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1.
Am J Clin Pathol ; 155(6): 802-814, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1272956

ABSTRACT

OBJECTIVES: The novel coronavirus, severe acute respiratory syndrome coronavirus 2, causing coronavirus disease 2019 (COVID-19) remains a global health threat and a significant source of human morbidity and mortality. While the virus primarily induces lung injury, it also has been reported to cause hepatic sequelae. METHODS: We aimed to detect the virus in formalin-fixed tissue blocks and document the liver injury patterns in patients with COVID-19 compared with a control group. RESULTS: We were able to detect viral RNA in the bronchioalveolar cell blocks (12/12, 100%) and formalin-fixed, paraffin-embedded tissue of the lung (8/8, 100%) and liver (4/9, 44%) of patients with COVID-19. Although the peak values of the main liver enzymes and bilirubin were higher in the patients with COVID-19 compared with the control group, the differences were not significant. The main histologic findings were minimal to focal mild portal tract chronic inflammation (7/8, 88%, P < .05) and mild focal lobular activity (6/8, 75%, P = .06). CONCLUSIONS: We found that most patients who died of COVID-19 had evidence of mild focal hepatitis clinically and histologically; however, the virus was detected in less than half of the cases.


Subject(s)
COVID-19/virology , Formaldehyde , Liver/pathology , SARS-CoV-2/pathogenicity , Tissue Fixation , Adult , Aged , Aged, 80 and over , Female , Humans , Inflammation/pathology , Liver/virology , Lung/pathology , Lung/virology , Male , Middle Aged , RNA, Viral/genetics , Tissue Fixation/methods
2.
Sci Transl Med ; 12(574)2020 12 16.
Article in English | MEDLINE | ID: covidwho-1207479

ABSTRACT

Lung transplantation can potentially be a life-saving treatment for patients with nonresolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with nonresolving COVID-19-associated respiratory failure. We performed single-molecule fluorescence in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single-cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm postmortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single-cell RNA sequencing data from the lungs of patients with late-stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.


Subject(s)
COVID-19/surgery , Lung Transplantation , Lung/surgery , Pulmonary Fibrosis/surgery , Adult , Aged, 80 and over , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19/virology , COVID-19 Nucleic Acid Testing , Databases, Factual , Disease Progression , Female , Humans , In Situ Hybridization, Fluorescence , Lung/physiopathology , Lung/virology , Male , Middle Aged , Pulmonary Fibrosis/diagnosis , Pulmonary Fibrosis/physiopathology , Pulmonary Fibrosis/virology , RNA-Seq , Recovery of Function , Retrospective Studies , Severity of Illness Index , Single-Cell Analysis , Treatment Outcome
3.
Am J Clin Pathol ; 155(6): 802-814, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1207252

ABSTRACT

OBJECTIVES: The novel coronavirus, severe acute respiratory syndrome coronavirus 2, causing coronavirus disease 2019 (COVID-19) remains a global health threat and a significant source of human morbidity and mortality. While the virus primarily induces lung injury, it also has been reported to cause hepatic sequelae. METHODS: We aimed to detect the virus in formalin-fixed tissue blocks and document the liver injury patterns in patients with COVID-19 compared with a control group. RESULTS: We were able to detect viral RNA in the bronchioalveolar cell blocks (12/12, 100%) and formalin-fixed, paraffin-embedded tissue of the lung (8/8, 100%) and liver (4/9, 44%) of patients with COVID-19. Although the peak values of the main liver enzymes and bilirubin were higher in the patients with COVID-19 compared with the control group, the differences were not significant. The main histologic findings were minimal to focal mild portal tract chronic inflammation (7/8, 88%, P < .05) and mild focal lobular activity (6/8, 75%, P = .06). CONCLUSIONS: We found that most patients who died of COVID-19 had evidence of mild focal hepatitis clinically and histologically; however, the virus was detected in less than half of the cases.


Subject(s)
COVID-19/virology , Formaldehyde , Liver/pathology , SARS-CoV-2/pathogenicity , Tissue Fixation , Adult , Aged , Aged, 80 and over , Female , Humans , Inflammation/pathology , Liver/virology , Lung/pathology , Lung/virology , Male , Middle Aged , RNA, Viral/genetics , Tissue Fixation/methods
4.
Nature ; 590(7847): 635-641, 2021 02.
Article in English | MEDLINE | ID: covidwho-1019856

ABSTRACT

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.


Subject(s)
COVID-19/immunology , COVID-19/virology , Macrophages, Alveolar/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , COVID-19/genetics , Cohort Studies , Humans , Interferon-gamma/immunology , Interferons/immunology , Interferons/metabolism , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/virology , Pneumonia, Viral/genetics , RNA-Seq , SARS-CoV-2/immunology , Signal Transduction/immunology , Single-Cell Analysis , T-Lymphocytes/metabolism , Time Factors
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