Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study

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.

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

“…Several recent tissue-based studies assessing CNS alterations in fatal COVID-19 have provided the first hints at histopathological changes occurring in COVID-19 such as hypoxia-related pathology including CNS infarction due to cerebral thromboembolism and signs of a CNS-intrinsic myeloid cell response [32][33][34][35][36][37][38] and/or have presented data on the presence of viral RNA in the CNS 4,39 .…”

The Many Faces of Covid-19 at a Glance: A University Hospital Multidisciplinary Account From Milan, Italy

“…A review of 28 papers by Maiese et al on a total of 341 cases showed alveolar damage with hyaline membrane formation and microthrombi in pulmonary vessels ( 43 ). In a recent autopsy study by Schurink et al in SARS-CoV-2, multiple organs had infected cells, especially in the lungs, but during the disease course these decreased ( 44 ). SARS-CoV-2-positive tissues also included heart, kidneys, and gastrointestinal tract.…”

Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

“…They conclude this suggests CD8+ T cells indeed contribute to viral clearance but may exert a degree of end organ damage ( 18 ). Schurink et al found either one of two types of T cell infiltration in all autopsies: a CD8+ infiltrate causing DAD, or a CD4+ interstitial infiltrate with exudative diffuse alveolar damage and bronchopneumonia ( 19 ).…”

“…Combined with the apparent downregulation of FOXP3 in CD4+ CD25+ T cells and their expression of FASL in Covid-19 patients ( 21 ), this could bode poorly for organs and immune-privileged sites. Following Covid-19 even canonically immune-privileged sites like the eye have inflammatory infiltrates ( 22 ) along with organs like the heart ( 19 ). Israelow et al observe hyperactivation of CD8+ cells and their infiltration into the lung in a murine model of Covid-19 ( 23 ).…”

“…Akt inhibition has also been proposed on the basis of an anti-viral effect (42)(43)(44). However, it appears that in presenting stages of Covid-19 disease antiviral agents seem to have questionable therapeutic benefit, possibly due to the disease entering an immunopathological stage of exuberant lymphocytic response (19). Sorbera et al claim SARS-Cov-induced apoptosis via a caspase-dependent mechanism may suggest inhibition of the Fas/FasL interaction may have efficacy in Sars-Cov-2, but the rationale disregards differentiation (45).…”