more frequent in the VEP group (10.3% versus 4.1%). The frequencies of any bleeding and mucosal bleeding were higher in case of platelet count 〈 20 x 109/L in both groups. Severe bleeding occurred with platelet count 〈 20 x 109/L in all EP cases (n=4) while they occurred at any platelet count in the VEP group. In the VEP group, 85.1% of the patients were treated for ITP, versus 80.4% in the EP group. Among treated patients, 36.5% in the VEP group had steroids alone and 60.3% steroids plus intravenous immunoglobulin (IVIg), in comparison with 50.0% and 48.7% in the EP group, respectively. Second-line treatment was prescribed in 39.1% of VEP versus 37.5% of EP: thrombopoietin receptor agonists (13.8% versus 13.4%), dapsone (8.1% versus 8.2%), rituximab (6.9% versus 6.2%), and danazol (6.9% versus 4.1%). In univariate analysis, the factors associated with any bleeding in the VEP group were: female sex (odds ratio - OR: 1.97; 95% confidence interval - CI: 0.79-4.93), polypharmacy (OR: 2.64; 95% CI: 1.08-6.48); infection within the six weeks before ITP onset (OR: 2.60; 95% CI: 0.66-10.4) and platelet count 〈 20 x 109/L (OR: 10.0; 95% CI: 3.49-28.63). In univariate analysis, the main factors associated with severe bleeding were exposure to anticoagulant (OR: 7.61; 95% CI: 1.77-32.83), polypharmacy (OR: 5.28; 95% CI: 0.63-44.30), a Charlson's Comorbidity Index score ³1 (OR: 4.32; 95% CI: 0.51-36.38); the OR for a platelet count 〈 20 x 109/L was 1.54 (95% CI: 0.38-6.16). Conclusion: VEP had more frequently severe bleeding at ITP onset. They were more frequently exposed to IVIg but did not require more frequently a second-line treatment. The pattern of second-line treatment was similar between VEP and EP. Platelet count 〈 20 x 109/L was a major risk factor for any bleeding in VEP. In contrast, exposure to anticoagulant, and not platelet count 〈 20 x 109/L, was highly associated with severe bleeding in VEP. Disclosures Comont: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Michel:Rigel: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Beyne-Rauzy:Cellgene: Research Funding; Novartis: Research Funding. Godeau:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Moulis:Amgen pharma: Research Funding, Speakers Bureau; Novartis pharma: Research Funding, Speakers Bureau; CSL Behring: Research Funding.

Abstract: Introduction: Eltrombopag has been marketed in Europe in 2010 for the treatment of chronic primary immune thrombocytopenia (ITP) lasting 12 months or longer from diagnosis, refractory to other treatments in splenectomized patients or patients who are contraindicated for splenectomy. Based on results of clinical trials, this marketing indication has been modified in 2019 for the treatment of patients aged 1 year and above with primary ITP lasting 6 months or longer from diagnosis and who are refractory to other treatments. However, data are lacking regarding the use, the efficacy and the safety of eltrombopag in the clinical practice in Europe. The ELEXTRA study was aimed at assessing these questions in France. Methods: Population source was the CARMEN-France registry. The CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) newly diagnosed for ITP in routine visit or hospital stay and detailed information on patients' characteristics and management of ITP are prospectively recorded. This registry has been implemented in other French centers since 2016, taking the name of CARMEN-France. ITP was defined by platelet count 〈 100 x 109/L and exclusion of other causes of thrombocytopenia. Study population consisted in all incident ITP adults included in the CARMEN-France registry from June 2013 to December 2018 and exposed to eltrombopag during the disease course. We described the time of exposure to eltrombopag from ITP diagnosis and patients' characteristics. Efficacy was assessed in patients who had a platelet count 〈 30 x 109/L at eltrombopag initiation. Overall response was defined by platelet count ≥30 x 109/L and complete response by platelet count ≥100 x 109/L. Adverse drug reactions (ADRs) that occurred during exposure to eltrombopag were collected and assessed using the World Health Organization causality assessment scale. All ADRs at least "possible" were described. Results: Out of 552 patients included in the registry, 81 (14.7%) had been exposed to eltrombopag for a median duration of 92 days (range: 1-1523). Mean age was 60.9 years (standard deviation: 20.9) and 45 (55.6%) were males; 36 (44.4%) had at least one comorbidity of the Charlson Comorbidity Index score; 45 (55.6%) had at least one cardiovascular risk factor (not including age and sex) and 4 (4.9%) a history of venous thrombosis. At ITP diagnosis, median platelet count was 7 x 109/L (range: 1-88 x 109/L) and 67 (82.7%) patients had bleeding. Median time from ITP onset to first exposure to eltrombopag was 2.7 months (range: 0.2-72.2): 43 (53.1%) patients were exposed before 3 months of ITP duration, 8 (9.9%) between 3 and 6 months, 18 (22.2%) between 6 and 12 months and 12 (14.8%) after 12 months. Exposures to ITP treatments before eltrombopag initiation were: corticosteroids in 75 (92.6%) patients, intravenous immunoglobulin (IVIg) in 61 (75.3%), dapsone in 15 (18.5%), rituximab in 14 (17.3%), romiplostim in 10 (12.3%), hydroxychloroquine in 9 (11.1%), danazol in 5 (6.2%), vinblastine in 3 (3.7%), azathioprine in 1 (1.2%), ciclosporin in 1 (1.2%) and splenectomy in none. Eltrombopag was used as second-line agent in 24 (28.6%) patients and third-line in 20 (24.7%). Among the 81 patients, 39 (48.1%) had a platelet count 〈 30 x 109/L at eltrombopag initiation; 34 (87.2%) achieved overall response and 31 (79.5%) complete response. These response rates were stable across disease duration phases ( 〈 3 months, 3-6 months and 〉 6 months), age groups ( 〈 60 vs. ≥60 years), Charlson Comorbidity Index score (0, 1-2 and ≥3). Among the 34 patients who achieved overall response, 29 (85.3%) had a concomitant exposure to ITP treatment at eltrombopag initiation (including steroids, n=12; IVIg during the past month, n=15; rituximab in the past 6 months, n=5). Overall, 17 ADRs were reported: the most frequent were: rash (n=3), thrombosis (n=3: 1 deep vein thrombosis, 1 pulmonary embolism and 1 ischemic stroke), thrombocytosis (n=2), hepatitis (n=2) and bronchitis (n=2). Conclusion: In the French real-life practice, eltrombopag is used early in ITP course. Efficacy is similar to efficacy in clinical trials, and is stable by subgroups of patients. The profile of ADRs identified in clinical trials is also confirmed. Introduction: Eltrombopag has been marketed in Europe in 2010 for the treatment of chronic primary immune thrombocytopenia (ITP) lasting 12 months or longer from diagnosis, refractory to other treatments in splenectomized patients or patients who are contraindicated for splenectomy. Based on results of clinical trials, this marketing indication has been modified in 2019 for the treatment of patients aged 1 year and above with primary ITP lasting 6 months or longer from diagnosis and who are refractory to other treatments. However, data are lacking regarding the use, the efficacy and the safety of eltrombopag in the clinical practice in Europe. The ELEXTRA study was aimed at assessing these questions in France. Methods: Population source was the CARMEN-France registry. The CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) newly diagnosed for ITP in routine visit or hospital stay and detailed information on patients' characteristics and management of ITP are prospectively recorded. This registry has been implemented in other French centers since 2016, taking the name of CARMEN-France. ITP was defined by platelet count 〈 100 x 109/L and exclusion of other causes of thrombocytopenia. Study population consisted in all incident ITP adults included in the CARMEN-France registry from June 2013 to December 2018 and exposed to eltrombopag during the disease course. We described the time of exposure to eltrombopag from ITP diagnosis and patients' characteristics. Efficacy was assessed in patients who had a platelet count 〈 30 x 109/L at eltrombopag initiation. Overall response was defined by platelet count ≥30 x 109/L and complete response by platelet count ≥100 x 109/L. Adverse drug reactions (ADRs) that occurred during exposure to eltrombopag were collected and assessed using the World Health Organization causality assessment scale. All ADRs at least "possible" were described. Results: Out of 552 patients included in the registry, 81 (14.7%) had been exposed to eltrombopag for a median duration of 92 days (range: 1-1523). Mean age was 60.9 years (standard deviation: 20.9) and 45 (55.6%) were males; 36 (44.4%) had at least one comorbidity of the Charlson Comorbidity Index score; 45 (55.6%) had at least one cardiovascular risk factor (not including age and sex) and 4 (4.9%) a history of venous thrombosis. At ITP diagnosis, median platelet count was 7 x 109/L (range: 1-88 x 109/L) and 67 (82.7%) patients had bleeding. Median time from ITP onset to first exposure to eltrombopag was 2.7 months (range: 0.2-72.2): 43 (53.1%) patients were exposed before 3 months of ITP duration, 8 (9.9%) between 3 and 6 months, 18 (22.2%) between 6 and 12 months and 12 (14.8%) after 12 months. Exposures to ITP treatments before eltrombopag initiation were: corticosteroids in 75 (92.6%) patients, intravenous immunoglobulin (IVIg) in 61 (75.3%), dapsone in 15 (18.5%), rituximab in 14 (17.3%), romiplostim in 10 (12.3%), hydroxychloroquine in 9 (11.1%), danazol in 5 (6.2%), vinblastine in 3 (3.7%), azathioprine in 1 (1.2%), ciclosporin in 1 (1.2%) and splenectomy in none. Eltrombopag was used as second-line agent in 24 (28.6%) patients and third-line in 20 (24.7%). Among the 81 patients, 39 (48.1%) had a platelet count 〈 30 x 109/L at eltrombopag initiation; 34 (87.2%) achieved overall response and 31 (79.5%) complete response. These response rates were stable across disease duration phases ( 〈 3 months, 3-6 months and 〉 6 months), age groups ( 〈 60 vs. ≥60 years), Charlson Comorbidity Index score (0, 1-2 and ≥3). Among the 34 patients who achieved overall response, 29 (85.3%) had a concomitant exposure to ITP treatment at eltrombopag initiation (including steroids, n=12; IVIg during the past month, n=15; rituximab in the past 6 months, n=5). Overall, 17 ADRs were reported: the most frequent were: rash (n=3), thrombosis (n=3: 1 deep vein thrombosis, 1 pulmonary embolism and 1 ischemic stroke), thrombocytosis (n=2), hepatitis (n=2) and bronchitis (n=2). Conclusion: In the French real-life practice, eltrombopag is used early in ITP course. Efficacy is similar to efficacy in clinical trials, and is stable by subgroups of patients. The profile of ADRs identified in clinical trials is also confirmed. Disclosures Moulis: Novartis pharma: Research Funding, Speakers Bureau; Amgen pharma: Research Funding, Speakers Bureau; CSL Behring: Research Funding. OffLabel Disclosure: Eltrombopag was used off-label in some patients in this real-life study

Abstract: Introduction:There are discrepancies across recommendations about the indication of bone marrow smear in adults diagnosed for immune thrombocytopenia (ITP). The 2011 American Society of Hematology guidelines do not recommend bone marrow smear in case of typical ITP. In contrast, the 2010 international consensus and the 2017 French guidelines recommend systematic bone marrow smear in adults aged 〉 60 years even in case of typical ITP to detect a blood cancer, particularly myelodysplastic syndrome. This recommendation is driven from expert consensus. Data are lacking about the positivity rate of this examination in older patients with typical ITP. The aim of this study was to assess the positivity rate of bone marrow smear at ITP diagnosis in 〉 60-year-old patients with no other clinical or biological sign of hematological malignancy. Methods:Data source was theCARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry. All adult patients with an incident diagnosis of ITP in the French Midi-Pyrénées region (South of France, 3 million inhabitants) are prospectively enrolled since June 2013 in the multicenter CARMEN registry. ITP is defined by international guidelines (platelet count 〈 100 x 109/L and exclusion of other causes of thrombocytopenia). Investigations performed at ITP diagnosis in a real-life basis, including bone marrow smear, are recorded with their results. Study population was selected among the patients included in the CARMEN registry from June 2013 to December 2018. Inclusion criteria were: age 〉 60 years; absence of clinical signs of hematological malignancy (lymphadenopathy, hepatomegaly, splenomegaly); isolated thrombocytopenia on blood count; bone marrow smear performed at ITP diagnosis. We described patients with abnormal bone marrow smear and implications for ITP management. Results:We identified 114patients (66 men and 48 women) satisfying all inclusion criteria. Mean age at ITP diagnosis was 76 years (standard deviation - SD: 9 years). Platelet count at diagnosis was 32.7 x 109/L (SD: 27.7 x 109/L) and 58 patients presented with bleeding: skin bleeding only (n=33), oral bleeding (n=17), epistaxis (n=10) and hematuria (n=3). Only one patient had an abnormal bone marrow smear corresponding to a characterized hematological disease: a myelodysplastic syndrome. It was a 62-year-old man without medical history who presented in 2014 with extensive skin bleeding, and isolated thrombocytopenia (6 x 109/L). Other blood count parameters were: hemoglobin: 15.2 g/dL; MCV: 83 fL; leukocytes: 5.3 x 109/L; polynuclear neutrophils: 3.5 x 109/L; lymphocytes: 1.0 x 109/L; monocytes: 0,3 x 109/L . Bone marrow smear revealed normal cellularity. The megakaryocytic lineage was normally represented with significant number of megakaryocytes with multiple separated nuclei. Significant dysgranulopoiesis was also observed with pseudo-Pelger-Huët anomaly and cytoplasmic hypogranulation. Some erythroblasts with defective haemoglobination or cytoplasmic vacuolation were present. This aspect was compatible with the diagnosis of myelodysplastic syndrome with multilineage dysplasia (MDS-MLD). Karyotype was normal. The patient was initially treated for ITP with steroids and intravenous immunoglobulins (with partial response), then with danazol (complete response), eltrombopag (after loss of response to danazol and ocular bleeding, resulting in complete response) and more recently romiplostim (after loss of response to eltrombopag, resulting in complete response). He was treated in 2019 by rituximab to spare exposure to thrombopoietin receptor agonists, without efficacy. Before Rituximab, another bone marrow smear was performed (4 years after the first one) with the same cytologic and cytogenetic features (MLD-MDS with normal caryotype). Conclusions:Diagnosis of hematological malignancy is very uncommon in 〉 60 year-old patients who present with typical ITP. Myelodysplastic syndrome was found in 1 (0.8%) patient in this series, and did not impact the management or the evolution of the patient with a five-year follow-up. Overall, this study sustains guidelines that does not recommend systematic testing for bone marrow examination in 〉 60 year-old patients with typical ITP. Disclosures Comont: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beyne-Rauzy:Novartis: Research Funding; Cellgene: Research Funding. Moulis:CSL Behring: Research Funding; Amgen pharma: Research Funding, Speakers Bureau; Novartis pharma: Research Funding, Speakers Bureau.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 〈 70 y and in 〉 4% of those 〉 70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals 〈 70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals 〈 40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

Abstract: Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients 〉 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% 〉 80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 〈 70 years, 2.3% between 70 and 80 years, and 6.3% 〉 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.

Abstract: Patients with venous thromboembolism (VTE) require immediate treatment with anticoagulants such as acenocoumarol. This multicentre randomised clinical trial evaluated the effectiveness of a dosing pharmacogenetic algorithm versus a standard-of-care dose adjustment at the beginning of acenocoumarol treatment. We included 144 patients with VTE. On the day of recruitment, a blood sample was obtained for genotyping (CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2, APOE). Dose adjustment was performed on day 3 or 4 after the start of treatment according to the assigned group and the follow-up was at 12 weeks. The principal variable was the percentage of patients with an international normalised ratio (INR) within the therapeutic range on day 7. Thirty-four (47.2%) patients had an INR within the therapeutic range at day 7 after the start of treatment in the genotype-guided group compared with 14 (21.9%) in the control group (p = 0.0023). There were no significant differences in the time to achieve a stable INR, the number of INRs within the range in the first 6 weeks and at the end of study. Our results suggest the use of a pharmacogenetic algorithm for patients with VTE could be useful in achieving target INR control in the first days of treatment.

Abstract: Background: Adherence to a Mediterranean diet seems to be inversely associated with C-reactive protein (CRP) concentration. A 14-point Mediterranean Diet Adherence Screener (MEDAS) has been developed to assess dietary compliance. Objective: The aim of this study was to assess whether each of the MEDAS questions as well as their final score were associated with the levels of CRP in general Spanish population. Methods: Cross-sectional analysis of 1411 subjects (mean age 61 years, 43.0% males) randomly selected from the general population. CRP levels were determined by a commercial ELISA kit. Adherence to the Mediterranean diet was measured by the 14-point MEDAS. Results: There was an inverse correlation between adherence to the Mediterranean diet and the CRP concentration, even after adjusting by age, gender, hypertension, metabolic syndrome, body mass index, statin treatment and hypertension treatment (p = 0.041). Subjects who consume ≥2 servings of vegetables per day (p = 0.003), ≥3 pieces of fruit per day (p = 0.003), ≥1 serving of butter, margarine, or cream per day (p = 0.041) or ≥3 servings of fish/seafood per week (p = 0.058) had significantly lower levels of CRP. Conclusions: Adherence to a Mediterranean-type diet measured by a simple questionnaire is associated with lower CRP concentration. However, this association seems to be particularly related to a higher consumption of vegetables, fruits, dairy products, and fish.