High incidence of persistent COVID-19 among patients with lymphoma treated with B-cell depleting immunotherapy

Introduction Treatment of B-lineage lymphoma with B-cell depleting immunotherapy causes B-cell aplasia and impairs immune response. Case studies have reported patients treated with anti-CD20 therapy who suffered from persistent Covid-19. We aimed to assess the incidence, risk factors and long-term outcomes of persistent Covid-19 in patients with lymphoma. Patients and methods This retrospective multicentric study was conducted in 16 French hospitals. All adult patients with lymphoma who were admitted for Covid-19 in March and April 2020 were included. Persistent Covid-19 was defined as persisting severe Covid-19 symptoms requiring in-hospital stay for >30 days. Patients who re-experienced severe Covid-19 symptoms after initial improvement, requiring repeated hospitalizations for a total in-hospital length of stay >30 days were added to the persistent Covid-19 cases. Results One hundred eleven patients were included. Thirty days after admission for Covid-19, 24 patients had died, 55 had been definitively discharged from hospital, 31 were still hospitalized and 1 was later rehospitalized for Covid-19 recurrence. The incidence of persistent Covid-19 was 32/111 (29%). Patients with persistent Covid-19 had a median age of 64 years (range, 43-87) and 63% were male. Twenty-two patients (69%) had at least one significant comorbidity. None of the patients with T-cell (n=8) lymphoma or classical Hodgkin's disease (n=8) experienced persistent Covid-19. In the 32 patients with persistent Covid-19, the median time between first admission and final discharge was 58 days (range, 31-235) and the median duration of Covid-19 symptoms was 83 days (range, 32-237). Eight patients received corticosteroids and 9 convalescent plasma: all patients recovered from their symptoms, except one. Overall, 9 patients with persistent Covid-19 died (27%). After a median follow-up of 191 days (range, 3-260), the 6-month overall survival was 69% (95% CI 60-78%) for the whole cohort. In multivariate analysis, administration of anti-CD20 monoclonal antibody within 12 months before admission to hospital for Covid-19 was both associated with decreased overall survival (HR 2.13, 95% CI 1.03-4.44, p = 0.043) and prolonged in-hospital stay (HR 1.97, 95% CI 1.24-3.13, p = 0.004). The two other significant factors associated with decreased overall survival and prolonged in-hospital stay: age ≥ 70 years and refractory or relapsed lymphoma. Conclusion Patients with B-cell non-Hodgkin lymphoma hospitalized for Covid-19 have a high incidence of prolonged evolution of SARS-CoV-2 infection. Administration of anti-CD20 therapy within the last 12 months is one of the main risk factors for longer in-hospital stay and death of Covid-19. The risk of persistent Covid-19 was also higher in patients older than 70 years or with refractory or relapsed disease. These findings may contribute to guide the management of lymphoma patients during the Covid-19 pandemic.

Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak.

BACKGROUND: The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear. OBJECTIVES: To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus. METHODS: This observational study was conducted during 9-16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included. RESULTS: Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic-natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL. CONCLUSIONS: Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.

Étude prospective des événements thromboemboliques veineux chez les patients hospitalisés pour COVID-19 : anomalies associées de l’hémostase et suivi clinicobiologique à 6 mois

Introduction La COVID-19 est associée à un risque élevé d’événement thromboembolique veineux (ETEV), thrombose veineuse profonde (TVP) et/ou embolie pulmonaire (EP) en particulier chez les patients hospitalisés. Objectifs Caractériser le déséquilibre de la balance hémostatique chez ces patients et décrire la prise en charge et l’évolution à 6 mois des patients avec ETEV. Méthodes Étude prospective incluant des patients consécutifs hospitalisés en réanimation ou en médecine pour COVID-19, avec : – un écho-Doppler veineux systématique à l’admission en réanimation puis 7jours plus tard en cas de négativité et en cas de symptômes de TVP en service de médecine ;– un angioscanner thoracique réalisé en cas de suspicion d’EP ;– un bilan d’hémostase réalisé à l’admission ;– le suivi des patients ayant présenté un ETEV à 1, 3 et 6 mois afin de colliger les événements thrombotiques et hémorragiques. Résultats Du 17.03 au 11.04.2020, 133 patients d’âge médian 65 ans (72 % hommes) ont été hospitalisés pour COVID-19. Trente-huit patients ont présenté un ETEV (63 % TVP, 24 % EP, 13 % TVP+EP) dont 9 sont décédés pendant l’hospitalisation, 2 ont été transférés et 26 suivis. Nos résultats montrent : – un taux de D-dimères>3300ng/mL prédictif d’un ETEV avec une VPP 66 % (IC95 % : 51–79) et VPN 80 % (IC95 % : 65–90) en réanimation ;– une discordance significative entre les activités anticoagulante/chromogénique de la protéine C (p=.002 chez les patients ETEV+) évocatrice d’une résistance acquise à la protéine C activée ;– une association entre les taux de facteur Willebrand et d’ADAMTS13 et les ETEV (p=.05 et p=.005 respectivement) d’une part et entre les taux d’ADAMTS13/D-dimères et la mortalité d’autre part ;– des anticorps antiphospholipides présents chez 88 % des patients en réanimation, non associés à la survenue d’ETEV. Les 26 patients suivis avec ETEV ont été traités par apixaban (22), rivaroxaban (2) ou tinzaparine (2) durant 3 à 6 mois. Un infarctus du myocarde et 2 saignements mineurs ont été recensés. Aucune récidive d’ETEV n’a été observée. Conclusions La fréquence élevée d’ETEV chez les patients hospitalisés pour COVID-19 est associée à un profil biologique de thrombo-inflammation, avec un déséquilibre marqué entre facteurs prothrombotiques/inhibiteurs naturels de la coagulation et de l’axe VWF/ADAMTS13. Le traitement par anticoagulant oral direct est une option thérapeutique possible pour le traitement d’un ETEV lié à une hospitalisation pour COVID-19.

Pathophysiology and abnormalities of hemostasis in intensive care patients with Covid-19

Coronavirus disease 2019 (Covid-19), a severe acute respiratory syndrome caused by coronavirus 2 (Sars-CoV-2), has now spread to all continents. About 5-10 % of Covid-19 patients require intensive care unit admission and mechanical ventilation. Critically ill Covid-19 patients are prone to develop hypoxia, excessive inflammation and frequent thrombotic manifestations affecting both the macrocirculation and the microcirculation.