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Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study.
Schurink, Bernadette; Roos, Eva; Radonic, Teodora; Barbe, Ellis; Bouman, Catherine S C; de Boer, Hans H; de Bree, Godelieve J; Bulle, Esther B; Aronica, Eleonora M; Florquin, Sandrine; Fronczek, Judith; Heunks, Leo M A; de Jong, Menno D; Guo, Lihui; du Long, Romy; Lutter, Rene; Molenaar, Pam C G; Neefjes-Borst, E Andra; Niessen, Hans W M; van Noesel, Carel J M; Roelofs, Joris J T H; Snijder, Eric J; Soer, Eline C; Verheij, Joanne; Vlaar, Alexander P J; Vos, Wim; van der Wel, Nicole N; van der Wal, Allard C; van der Valk, Paul; Bugiani, Marianna.
  • Schurink B; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Roos E; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Radonic T; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Barbe E; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Bouman CSC; Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • de Boer HH; Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • de Bree GJ; Department of Forensic Medicine, Netherlands Forensic Institute, The Hague, Netherlands.
  • Bulle EB; Department of Internal Medicine, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Aronica EM; Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Florquin S; Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Fronczek J; Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Heunks LMA; Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • de Jong MD; Department of Forensic Medicine, Netherlands Forensic Institute, The Hague, Netherlands.
  • Guo L; Department of Intensive Care Medicine, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • du Long R; Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Lutter R; Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Molenaar PCG; Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Neefjes-Borst EA; Department of Pulmonary Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Niessen HWM; Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • van Noesel CJM; Department of Pulmonary Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Roelofs JJTH; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Snijder EJ; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Soer EC; Department of Cardiac Surgery, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Verheij J; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Vlaar APJ; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
  • Vos W; Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.
  • van der Wel NN; Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • van der Wal AC; Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • van der Valk P; Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Bugiani M; Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.
Lancet Microbe ; 1(7): e290-e299, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1087376
Semantic information from SemMedBD (by NLM)
1. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
2. Virus present PROCESS_OF Patients
Subject
Virus present
Predicate
PROCESS_OF
Object
Patients
3. 2019 novel coronavirus CAUSES Blood Coagulation Disorders
Subject
2019 novel coronavirus
Predicate
CAUSES
Object
Blood Coagulation Disorders
4. Duration CAUSES Underlying
Subject
Duration
Predicate
CAUSES
Object
Underlying
5. Academic Medical Centers LOCATION_OF Prospective Cohort Study
Subject
Academic Medical Centers
Predicate
LOCATION_OF
Object
Prospective Cohort Study
6. Measles Virus Nucleoprotein PART_OF 2019 novel coronavirus
Subject
Measles Virus Nucleoprotein
Predicate
PART_OF
Object
2019 novel coronavirus
7. Measles Virus Nucleoprotein ASSOCIATED_WITH Disease Progression
Subject
Measles Virus Nucleoprotein
Predicate
ASSOCIATED_WITH
Object
Disease Progression
8. Lung LOCATION_OF Present
Subject
Lung
Predicate
LOCATION_OF
Object
Present
9. Tropism PROCESS_OF Organ
Subject
Tropism
Predicate
PROCESS_OF
Object
Organ
10. Brain LOCATION_OF Inflammatory Response
Subject
Brain
Predicate
LOCATION_OF
Object
Inflammatory Response
11. Heart LOCATION_OF Inflammatory Response
Subject
Heart
Predicate
LOCATION_OF
Object
Inflammatory Response
12. Kidney LOCATION_OF Inflammatory Response
Subject
Kidney
Predicate
LOCATION_OF
Object
Inflammatory Response
13. Liver LOCATION_OF Inflammatory Response
Subject
Liver
Predicate
LOCATION_OF
Object
Inflammatory Response
14. Lung LOCATION_OF Inflammatory Response
Subject
Lung
Predicate
LOCATION_OF
Object
Inflammatory Response
15. Medulla Oblongata LOCATION_OF Inflammation
Subject
Medulla Oblongata
Predicate
LOCATION_OF
Object
Inflammation
16. Structure of olfactory bulb LOCATION_OF Inflammation
Subject
Structure of olfactory bulb
Predicate
LOCATION_OF
Object
Inflammation
17. Toxic Epidermal Necrolysis PROCESS_OF Patients
Subject
Toxic Epidermal Necrolysis
Predicate
PROCESS_OF
Object
Patients
18. Thrombus PROCESS_OF Patients
Subject
Thrombus
Predicate
PROCESS_OF
Object
Patients
19. Brain LOCATION_OF Thrombus
Subject
Brain
Predicate
LOCATION_OF
Object
Thrombus
20. Heart LOCATION_OF Thrombus
Subject
Heart
Predicate
LOCATION_OF
Object
Thrombus
21. Kidney LOCATION_OF Thrombus
Subject
Kidney
Predicate
LOCATION_OF
Object
Thrombus
22. Liver LOCATION_OF Thrombus
Subject
Liver
Predicate
LOCATION_OF
Object
Thrombus
23. Lung LOCATION_OF Thrombus
Subject
Lung
Predicate
LOCATION_OF
Object
Thrombus
24. Spleen LOCATION_OF Thrombus
Subject
Spleen
Predicate
LOCATION_OF
Object
Thrombus
25. Neutrophil Extracellular Traps PART_OF neutrophil
Subject
Neutrophil Extracellular Traps
Predicate
PART_OF
Object
neutrophil
26. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
27. Virus present PROCESS_OF Patients
Subject
Virus present
Predicate
PROCESS_OF
Object
Patients
28. 2019 novel coronavirus CAUSES Blood Coagulation Disorders
Subject
2019 novel coronavirus
Predicate
CAUSES
Object
Blood Coagulation Disorders
29. Duration CAUSES Underlying
Subject
Duration
Predicate
CAUSES
Object
Underlying
30. Academic Medical Centers LOCATION_OF Prospective Cohort Study
Subject
Academic Medical Centers
Predicate
LOCATION_OF
Object
Prospective Cohort Study
31. Measles Virus Nucleoprotein PART_OF 2019 novel coronavirus
Subject
Measles Virus Nucleoprotein
Predicate
PART_OF
Object
2019 novel coronavirus
32. Measles Virus Nucleoprotein ASSOCIATED_WITH Disease Progression
Subject
Measles Virus Nucleoprotein
Predicate
ASSOCIATED_WITH
Object
Disease Progression
33. Lung LOCATION_OF Present
Subject
Lung
Predicate
LOCATION_OF
Object
Present
34. Tropism PROCESS_OF Organ
Subject
Tropism
Predicate
PROCESS_OF
Object
Organ
35. Brain LOCATION_OF Inflammatory Response
Subject
Brain
Predicate
LOCATION_OF
Object
Inflammatory Response
36. Heart LOCATION_OF Inflammatory Response
Subject
Heart
Predicate
LOCATION_OF
Object
Inflammatory Response
37. Kidney LOCATION_OF Inflammatory Response
Subject
Kidney
Predicate
LOCATION_OF
Object
Inflammatory Response
38. Liver LOCATION_OF Inflammatory Response
Subject
Liver
Predicate
LOCATION_OF
Object
Inflammatory Response
39. Lung LOCATION_OF Inflammatory Response
Subject
Lung
Predicate
LOCATION_OF
Object
Inflammatory Response
40. Medulla Oblongata LOCATION_OF Inflammation
Subject
Medulla Oblongata
Predicate
LOCATION_OF
Object
Inflammation
41. Structure of olfactory bulb LOCATION_OF Inflammation
Subject
Structure of olfactory bulb
Predicate
LOCATION_OF
Object
Inflammation
42. Toxic Epidermal Necrolysis PROCESS_OF Patients
Subject
Toxic Epidermal Necrolysis
Predicate
PROCESS_OF
Object
Patients
43. Thrombus PROCESS_OF Patients
Subject
Thrombus
Predicate
PROCESS_OF
Object
Patients
44. Brain LOCATION_OF Thrombus
Subject
Brain
Predicate
LOCATION_OF
Object
Thrombus
45. Heart LOCATION_OF Thrombus
Subject
Heart
Predicate
LOCATION_OF
Object
Thrombus
46. Kidney LOCATION_OF Thrombus
Subject
Kidney
Predicate
LOCATION_OF
Object
Thrombus
47. Liver LOCATION_OF Thrombus
Subject
Liver
Predicate
LOCATION_OF
Object
Thrombus
48. Lung LOCATION_OF Thrombus
Subject
Lung
Predicate
LOCATION_OF
Object
Thrombus
49. Spleen LOCATION_OF Thrombus
Subject
Spleen
Predicate
LOCATION_OF
Object
Thrombus
50. Neutrophil Extracellular Traps PART_OF neutrophil
Subject
Neutrophil Extracellular Traps
Predicate
PART_OF
Object
neutrophil
ABSTRACT

Background:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy.

Methods:

This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course.

Findings:

Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41-78). Median disease course (time from onset of symptoms to death) was 22 days (range 5-44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5-44]; ten patients with neutrophilic plugs, 21 days [5-44]). Neutrophilic plugs were observed in two forms solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets..

Interpretation:

In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19.

Funding:

Amsterdam UMC Corona Research Fund.

Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Type of study: Etiology study / Observational study / Prognostic study Language: English Journal: Lancet Microbe Clinical aspect: Etiology / Prognosis Year: 2020

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Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Type of study: Etiology study / Observational study / Prognostic study Language: English Journal: Lancet Microbe Clinical aspect: Etiology / Prognosis Year: 2020
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