For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
3
views
13
references
 Top references
cited by
74
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
1 collections
    0
    shares
      746
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      Inflammasome formation in the lungs of patients with fatal COVID-19

      brief-report

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective

          The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS).

          Methods

          Samples from four patients with confirmed COVID-19 pneumonia who had been hospitalized at the Hospital of the University of Trieste (Italy) and died of ARDS and four lung samples from a historical repository from subjects who had died of cardiopulmonary arrest and had not been placed on mechanical ventilation and without evidence of pulmonary infection at postmortem examination were collected. Pathology samples had been fixed in formalin 10% at time of collection and subsequently embedded in paraffin. We conducted staining for ASC (Apoptosis-associated Speck-like protein containing a Caspase recruitment domain), NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), and cleaved caspase-1.

          Results

          Intense expression of the inflammasome was detected, mainly in leukocytes, within the lungs of all patients with fatal COVID-19 in the areas of lung injury. The number of ASC inflammasome specks per high power fields was significantly higher in the lungs of patients with fatal COVID-19 as compared with the lungs of control subjects (52 ± 22 vs 6 ± 3, P = 0.0064).

          Conclusions

          These findings identify the presence of NLRP3 inflammasome aggregates in the lungs of fatal COVID-19 pneumonia thus providing the potential molecular link between viral infection and cytokine release syndrome.

          Electronic supplementary material

          The online version of this article (10.1007/s00011-020-01413-2) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references13

          • Record: found
          • Abstract: found
          • Article: not found

          Clinical Characteristics of Coronavirus Disease 2019 in China

          Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)
          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
          Article 0 comments Cited 13813 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

            Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
            Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
            Article 0 comments Cited 9944 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

              Giulio Cavalli, Giacomo De Luca, Corrado Campochiaro … (2020)
              Summary Background Mortality of patients with coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammation is high. In areas of pandemic outbreak, the number of patients can exceed maximum capacity of intensive care units (ICUs), and, thus, these individuals often receive non-invasive ventilation outside of the ICU. Effective treatments for this population are needed urgently. Anakinra is a recombinant interleukin-1 receptor antagonist that might be beneficial in this patient population. Methods We conducted a retrospective cohort study at the San Raffaele Hospital in Milan, Italy. We included consecutive patients (aged ≥18 years) with COVID-19, moderate-to-severe ARDS, and hyperinflammation (defined as serum C-reactive protein ≥100 mg/L, ferritin ≥900 ng/mL, or both) who were managed with non-invasive ventilation outside of the ICU and who received standard treatment of 200 mg hydroxychloroquine twice a day orally and 400 mg lopinavir with 100 mg ritonavir twice a day orally. We compared survival, mechanical ventilation-free survival, changes in C-reactive protein, respiratory function, and clinical status in a cohort of patients who received additional treatment with anakinra (either 5 mg/kg twice a day intravenously [high dose] or 100 mg twice a day subcutaneously [low dose]) with a retrospective cohort of patients who did not receive anakinra (referred to as the standard treatment group). All outcomes were assessed at 21 days. This study is part of the COVID-19 Biobank study, which is registered with ClinicalTrials.gov, NCT04318366. Findings Between March 17 and March 27, 2020, 29 patients received high-dose intravenous anakinra, non-invasive ventilation, and standard treatment. Between March 10 and March 17, 2020, 16 patients received non-invasive ventilation and standard treatment only and comprised the comparison group for this study. A further seven patients received low-dose subcutaneous anakinra in addition to non-invasive ventilation and standard treatment; however, anakinra treatment was interrupted after 7 days because of a paucity of effects on serum C-reactive protein and clinical status. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein and progressive improvements in respiratory function in 21 (72%) of 29 patients; five (17%) patients were on mechanical ventilation and three (10%) died. In the standard treatment group, eight (50%) of 16 patients showed respiratory improvement at 21 days; one (6%) patient was on mechanical ventilation and seven (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (p=0·009). Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard treatment group (p=0·15). Bacteraemia occurred in four (14%) of 29 patients receiving high-dose anakinra and two (13%) of 16 patients receiving standard treatment. Discontinuation of anakinra was not followed by inflammatory relapses. Interpretation In this retrospective cohort study of patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the ICU, treatment with high-dose anakinra was safe and associated with clinical improvement in 72% of patients. Confirmation of efficacy will require controlled trials. Funding None.
              Article 0 comments Cited 538 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Stefano Toldo: stefano.toldo@vcuhealth.org
                Journal
                Journal ID (nlm-ta): Inflamm Res
                Journal ID (iso-abbrev): Inflamm Res
                Title: Inflammation Research
                Publisher: Springer International Publishing (Cham )
                ISSN (Print): 1023-3830
                ISSN (Electronic): 1420-908X
                Publication date (Electronic): 20 October 2020
                Pages: 1-4
                Affiliations
                [1 ]GRID grid.224260.0, ISNI 0000 0004 0458 8737, VCU Pauley Heart Center, , Virginia Commonwealth University, ; 1220 E Broad St, Richmond, VA 23298 USA
                [2 ]GRID grid.5133.4, ISNI 0000 0001 1941 4308, Istituto di Anatomia Patologica, , Università di Trieste, ; Trieste, Italy
                [3 ]GRID grid.5133.4, ISNI 0000 0001 1941 4308, Istitituto di Cardiologia, , Università di Trieste, ; Trieste, Italy
                [4 ]GRID grid.224260.0, ISNI 0000 0004 0458 8737, Anatomic Pathology, , Virginia Commonwealth University, ; Richmond, VA USA
                [5 ]GRID grid.224260.0, ISNI 0000 0004 0458 8737, Division of Pulmonary and Critical Care Medicine, , Virginia Commonwealth University, ; Richmond, VA USA
                Author notes

                Responsible Editor: John Di Battista.

                Author information
                http://orcid.org/0000-0002-1930-785X
                Article
                Publisher ID: 1413
                DOI: 10.1007/s00011-020-01413-2
                PMC ID: 7572246
                PubMed ID: 33079210
                SO-VID: 6accf8ad-e97d-412c-bf63-fb878bfad142
                Copyright © © Springer Nature Switzerland AG 2020
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 13 August 2020
                Date revision received : 1 October 2020
                Date accepted : 12 October 2020
                Funding
                Funded by: United States of America National Institute of Health NHLBI
                Award ID: R01HL150115
                Award Recipient :
                Categories
                Subject: Short Communication

                ScienceOpen disciplines: Immunology
                Keywords: sars-cov-2,covid-19,nlrp3 inflammasome,il-1,cytokine release syndrome
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: sars-cov-2, covid-19, nlrp3 inflammasome, il-1, cytokine release syndrome

                Comments

                Comment on this article

                scite_

                Similar content746

                See all similar

                Cited by74

                See all cited by

                Most referenced authors1,131

                See all reference authors