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3.
Front Immunol ; 12: 750229, 2021.
Article in English | MEDLINE | ID: covidwho-1506957

ABSTRACT

Improving COVID-19 intervention strategies partly relies on animal models to study SARS-CoV-2 disease and immunity. In our pursuit to establish a model for severe COVID-19, we inoculated young and adult male ferrets intranasally or intratracheally with SARS-CoV-2. Intranasal inoculation established an infection in all ferrets, with viral dissemination into the brain and gut. Upon intratracheal inoculation only adult ferrets became infected. However, neither inoculation route induced observable COVID-19 symptoms. Despite this, a persistent inflammation in the nasal turbinates was prominent in especially young ferrets and follicular hyperplasia in the bronchi developed 21 days post infection. These effects -if sustained- might resemble long-COVID. Respiratory and systemic cellular responses and antibody responses were induced only in animals with an established infection. We conclude that intranasally-infected ferrets resemble asymptomatic COVID-19 and possibly aspects of long-COVID. Combined with the increasing portfolio to measure adaptive immunity, ferrets are a relevant model for SARS-CoV-2 vaccine research.


Subject(s)
Bronchi/pathology , COVID-19/complications , COVID-19/immunology , Ferrets/immunology , SARS-CoV-2/physiology , Administration, Intranasal , Age Factors , Animals , Asymptomatic Diseases , Disease Models, Animal , Ferrets/virology , Humans , Hyperplasia , Immunity, Cellular , Immunity, Humoral , Injection, Intratympanic , Male , Virus Internalization
4.
Emerg Microbes Infect ; 10(1): 2194-2198, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1504286

ABSTRACT

Inactivated coronaviruses, including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), as potential vaccines have been reported to result in enhanced respiratory diseases (ERDs) in murine and nonhuman primate (NHP) pneumonia models after virus challenge, which poses great safety concerns of antibody-dependent enhancement (ADE) for the rapid wide application of inactivated SARS-CoV-2 vaccines in humans, especially when the neutralizing antibody levels induced by vaccination or initial infection quickly wane to nonneutralizing or subneutralizing levels over the time. With passive transfer of diluted postvaccination polyclonal antibodies to mimic the waning antibody responses after vaccination, we found that in the absence of cellular immunity, passive infusion of subneutralizing or nonneutralizing anti-SARS-CoV-2 antibodies could still provide some level of protection against infection upon challenge, and no low-level antibody-enhanced infection was observed. The anti-SARS-CoV-2 IgG-infused group and control group showed similar, mild to moderate pulmonary immunopathology during the acute phase of virus infection, and no evidence of vaccine-related pulmonary immunopathology enhancement was found. Typical immunopathology included elevated MCP-1, IL-8 and IL-33 in bronchoalveolar lavage fluid; alveolar epithelial hyperplasia; and exfoliated cells and mucus in bronchioles. Our results corresponded with the recent observations that no pulmonary immunology was detected in preclinical studies of inactivated SARS-CoV-2 vaccines in either murine or NHP pneumonia models or in large clinical trials and further supported the safety of inactivated SARS-CoV-2 vaccines.


Subject(s)
Antibodies, Viral/immunology , Antibody-Dependent Enhancement , COVID-19 Vaccines/immunology , COVID-19/immunology , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Alveolar Epithelial Cells/pathology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/toxicity , Bronchioles/chemistry , Bronchioles/pathology , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , COVID-19/pathology , COVID-19/virology , Cytokines/analysis , Humans , Hyperplasia , Immunoglobulin G/immunology , Immunoglobulin G/toxicity , Lung/pathology , Macaca mulatta , Male , Mice , Mucus , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Vaccines, Inactivated/immunology
5.
Arch Pathol Lab Med ; 145(11): 1328-1340, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1485410

ABSTRACT

CONTEXT.­: SARS-CoV-2 can undergo maternal-fetal transmission, heightening interest in the placental pathology findings from this infection. Transplacental SARS-CoV-2 transmission is typically accompanied by chronic histiocytic intervillositis together with necrosis and positivity of syncytiotrophoblast for SARS-CoV-2. Hofbauer cells are placental macrophages that have been involved in viral diseases, including HIV and Zika virus, but their involvement in SARS-CoV-2 is unknown. OBJECTIVE.­: To determine whether SARS-CoV-2 can extend beyond the syncytiotrophoblast to enter Hofbauer cells, endothelium, and other villous stromal cells in infected placentas of liveborn and stillborn infants. DESIGN.­: Case-based retrospective analysis by 29 perinatal and molecular pathology specialists of placental findings from a preselected cohort of 22 SARS-CoV-2-infected placentas delivered to pregnant women testing positive for SARS-CoV-2 from 7 countries. Molecular pathology methods were used to investigate viral involvement of Hofbauer cells, villous capillary endothelium, syncytiotrophoblast, and other fetal-derived cells. RESULTS.­: Chronic histiocytic intervillositis and trophoblast necrosis were present in all 22 placentas (100%). SARS-CoV-2 was identified in Hofbauer cells from 4 of 22 placentas (18.2%). Villous capillary endothelial staining was positive in 2 of 22 cases (9.1%), both of which also had viral positivity in Hofbauer cells. Syncytiotrophoblast staining occurred in 21 of 22 placentas (95.5%). Hofbauer cell hyperplasia was present in 3 of 22 placentas (13.6%). In the 7 cases having documented transplacental infection of the fetus, 2 (28.6%) occurred in placentas with Hofbauer cell staining positive for SARS-CoV-2. CONCLUSIONS.­: SARS-CoV-2 can extend beyond the trophoblast into the villous stroma, involving Hofbauer cells and capillary endothelial cells, in a small number of infected placentas. Most cases of SARS-CoV-2 transplacental fetal infection occur without Hofbauer cell involvement.


Subject(s)
COVID-19/transmission , COVID-19/virology , Infectious Disease Transmission, Vertical , Macrophages/virology , Placenta/virology , Pregnancy Complications, Infectious/virology , SARS-CoV-2/pathogenicity , Adult , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Endothelium/pathology , Endothelium/virology , Female , Humans , Hyperplasia/pathology , Hyperplasia/virology , Infant, Newborn , Macrophages/pathology , Macrophages/physiology , Male , Placenta/pathology , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/pathology , Retrospective Studies , SARS-CoV-2/immunology , Stillbirth , Trophoblasts/pathology , Trophoblasts/virology
6.
Hum Pathol ; 116: 49-62, 2021 10.
Article in English | MEDLINE | ID: covidwho-1309235

ABSTRACT

Severe COVID-19 results in a glucocorticoid responsive form of acute respiratory distress (ARDS)/diffuse alveolar damage (DAD). Herein we compare the immunopathology of lung tissue procured at autopsy in patients dying of SARS-CoV-2 with those dying of DAD prior to the COVID-19 pandemic. Autopsy gross and microscopic features stratified by duration of illness in twelve patients who tested positive for SARS-CoV-2 viral RNA, as well as seven patients dying of DAD prior to the COVID-19 pandemic were evaluated with multiplex (5-plex: CD4, CD8, CD68, CD20, AE1/AE3) and SARS-CoV immunohistochemistry to characterize the immunopathologic stages of DAD. We observed a distinctive pseudopalisaded histiocytic hyperplasia interposed between the exudative and proliferative phase of COVID-19 associated DAD, which was most pronounced at the fourth week from symptom onset. Pulmonary macrothrombi were seen predominantly in cases with pseudopalisaded histiocytic hyperplasia and/or proliferative phase DAD. Neither pseudopalisaded histiocytic hyperplasia nor pulmonary macrothrombi was seen in non-COVID-19 DAD cases, whereas microthrombi were common in DAD regardless of etiology. The inflammatory pattern of pseudopalisaded histiocytic hyperplasia may represent the distinctive immunopathology associated with the dexamethasone responsive form of DAD seen in severe COVID-19.


Subject(s)
COVID-19/pathology , Histiocytes/pathology , Lung/pathology , Pulmonary Alveoli/pathology , Adult , Aged , Aged, 80 and over , Cell Proliferation/physiology , Female , Humans , Hyperplasia/pathology , Male , Middle Aged
7.
Int J Dermatol ; 60(1): 73-80, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-919217

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a systemic multi-organ viral illness. Previous studies have found that many patients had a procoagulant state and/or severe hypoxemia with relatively well-preserved lung mechanics. Mechanisms underlying the damage to vascular tissues are not well-elucidated yet. Histological data in COVID-19 patients are still limited and are mainly focused on post-mortem analysis. Given that the skin is affected by COVID-19 and the relative ease of its histological examination, we aimed to examine the histology of skin lesions in COVID-19 patients to better understand the disease's pathology. METHODS: Five skin lesions from COVID-19 adult patients were selected for a deep histological tissue examination. RESULTS: A strong vasculopathic reaction pattern based on prominent vascular endothelial and myointimal cell growth was identified. Endothelial cell distortion generated vascular lumen obliteration and striking erythrocyte and serum extravasation. Significant deposition of C4d and C3 throughout the vascular cell wall was also identified. A regenerative epidermal hyperplasia with tissue structure preservation was also observed. CONCLUSIONS: COVID-19 could comprise an obliterative microangiopathy consisting on endothelial and myointimal growth with complement activation. This mechanism, together with the increased vascular permeability identified, could contribute to obliteration of the vascular lumen and hemorrhage in COVID-19. Thus, anticoagulation by itself could not completely reverse vascular lumen obliteration, with consequent increased risk of hemorrhage. Findings of this study could contribute to a better understanding of physiopathological mechanisms underlying COVID-19 on living patients and could help further studies find potential targets for specific therapeutic interventions in severe cases.


Subject(s)
COVID-19/complications , Endothelial Cells/pathology , Myocytes, Smooth Muscle/pathology , Skin Diseases/pathology , Vascular Diseases/pathology , Aged , Blood Vessels/pathology , CD3 Complex/metabolism , CD4 Antigens/metabolism , Endothelium/metabolism , Endothelium/pathology , Humans , Hyperplasia/pathology , Hyperplasia/virology , SARS-CoV-2 , Skin/blood supply , Skin Diseases/virology , Vascular Diseases/virology
8.
Int J Legal Med ; 135(1): 329-339, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-734096

ABSTRACT

This paper describes three autopsy cases with postmortem diagnosis of SARS-CoV-2 infection, with detailed macroscopic examination as well as advanced microscopic studies of organ tissues collected using hematoxylin-eosin stains and immunohistochemical markers. Two of the cases were admitted briefly in the County Clinical Emergency Hospital of Sibiu, and one was found deceased at his home address. All three autopsies were completed at the County morgue, in the COVID-19 restricted area, using complete protective equipment. The lungs of the patients seemed to be the center organ of invasion and pathogenesis of the novel coronavirus with diffuse areas of condensation, subpleural retraction zones but with different aspect of the classic bacterial bronchopneumonia. Microscopic evaluation revealed viral cytopathic effect of type II pneumocytes with a couple of cells that presented cytoplasmic and nuclear inclusions and who tend to form clusters mimicking multinucleated giant cells. Hyaline membranes and destruction of the alveolar wall as well as microthrombi formation within the small blood vessels were constantly found in almost all our three cases. The spleen had sustained white pulp atrophy with absence of lymphoid follicles. There were no microscopic signs of viral infection on the myocardium or the other organs.


Subject(s)
COVID-19/pathology , Lung/pathology , Adult , Aged , Alveolar Epithelial Cells/pathology , Autopsy , Cell Nucleus/pathology , Cytoplasm/pathology , Female , Humans , Hyperplasia , Immunohistochemistry , Kidney/pathology , Lung/metabolism , Lymphocytes/pathology , Male , Myocardium/pathology , Neutrophils/metabolism , Pulmonary Alveoli/pathology , Spleen/pathology , Thrombosis/pathology
9.
Int J Legal Med ; 134(6): 2209-2214, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-695582

ABSTRACT

A 75-year-old man presented to a French hospital with a 4-day fever after returning from a coronavirus disease-19 (COVID-19) cluster region. A reverse-transcription polymerase chain reaction test was positive for severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) using a nasopharyngeal swab sample. After he returned home and a telephone follow-up, he was found deceased 9 days after first showing symptoms. Whole-body, non-enhanced, post-mortem computed tomography (PMCT) and a forensic autopsy were performed approximately 48 h after death, with sanitary precautions. The PMCT showed bilateral and diffuse crazy-paving lung opacities, with bilateral pleural effusions. Post-mortem virology studies detected the presence of SARS-CoV-2 (B.1 lineage) in the nasopharynx, plasma, lung biopsies, pleural effusion and faeces confirming the persistence of viral ribonucleic acid 48 h after death. Microscopic examination showed that severe lung damage was responsible for his death. The main abnormality was diffuse alveolar damage, associated with different stages of inflammation and fibrosis. This case is one of the first to describe complete post-mortem data for a COVID-19 death and highlights the ability of PMCT to detect severe involvement of the lungs before autopsy in an apparently natural death. The present pathology results are concordant with previously reported findings and reinforce the disease pathogenesis hypothesis of combined viral replication with an inappropriate immune response.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Lung/diagnostic imaging , Lung/pathology , Pneumonia, Viral/pathology , Aged , Alveolar Epithelial Cells/pathology , Autopsy , COVID-19 , Fibrin/metabolism , Humans , Hyperplasia , Male , Pandemics , Pleural Effusion/diagnostic imaging , Pleural Effusion/pathology , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/pathology , SARS-CoV-2 , Tomography, X-Ray Computed
10.
Mod Pathol ; 33(11): 2139-2146, 2020 11.
Article in English | MEDLINE | ID: covidwho-634770

ABSTRACT

The spectrum of COVID-19 infection includes acute respiratory distress syndrome (ARDS) and macrophage activation syndrome (MAS), although the histological basis for these disorders has not been thoroughly explored. Post-mortem pulmonary and bone marrow biopsies were performed in 33 patients. Samples were studied with a combination of morphological and immunohistochemical techniques. Bone marrow studies were also performed in three living patients. Bone marrow post-mortem studies showed striking lesions of histiocytic hyperplasia with hemophagocytosis (HHH) in most (16/17) cases. This was also observed in three alive patients, where it mimicked the changes observed in hemophagocytic histiocytosis. Pulmonary changes included a combination of diffuse alveolar damage with fibrinous microthrombi predominantly involving small vessels, in particular the alveolar capillary. These findings were associated with the analytical and clinical symptoms, which helps us understand the respiratory insufficiency and reveal the histological substrate for the macrophage activation syndrome-like exhibited by these patients. Our results confirm that COVID-19 infection triggers a systemic immune-inflammatory disease and allow specific therapies to be proposed.


Subject(s)
Coronavirus Infections/pathology , Histiocytes/pathology , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphohistiocytosis, Hemophagocytic/virology , Pneumonia, Viral/pathology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Aged , Aged, 80 and over , Betacoronavirus , Bone Marrow/pathology , COVID-19 , Female , Humans , Hyperplasia/pathology , Hyperplasia/virology , Lung/pathology , Male , Middle Aged , Pandemics , SARS-CoV-2
11.
EBioMedicine ; 57: 102833, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-613483

ABSTRACT

BACKGROUND: The novel coronavirus pneumonia COVID-19 caused by SARS-CoV-2 infection could lead to a series of clinical symptoms and severe illnesses, including acute respiratory distress syndrome (ARDS) and fatal organ failure. We report the fundamental pathological investigation in the lungs and other organs of fatal cases for the mechanistic understanding of severe COVID-19 and the development of specific therapy in these cases. METHODS: The autopsy and pathological investigations of specimens were performed on bodies of two deceased cases with COVID-19. Gross anatomy and histological investigation by Hematoxylin and eosin (HE) stained were reviewed on each patient. Alcian blue/periodic acid-Schiff (AB-PAS) staining and Masson staining were performed for the examinations of mucus, fibrin and collagen fiber in lung tissues. Immunohistochemical staining was performed on the slides of lung tissues from two patients. Real-time PCR was performed to detect the infection of SARS-CoV-2. Flow cytometry analyses were performed to detect the direct binding of S protein and the expression of ACE2 on the cell surface of macrophages. FINDINGS: The main pathological features in lungs included extensive impairment of type I alveolar epithelial cells and atypical hyperplasia of type II alveolar cells, with formation of hyaline membrane, focal hemorrhage, exudation and pulmonary edema, and pulmonary consolidation. The mucous plug with fibrinous exudate in the alveoli and the dysfunction of alveolar macrophages were characteristic abnormalities. The type II alveolar epithelial cells and macrophages in alveoli and pulmonary hilum lymphoid tissue were infected by SARS-CoV-2. S protein of SARS-CoV-2 directly bound to the macrophage via the S-protein-ACE2 interaction. INTERPRETATION: Infection of alveolar macrophage by SARS-CoV-2 might be drivers of the "cytokine storm", which might result in damages in pulmonary tissues, heart and lung, and lead to the failure of multiple organs . FUNDING: Shanghai Guangci Translational Medical Research Development Foundation, Shanghai, China.


Subject(s)
Alveolar Epithelial Cells/pathology , Coronavirus Infections/pathology , Cytokine Release Syndrome/pathology , Lung/pathology , Macrophages, Alveolar/pathology , Pneumonia, Viral/pathology , Angiotensin-Converting Enzyme 2 , Autopsy , Betacoronavirus , COVID-19 , China , Coronavirus Infections/mortality , Cytokine Release Syndrome/mortality , Cytokines/blood , Cytokines/metabolism , Female , Humans , Hyperplasia/pathology , Male , Middle Aged , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/mortality , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
12.
Int J Legal Med ; 134(4): 1285-1290, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-544132

ABSTRACT

Forensic investigations generally contain extensive morphological examinations to accurately diagnose the cause of death. Thus, the appearance of a new disease often creates emerging challenges in morphological examinations due to the lack of available data from autopsy- or biopsy-based research. Since late December 2019, an outbreak of a novel seventh coronavirus disease has been reported in China caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). On March 11, 2020, the new clinical condition COVID-19 (Corona-Virus-Disease-19) was declared a pandemic by the World Health Organization (WHO). Patients with COVID-19 mainly have a mild disease course, but severe disease onset might result in death due to proceeded lung injury with massive alveolar damage and progressive respiratory failure. However, the detailed mechanisms that cause organ injury still remain unclear. We investigated the morphological findings of a COVID-19 patient who died during self-isolation. Pathologic examination revealed massive bilateral alveolar damage, indicating early-phase "acute respiratory distress syndrome" (ARDS). This case emphasizes the possibility of a rapid severe disease onset in previously mild clinical condition and highlights the necessity of a complete autopsy to gain a better understanding of the pathophysiological changes in SARS-CoV-2 infections.


Subject(s)
Betacoronavirus , Coronavirus Infections/pathology , Lung/pathology , Pneumonia, Viral/pathology , Alveolar Epithelial Cells/pathology , Autopsy , COVID-19 , Cough/virology , Diabetes Mellitus, Type 2 , Fever/virology , Fibrin/metabolism , Fibrosis/pathology , Humans , Hyperplasia/pathology , Hypertension , Lung/metabolism , Lymphocytes/pathology , Macrophages/pathology , Male , Megakaryocytes/pathology , Metaplasia/pathology , Middle Aged , Neutrophils/pathology , Pandemics , Quarantine , SARS-CoV-2 , Tachycardia/virology , Thrombosis/pathology
13.
Int J Legal Med ; 134(6): 2205-2208, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-621065

ABSTRACT

"Severe acute respiratory syndrome" (SARS) due to coronavirus (SARS-CoV-2) infection is a well-known cause of death. Sometimes, demise can occur unexpectedly in apparently previous healthy individual after a brief period of trivial flu-like symptoms. In these doubtful cases, the forensic pathologist could be requested to define the cause of death occurred outside the hospital. In this report, the authors describe two autopsied cases of SARS-CoV-2-related deaths which occurred suddenly at home and were not preceded by hospitalization, highlighting associated histopathologic patterns and correlating them to pathophysiology of viral infection.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Lung/pathology , Pneumonia, Viral/pathology , Adrenal Cortex/pathology , Aged , Alveolar Epithelial Cells/pathology , Autopsy , COVID-19 , Cell Aggregation , Eosinophils/pathology , Female , Humans , Hyperplasia , Intranuclear Inclusion Bodies/pathology , Megakaryocytes/pathology , Microscopy , Middle Aged , Multimorbidity , Pandemics , Pulmonary Embolism/pathology , SARS-CoV-2 , Splenomegaly/pathology
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