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Histopathology is a powerful tool to understand the COVID-19 pathogenesis and come up with rational treatment strategies in real time. We present lung histopathological features of biopsies of fatal COVID-19 cases together with anakinra (Kineret ®) Il-1α and IL-1β receptor blocking treatment of the disease. Lung biopsy of 8 cases were scored for alveolar, vascular and inflammatory features on a 4-point scale (none-severe) by 3 lung pathologists; consensus score was used. Anakinra was given in off-label setting to 3 COVID-19 cases receiving ICU treatment including mechanical ventilation. Lung pathology includes 1. Extensive epithelial damage with regenerative metaplasia with co-localization of neutrophils and macrophages, together with organizing pneumonia and scarring, 2. Alveolar oedema, haemorrhage, diffuse alveolar damage and a dominant pattern of acute and chronic arterial thrombosis in all cases as manifestations of vascular leakage and its sequelae, and 3. plasma cell or T cell endothelitis of the pulmonary arteries as a characteristic feature to COVID-19 in six out of eight cases, indicating a role for plasma cells or T cells in its vascular pathology. The temporal heterogeneity of both the epithelial damage and repair and the thrombosis and thrombotic arteriopathy within in all cases indicated ongoing disease. The anakinra-treated cases showed a rapid response with extubation in 2-4 days, drop in fever and inflammatory parameters. We propose that these distinctive features of COVID-19 are initiated through the IL-1 innate immunity pathway and operated by plasma cells. We further provide proof of concept that the IL-1 receptor antagonist anakinra was beneficial in the late and severe stage of COVID-19 disease. Funding: MGN was supported by an ERC Advanced Grant and a Spinoza Grant of the Netherlands Organization for Scientific Research (NWO). Declaration of Interest: None to declare. Ethical Approval: Only fully anonymized archival tissue was used in this study, for which ethical approval and informed consent is not required by law or by the institutional review board of Radboudumc.

Contains fulltext : 108353.pdf (Publisher’s version ) (Closed access) BACKGROUND: /st> Transpulmonary ultrasound dilution (TPUD) is a promising method for cardiac output (CO) measurement in severely ill neonates. The incidence of lung injury in this population is high, which might influence CO measurement using TPUD because of altered lung perfusion. We evaluated the influence of lung injury on the accuracy and precision of CO measurement using TPUD in an animal model. METHODS: /st> In nine neonatal lambs, central venous and arterial catheters were inserted and connected to the TPUD monitor. Repeated lavages with warmed isotonic saline were performed to gradually induce lung injury. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe around the main pulmonary artery (COufp). An increase in oxygenation index was used as an indicator of induced lung injury during the experiment. Post-mortem lung injury was confirmed by histopathological examination. RESULTS: /st> Fifty-five sessions of three paired CO measurements were analysed. The mean COufp was 1.53 litre min(-1) (range 0.66-2.35 litre min(-1)), and the mean COtpud was 1.65 litre min(-1) (range 0.78-2.91 litre min(-1)). The mean bias (standard deviation) between the two methods was 0.13 (0.15) litre min(-1) with limits of agreement of +/-0.29 litre min(-1). The overall percentage error was 19.1%. The accuracy and precision did not change significantly during progressive lung injury. Histopathological severity scores were consistent with heterogeneous lung injury. The capability to track changes in CO using TPUD was moderate to good. CONCLUSIONS: /st> The accuracy and precision of CO measurement using TPUD is not influenced in the presence of heterogeneous lung injury in an animal model.