COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study

International audienc

Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study

International audienceMutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a "snapshot" of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment

Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study

International audienc

High Prevalence of BTK Mutations on Ibrutinib Therapy after 3 Years of Treatment in a Real-Life Cohort of CLL Patients: A Study from the French Innovative Leukemia Organization (FILO) Group

Abstract Background Long-term outcome of chronic lymphocytic leukemia (CLL) patients (pts) under ibrutinib therapy has been evaluated within clinical trials, and CLL progression seems to be strongly linked with the onset of BTK and PLCg2 mutations. These mutations have largely been studied in resistant pts. Limited data are available regarding the BTK and/or PLCγ2 mutations in pts on ibrutinib without evidence of disease progression. Ibrutinib was available in France during 2014 as an early access program (EAP) thus allowing the evaluation of prolonged use of Ibrutinib in a real-life setting. The objective of this study was to analyze the genetic profile of pts still on Ibrutinib after at least 3 years of treatment. We also explored minimal residual disease (MRD) and T-lymphocyte subsets. Results Data were collected from all pts who received ibrutinib via the EAP in 29 centers of the FILO group. Between February 2014 and April 2015, 204 pts began ibrutinib treatment. Only 63 (31%) remained on therapy 3 years later and blood samples were collected for 57 of them. For these 57 pts, median age at ibrutinib initiation was 67.7 years (46.9 to 84.1). Forty-five percent and 42.5% pts presented with 11q or 17p deletion respectively, and 17/18 pts tested harbored unmutated IGVH genes. Pts received a median number of 2 (0-5) previous therapies, consisting mainly of fludarabine-based regimens (73%), bendamustine + rituximab (48%), chlorambucil + anti-CD20 antibody (25%) or alemtuzumab (16%). The best response on ibrutinib therapy was clinical complete response, partial response and partial response with lymphocytosis in 31%, 56% and 13% of cases respectively. Median time between ibrutinib initiation and blood sample collection was 3.5 years (2.75 to 4.2). Median lymphocyte count was 2.62 G/L (0.37 to 121), and median CLL cell count was 0.52 G/L (0-117). No patient achieved MRD 1) was not different between pts harboring BTK mutations or not (p=0.2). Study of T lymphocyte subsets showed a highly variable CD4/CD8 T- cell ratio (median=1, range 0.41-3.42), but, interestingly, the median number of CD4 T-cells was 584/mm3 (141-2481), with 92% of pts presenting with CD4 T-cells >250/mm3. This result suggests that ibrutinib treatment may not affect CD4 T-cell counts. With a median follow-up of 3.5 months from sample collection, 12/57 pts (21%) discontinued ibrutinib because of CLL progression (N=8), Richter syndrome (N=1), adverse event (N=1), septic shock (N=1) and unknown reason (N=1). Twelve pts progressed within 6 months after sample collection. Among them, BTK mutations were present in 11/12 cases and PLCγ2 in 2 cases. Only one patient experienced progression without BTK or PLCγ2 mutations. BTK mutations were found in 6 pts without evidence of progression at the time of last follow-up and longitudinal analysis is ongoing. Variant allele frequencies of BTK mutations were highly variable between pts (range 0.2%-73%) and were not different between progressing and non-progressing pts (p=0.2). Conclusion and perspectives In this real-life setting, only one third of pts remained on ibrutinib after 3 years. Even after such a long treatment exposure, ibrutinib as a monotherapy did not appear to induce complete immunophenotypic response. Fifty-seven percent of pts with CLL cell count > 0.5 G/L had BTK C481 mutations, and BTK mutations were found in all but one pt who progressed. This study also highlighted the onset of BTK and PLCγ2 mutations in long-term responders on therapy, before any evidence of disease progression. Disclosures Quinquenel: Jansen Cilag: Honoraria, Research Funding; Abbvie: Honoraria. Fornecker:Takeda: Honoraria; Servier: Honoraria. Ysebaert:Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding. Guieze:abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria. Feugier:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Taverna:Sunesis Pharmaceuticals: Employment. Fox:Sunesis Pharmaceuticals: Employment; Amphivena Therapeutics: Employment. Cymbalista:AbbVie, Inc: Honoraria; Sunesis: Research Funding; Janssen: Honoraria; Gilead: Honoraria. Baran-Marszak:Sunesis: Research Funding

French law: what about a reasoned reimbursement of serum vitamin D assays?

International audienceThe number of serum 25-hydroxyvitamin D (25OHD) assays has increased tenfold in France in less than 10 years, sometimes for invalidated reasons. In 2013, the French National Authority for Health (Haute autorité de santé, or HAS) limited the indications for serum 25OHD measurements to rickets/osteomalacia, older adults with recurrent falls, monitoring of kidney transplant in adults, and surgical treatment of obesity in adults. Our aim here was to note that other indications for serum 25OHD measurements are supported by previous literature and by a number of national and international recommendations, in particular the following: any situation of bone fragility, any chronic renal failure <45 mL/min/1.73m(2), any situation of malabsorption, clinical signs consistent with vitamin D deficiency or vitamin D overload, and calcium phosphorus evaluation. We suggest that the measurement of serum 25OHD concentration should remain reimbursed as part of these extended indications

Ostéopathies fragilisantes, maladie rénale chronique, malabsorptions, anomalies biologiques du métabolisme phosphocalcique : les bonnes indications pour un remboursement raisonné du dosage de vitamine D [Weakening osteopathies, chronic kidney disease, malabsorption, biological anomalies of calium/phosphorus metabolism: appropriate indications for a reasoned reimbursment of serum vitamin D measurement]

National audienceEditoria