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Microvascular Injury in the Brains of Patients with Covid-19


to the Editor:

We conducted high-resolution magnetic resonance imaging (magnetic resonance microscopy) of patients with coronovirus disease 2019 (Kovid-19) (medieval age, 50 years) and histopathic examination on microvascular changes in the olfactory bulb and brain stem Were focused. . (See the Materials and Methods section) Supplementary AddendumAvailable with the full text of this paper at NEJM.org.) The images were obtained from the brains of 13 patients with the use of an 11.7-Tesla scanner for an olfactory bulb of 25 μm and a resolution of 100 μm. Were done. For the brain. Abnormalities in the brain of 10 patients were noted. We examined the brains of patients who showed abnormalities through multiplex fluorescence imaging (in 5 patients) and chromogenic immunostaining (in 10 patients). We performed traditional histopathological examination of the brains of 18 patients. Fourteen patients had chronic illnesses, including diabetes and hypertension, and 11 were found dead or died suddenly and unexpectedly. Of the 16 patients with available medical history, 1 had delirium, 5 had mild respiratory symptoms, 4 had acute respiratory distress syndrome, 2 had pulmonary embolism, and 3 had undetectable symptoms (in Table S1). Supplementary Addendum).

Pathological studies of microvascular injury in the brains of patients dying of Kovid-19.

Panel A (magnetic resonance microscopy of the olfactory bulb) shows a field of hyperintense signal (arrow). Panel B shows the corresponding region on multiplex immunofluorescence imaging, with a focal region of fibrinogen leak (in the box, fibrinogen is shown in green, collagen IV is shown in yellow, and nuclei are shown in blue ). Panel B1 shows diffuse fibrinogen leakage in the parenchyma (a larger view showing marked blood vessel staining for collagen IV is shown in panel B2). Panel B2 (collagen IV immunostaining) shows intact (arrowhead) and thin (arrow) basal lamina with fibrinogen leakage in the parenchyma. Panel C illustrates Ponce’s magnetic resonance microscopy, and panel D (fibrinogen staining) shows areas of increased intensity corresponding to the vascular leakage seen on magnetic resonance microscopy. The area within the dashed lines in panels and panels C and D indicates vascular leakage. Panels represent imaging performed in patient IA1 through AE. Panel E (collagen IV immunostaining) shows areas of fibrinogen leakage in blood vessels in patient IA1. Panel F depicts magnetic resonance microscopy of the marrow in patient IA3. Yellow arrows denote the linear hypothecens signal, and red arrows denote the linear hyperintense signal. Panel G shows patient CD68 + perivascular macrophages in pons in NY6. Panel H shows perivascular astrocytosis in basal ganglia in patient NY5. Panel I depicts perivascular CD3 + cells in the cerebellum in patient 1. Panel J shows intratuminal and perivascular CD8 + cells in the patient NY6 in the parenchyma. Panel K depicts perineuronal IBA1 cells in patient N6 in pons. Panel L depicts CD68 + cells in the dorsal motor nucleus of the vagus nerve in patient IA1. Panel M shows a solitary nucleus in the marrow and panel N shows a pre-Botzinger complex in patient IA1. (Diaminobenzidine was stained in panels G through N)

Magnetic resonance microscopy showed puncture hyperintensities in 9 patients, representing areas of microvascular injury and fibrinial leakage. These features were observed on the corresponding histopathological examination performed with the use of fluorescence imaging (Figure 1A and 1B). These regions have shown a thinning of the basal lamina of endothelial cells, as determined by collagen IV immunostaining in 5 patients (Fig. 1B1 and 1B2). Confirmation of hypocrisy on imaging in 10 blood patientsFigure 1c) With areas surrounding fibrinogen leakageFigure 1D And figs. S1) and relatively intact vasculature (Figure 1E). Areas of linear hypotensives were interpreted as microhemorrhages (Figure 1F And figs. S2). The examined specimens had minimal perivascular inflammation, but no vascular occlusion, as previously described magazine.1 Perivascular-activated microglia, macrophage infiltration, and hypertrophic astrocytes were seen in 13 patients (Figure 1G and 1H, Fig. S3, and Table S4).2 There were CD3 + and CD8 + T cells in the perivascular space and in the lumen adjacent to endothelial cells in 8 patients who may have contributed to vascular injury (Figure 1I and 1J), As stated in the previous report.3 Activated microglia were found adjacent to neurons in 5 patients, suggesting neuronophagia in the olfactory bulb, sensia nigra, the dorsal motor nucleus of the vaginal nerve, and a pre-Botzinger complex in the marrow, which is involved in spontaneous generation of rhythmic breathing (1K through Figure 1N And figs. S3).

Severe acute respiratory syndrome coronavirus 2 was not detected through RNA sequencing of multiple primer sets, multiple regions of the brain, or in situ hybridization and immunostaining (Table S5). It is possible that the virus had cleared by the time of death, or that viral copy numbers were below the level of detection by our assay.

Multifocal microvascular injury was observed in brain and olfactory bulbs through magnetic resonance microscopy, histopathological evaluation, and immunohistochemical analysis of related sections, in a convenience sample of patients who died of Kovid-19, without evidence of viral infection. These findings may inform the interpretation of the changes observed on magnetic resonance imaging of puncture hypertension and magnetic hypotensives in patients with Kovid-19. Due to limited clinical information available, no conclusions can be drawn regarding the neurological characteristics of Kovid-19.

Myung-hwa Lee, Ph.D.
National Institute of Neurological Disorders and Stroke, Bethesda, MD

Daniel P. Pearl, MD
Uniformed Services University of the Health Sciences, Bethesda, MD

Govind Nair, Ph.D.
Wenxue Li, Ph.D.
Dragon Marik, Ph.D.
Helen Murray, Ph.D.
Stephen J. Dodd, Ph.D.
Alan P. Koretsky, Ph.D.
National Institute of Neurological Disorders and Stroke, Bethesda, MD

Jason A. Watts, M.D., Ph.D.
Vivian Cheung, MD
University of Michigan, Ann Arbor, MI

Eliezer Maslia, MD
National Institute on Aging, Bethesda, MD

Irene Horken-Szackali, MD
Robert Jones, MD
Defense Health Agency, Silver Spring, MD

Michelle Ann Strahm, MD
Office of the Chief Medical Examiner, New York, NY

Joel Monkur, MD
Defense Health Agency, Silver Spring, MD

Marco Hefti, MD
University of Iowa, Iowa City, IA

Rebecca D. Folketh, MD
Office of the Chief Medical Examiner, New York, NY

Avindra Nath, MD
National Institute of Neurological Disorders and Stroke, Bethesda, MD

Supported by Intramural Fund (K23NS109284) [to Dr. Hefti]) From there National Institute of Neurological Disorders and Stroke. The reagents used in this study (genomic RNA from SARS-CoV-2, isolate USA-WA1 / 2020, NR-52285) were deposited by the Centers for Disease Control and Prevention and obtained through the BEI Resources Society of the National Institute of Allergy And infectious diseases of the National Institutes of Health.

Disclosure forms The full text of this paper is available at NEJM.org provided by the authors.

The opinions expressed herein are those of the authors and are not representative of Uniformed Services University, the US Department of Defense, or the US Army, Navy, or Air Force or any other federal agency.

The paper was published on NEJM.org on December 30, 2020.

DRS. Folklore and Nath contributed equally to this paper.

  1. 1. Solomon I.H., Normandin E, Bhattacharya S., and others. Neuropathological features of Kovid-19. N angle j med 2020; 383:989992.

  2. 2. Mr Matke, Lutgemann M, Hagel See, and others. Neuropathology of patients with COVID-19 in Germany: a postmortem case series. Lancet Neurol 2020, 19:919929.

  3. 3. Varga Z, Flemer AJ, Steiger P, and others. Endothelial cell infection and endotritis in COVID-19. Knife 2020; 395:14171418.



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