Background: Thrombosis is a characteristic complication in coronavirus disease 2019 (COVID-19). Since coagulopathy has been observed over the entire clinical course, thrombosis might be a clue to understanding the specific pathology in COVID-19. Currently, there is limited epidemiological data of COVID-19-associated thrombosis in the Japanese population and none regarding variant strains of SARS-CoV-2. Here, we elucidate the risk factors and the pattern of thrombosis in COVID-19 patients.Methods: The patients consecutively admitted to Tokyo Medical and Dental University Hospital with COVID-19 were retrospectively analyzed. SARS-CoV-2 variants of concern/interest (VOC/VOI) carrying the spike protein mutants E484K, N501Y, or L452R were identified by PCR-based analysis. All thrombotic events were diagnosed by clinical symptoms, ultrasonography, and/or radiological tests.Results: Among the 516 patients, 32 patients experienced 42 thromboembolic events. Advanced age, severe respiratory conditions, and several abnormal laboratory markers were associated with the development of thrombosis. While thrombotic events occurred in 13% of the patients with a severe respiratory condition, those events still occurred in 2.5% of the patients who did not require oxygen therapy. Elevated D-dimer and ferritin levels on admission were independent risk factors of thrombosis (adjusted odds ratio 9.39 and 3.11, 95% confidence interval 2.08–42.3, and 1.06–9.17, respectively). Of the thrombotic events, 22 were venous, whereas 20 were arterial. While patients with thrombosis received anticoagulation and antiinflammatory therapies with a higher proportion, the mortality rate, organ dysfunctions, and bleeding complications in these patients were higher than those without thrombosis. The incidence of thrombosis in COVID-19 became less frequent over time, such as during the replacement of the earlier strains of SARS-CoV-2 by VOC/VOI and during increased use of anticoagulatory therapeutics.Conclusion: This study elucidated that elevated D-dimer and ferritin levels are useful biomarkers of thrombosis in COVID-19 patients. The comparable incidence of arterial thrombosis with venous thrombosis and the development of thrombosis in less severe patients required further considerations for the management of Japanese patients with COVID-19. Further studies would be required to identify high-risk populations and establish appropriate interventions for thrombotic complications in COVID-19.

Infection of the lungs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin I converting enzyme 2 (ACE2) receptor induces a type of systemic inflammation known as a cytokine storm. However, the precise mechanisms involved in severe coronavirus disease 2019 (COVID-19) pneumonia are unknown. Here, we show that interleukin-10 (IL-10) changed normal alveolar macrophages into ACE2-expressing M2c-type macrophages that functioned as spreading vectors for SARS-CoV-2 infection. The depletion of alveolar macrophages and blockade of IL-10 attenuated SARS-CoV-2 pathogenicity. Furthermore, genome-wide association and quantitative trait locus analyses identified novel mRNA transcripts in human patients, COVID-19 infectivity enhancing dual receptor (CiDRE), which has unique synergistic effects within the IL-10-ACE2 system in M2c-type macrophages. Our results demonstrate that alveolar macrophages stimulated by IL-10 are key players in severe COVID-19. Collectively, CiDRE expression levels are potential risk factors that predict COVID-19 severity, and CiDRE inhibitors might be useful as COVID-19 therapies.

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Obesity is one of the most significant risk factors for the deterioration and mortality associated with COVID-19 [1]. A certain proportion of COVID-19 patients experience marked elevations of inflammatory mediators, termed “cytokine storm”, resulting in the deterioration of the respiratory condition [2,3]. In the present study, we elucidate that the high visceral adipose tissue (VAT) burden was more closely related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients than other obesity-associated markers, including body mass index (BMI). To explore a novel stratification of COVID-19 patients, we infected mouse-adapted SARS-CoV-2 in several obese mice, revealing that VAT-dominant ob/ob mice and diet-induced obesity obese mice died after infection with low-titer mouse-adapted SARS-CoV-2 virus due to the subsequent cytokine storm, whereas none of the subcutaneous adipose tissue (SAT) dominant db/db mice or control lean wild-type mice died. SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased production of inflammatory cytokine represented by IL-6. As well as the anti-IL-6 treatment, the prevention of obesity by leptin administration improved the survival of SARS-CoV-2 infected ob/ob mice by reducing the viral protein burden and excessive immune responses.

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BackgroundThrombosis is a unique complication in coronavirus disease 2019 (COVID-19). We have reported that elevated ferritin and D-dimer on admission were the risk factors of thromboses by analyzing the patients sequentially admitted to our hospital due to COVID-19 (1). However, we have not analyzed thrombotic complications in the view of the antiphospholipid antibodies (aPLs), which are frequently detected in the COVID-19 patients.ObjectivesTo elucidate the thrombogenic effects of aPLs in COVID-19, we analyzed the development of thrombosis in three lupus models after SARS-CoV-2 infection. Additionally, we evaluated the association of thrombotic events and the serum profile of aPLs in Japanese patients with COVID-19.MethodsThree animal models of lupus (MRL-lpr/lpr, NZBxNZW F1 and NZW×BXSB F1) were evaluated in this study. NZW×BXSB F1 was also considered as a model of antiphospholipid syndrome (APS) since aPLs were detected with a high titer (2). Experimental SARS-CoV-2 infection was induced using mouse-passaged virus strain (3). The incidence of thromboses in the lungs and kidneys were identified by evaluating H&E staining and PTAH staining of paraffin-embedded sections. We have experienced 44 thrombotic events in 34 out of 594 patients admitted to our institute. As a non-thrombotic COVID-19, 68 patients were selected to make a 1 to 2 matched-pair based on the propensity score. In total 102 patients, seven types of aPLs (anti-cardiolipin (CL) IgG/IgM, anti-β2GP1 IgG/IgA/IgM, and anti-phosphatidyl serine/prothrombin complex (PS/PT) IgG/IgM) were measured using specific ELISA kits. The patients’ clinical characteristics and serological profile of aPLs were further evaluated.ResultsWe identified the development of thromboses in the lungs or kidneys in 6 out of 12 (50%) NZW×BXSB F1 mice after the SARS-CoV-2 infection, whereas no thrombosis was observed in non-infected mice. Further, there was no thrombosis in the other lupus models (0%) after the infection. These findings might suggest the pathogenic role of aPLs under the SARS-CoV-2 infection.Among our COVID-19 patients, 39 out of 102 (38%) were tested positive for one or more aPLs. The positive ratios of any aPLs were statistically indifferent between the patients with or without thrombosis; anti-CL IgG (8.8% vs 5.9%)/IgM (0% vs 5.9%), anti-β2GP1 IgG (21% vs 12%)/IgA (8.8% vs 15%)/IgM (0% vs 1.5%), and anti-PS/PT IgG (0% vs 2.9%)/IgM (12% vs 13%), respectively. In addition, their titers were relatively lower than those observed in APS patients. The patients’ characteristics and the prognosis of COVID-19 were comparable regardless of the detection of any aPLs. These findings suggested that COVID-19 associated aPLs were irrelevant to thrombotic complications.ConclusionThromboses were induced after the infection of SARS-CoV-2 only in the APS model. However, aPLs detected in COVID-19 patients have little impact on the development of thrombosis. SARS-CoV-2 infection might have a high risk of thrombosis, especially in APS patients, as shown in the case report (4). The discrepancy of its thrombogenic effects of aPLs might be explained by the low titer of the antibody or the diversity of antibody epitope. Further analyses are required to clarify the mechanisms of aPLs production and the development of thrombosis in COVID-19.References[1]Oba S, et al. Arterial and Venous Thrombosis Complicated in COVID-19: A Retrospective Single-Center Analysis in Japan. Front Cardiovasc Med. 2021 Nov 19;8:767074.[2]Hashimoto Y, et al. Anticardiolipin antibodies in NZW x BXSB F1 mice. A model of antiphospholipid syndrome. J Immunol. 1992 Aug 1;149(3):1063-8.[3]Iwata-Yoshikawa N, et al. A lethal mouse model for evaluating vaccine-associated enhanced respiratory disease during SARS-CoV-2 infection. Sci Adv. 2022 Jan 7;8(1):eabh3827.[4]Chidharla A, et al. A Case Report of COVID-Associated Catastrophic Antiphospholipid Syndrome Successfully Treated with Eculizumab. J Blood Med. 2021 Oct 30;12:929-933.Disclosure of InterestsSeiya Oba: None declared, Tadashi Hosoya Speakers bureau: Janssen Pharmaceutical K.K.Daiichi Sankyo Company, limitedAsahi Kasei CorporationOno pharmaceuticalsEisaiEli Lilly, Daisuke Kawata: None declared, Wenshi Lee: None declared, Mari Kamiya: None declared, Yoji Komiya: None declared, Hideyuki Iwai: None declared, Yuko Nukui: None declared, Shuji Tohda: None declared, Shinsuke Yasuda Speakers bureau: Abbvie,Asahi Kasei Pharma,Chugai Pharmaceutical,Eisai, Eli Lilly,GlaxoSmithKline,Mitsubishi Tanabe Pharma,Ono pharmaceutical,Pfizer., Consultant of: ImmunoForge, Grant/research support from: Abbvie,Asahi Kasei Pharma,Chugai Pharmaceutical,CSL Behring,Eisai,ImmunoForge,Mitsubishi Tanabe Pharma,Ono pharmaceutical

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