Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections

Abstract

Background SARS-CoV-2 is the cause of an ongoing pandemic with a projected 100,000 to 240,000 U.S. deaths. To date, documentation of histopathologic features in fatal cases of COVID-19 has been limited due to small sample size and incomplete organ sampling. Methods Post-mortem examinations were performed on 12 fatal COVID-19 cases in Washington State during February-March 2020. Clinical and laboratory data were reviewed. Tissue examination of all major organs was performed by light microscopy and electron microscopy. The presence of viral RNA in sampled tissues was tested by RT-PCR. Results All 12 patients were older with significant preexisting comorbidities. The major pulmonary finding was diffuse alveolar damage in the acute and/or organizing phases with virus identified in type I and II pneumocytes by electron microscopy. The kidney demonstrated viral particles in the tubular epithelium, endothelium, and podocytes without significant inflammation. Viral particles were also observed in the trachea and large intestines. SARS-CoV-2 RNA was detected in the cardiac tissue of a patient with lymphocytic myocarditis. RT-PCR also detected viral RNA in the subcarinal lymph nodes, liver, spleen, and large intestines. Conclusion SARS-CoV-2 represents the third novel coronavirus to cause widespread human disease since 2002. Similar to SARS and MERS, the primary pathology was diffuse alveolar damage with virus located in the pneumocytes. However, other major organs including the heart and kidneys may be susceptible to viral replication and damage leading to increased mortality in those with disseminated disease. Understanding the pathology of SARS-CoV-2 will be essential to design effective therapies.

A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

“…Lung sections from the two HIS-DRAGA survivors of SARS-CoV-2 infection were further analyzed to characterize pathological changes. As in recent reports based on human autopsies [57][58][59] , the H&E and Mason-trichrome staining of lung sections showed heavy parenchymal infiltrates around the large bronchioles and at peripheral areas of the lungs, as well as hCD45 + cells and human (CD3 + ) T cells dispersed throughout the lung parenchyma, which were more pronounced in the mouse infected with the high dose of virus ( Fig. 5).…”

“…route with non-mouse-adapted SARS-CoV-2, sustaining the infection for at least 14 days, and that they can develop severe human-like lung immunopathology, including T-cell infiltrates, alveolar damage and microthrombi. As in recent analyses of human autopsy samples from COVID-19 patients [57][58][59] , the lung infiltrates of infected DRAGA mice were intra-parenchymal, relatively diffuse, and grouped around terminal bronchioles and at the periphery.…”

Human iPSC-derived alveolar and airway epithelial cells can be cultured at air-liquid interface and express SARS-CoV-2 host factors

“…Enterocytes of the small intestine express ACE2 protein (Hamming 2004), and TMPRSS2 is also highly expressed in human colonic epithelium (Vaarala 2001). SARS-CoV-2 has been identified by electron microscopy in intestinal epithelial cells (Bradley 2020) and viral RNA has been isolated from fecal samples from COVID-19 patients (Xiao 2020, Wang 2020, Holshue 2020. Potential fecal-oral transmission represents an important area of further investigation with significant public health consequences.…”

“…Examination of the lungs of fatal cases of COVID-19 using transmission electron microscopy identified SARS-CoV-2 viral particles in alveolar epithelial type 2 cells (AT2s), type 1 cells, and epithelial cells of the trachea (Bradley 2020). Lung histology was characterized by typical ARDS findings including diffuse alveolar damage and evidence of airway inflammation in COVID-19 autopsy studies (Bradley 2020, Barton 2020, Zhang Allergy 2020. Outside of the lung, there is increasing evidence that gastrointestinal involvement in SARS-CoV-2 infection may also contribute to both disease severity and transmission (Wang 2020, Xu 2020.…”

Non-permissive SARS-CoV-2 infection in human neurospheres

“…Other brain areas lacked immunostaining, as listed in Table 1 (Supp Figure 1A). The heart and the lung, which have been previously demonstrated to be infected by SARS-CoV-2 (Bradley et al, 2020;Mallapaty, 2020;Remmelink et al, 2020;Tabary et al, 2020), were also positively stained (Table 1, Figure 1A). Tissues from infants that did not die by COVID-19 have not shown SARS-CoV-2 spike protein staining confirming the specificity of the antibody (Supp Figure 1B).…”