key: cord-1023155-ho8cj6j1
authors: Nakamura, Hideta; Kinjo, Takeshi; Arakaki, Wakako; Miyagi, Kazuya; Tateyama, Masao; Fujita, Jiro
title: Serum levels of receptor-interacting protein kinase-3 in patients with COVID-19
date: 2020-08-04
journal: Crit Care
DOI: 10.1186/s13054-020-03209-6
sha: 6d80a5ebe7379ff6e84f6713d6f74d023bda4e38
doc_id: 1023155
cord_uid: ho8cj6j1

nan

plasma aliquots were frozen within 12 h. RIPK-3 levels were measured using an enzyme-linked immunosorbent assay (Wuhan Huamei Biotech, Wuhan, China).

This observational study enrolled 16 COVID-19 patients (11 males, 68.8%) ( Table 1 ). Confirmation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was by real-time reverse transcription polymerase chain reaction of nasopharyngeal swabs. Patients' median age was 55 years (interquartile range [IQR] 40.5-71.5 years), and the median duration from symptom onset to hospitalization was 7 days (3.25-9 days). On admission, 14 patients (87.5%) were confirmed to have COVID-19 pneumonia by chest computed tomography, 10 patients were diagnosed with severe COVID-19 and ARDS, and 6 patients were diagnosed as mild. While hospitalized, the antiviral drug favipiravir was administrated to 11 patients (68.8%) in the context of a clinical trial, whereas azithromycin (n = 11, 68.8%), nafamostat (n = 12, 75%), and tocilizumab (n = 7, 43.7%) were commenced as off-label use. The median levels of serum RIPK-3 were significantly higher in severe COVID-19 cases than in mild cases (483.5 pg/ mL, IQR 329.6-867.7 pg/mL vs. 139.9 pg/mL, IQR 95.37-286.8 pg/mL, p = 0.0075) (Fig. 1 ). Fifteen patients recovered and were discharged, whereas three patients in the severe group were intubated due to severe acute respiratory failure and one of these patients died.

This is the first study to analyze RIPK-3 in COVID-19 patients. The higher serum RIPK-3 levels in severe patients suggest that RIPK-3-mediated signaling, such as necroptosis, might be involved in the development of acute lung injury associated with COVID-19 pneumonia. Siempos et al. reported plasma RIPK-3 levels were significantly higher in ARDS patients compared to those of non-ARDS patients [6] . Shashaty et al. demonstrated that among patients with sepsis or trauma, the change in plasma RIPK-3 levels 48 h after admission was independently associated with ARDS [3] . Because RIPK-3 mediates not only necroptosis but also other inflammatory pathways [2] , the elevation of RIPK-3 does not directly indicate the execution of necroptosis. To confirm the role of RIPK-3 in COVID-19-ARDS patients, further studies are needed including a larger number of participants and histological evaluation of lung tissues, especially since RIPK-3-mediated necroptosis could be a potential therapeutic target for COVID-19-related ARDS. IQR interquartile range, PaO 2 /FiO 2 ratio ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen Fig. 1 Serum levels of receptor-interacting kinase 3 (RIPK-3) in 16 patients with COVID-19. Serum RIPK-3 levels were measured by the enzyme-linked immunosorbent assay in patients with mild (n = 6) or severe (n = 10) COVID-19. For each dataset, the horizontal bars represent the median and interquartile range. Statistics were analyzed using Prism (GraphPad Software, CA, USA); p < 0.05 was considered significant

Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis

Collateral damage: necroptosis in the development of lung injury

Plasma receptor interacting protein kinase-3 levels are associated with acute respiratory distress syndrome in sepsis and trauma: a cohort study

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention

RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury

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Collaborating author names: Mariko Otsuki, Yuri Higure, Naoya Nishiyama, Masashi Nakamatsu, and Shusaku Haranaga. Department of Infectious, Respiratory and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Authors' contributions HN designed the study and had full access to all data in the study. TK and WA contributed to the laboratory work. MT and JF supervised the study and contributed to the writing of the manuscript. All authors contributed to data acquisition, data analysis, or data interpretation and reviewed and approved the final version of the manuscript.

Not applicable.Availability of data and materials Full de-identified data of the analyses are available upon request sent to the corresponding author.Ethics approval and consent to participate This study was approved by the ethics committee of the University of the Ryukyus for Medical and Health Research Involving Human Subjects (approval number: 1616).

Written informed consent was obtained from all patients.

Received: 17 July 2020 Accepted: 28 July 2020