Abstract
Ultrastructural analysis of autopsy samples from COVID-19 patients usually suffers from significant structural impairment possibly caused by the rather long latency between death of the patient and an appropriate sample fixation. To improve structural preservation of the tissue, we obtained samples from ventilated patients using a trans-bronchial “cryobiopsy” within 30 min after their death and fixed them immediately for electron microscopy. Samples of six COVID-19 patients with a documented histopathology were systematically investigated by thin section electron microscopy. The different samples and areas inspected revealed the ultrastructural correlates of the different phases of diffuse alveolar damage, including detachment of the alveolar epithelium, hyperplasia of type 2 cells, exudates, and accumulation of extracellular material, such as the hyaline membranes and fibrin. Macrophages and neutrophilic granulocytes were regularly detected. Structural integrity of endothelium was intact in regions where the alveolar epithelium was already detached. Aggregates of erythrocytes, leukocytes with fibrin, and thrombocytes were not observed. Coronavirus particles were only found in and around very few cells in one of the six patient samples. The type and origin of these cells could not be assessed although the overall structural preservation of the samples allowed the identification of pulmonary cell types. Hence, the observed alveolar damage is not associated with virus presence or structural impairment due to ongoing replication at later stages of the disease in fatal cases, which implies that the lung damage in these patients is at least propagated by alternative mechanisms, perhaps, an inappropriate immune or stress response.
Highlights
Since the emergence of COVID-19 in late 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) [1], tremendous efforts have been made to understand and to treat this disease [2]
The structural preservation of “cryobiopsies” was sufficient to detect cell types of lung alveoli and even coronavirus particles, which is difficult in autopsy material, most probably because of the long intervals between time of death of the patient and conservation of the material for electron microscopy (EM) [15–17]
In a control biopsy from a non-COVID-19 patient, the profiles in the rough endoplasmic reticulum (rER) were rarely found, which suggests that their formation could be due to either the COVID-19 disease or to the fact that the control patient was alive during biopsy
Summary
Since the emergence of COVID-19 in late 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) [1], tremendous efforts have been made to understand and to treat this disease [2]. Approved vaccines reduce virus transmission and a severe outcome of the disease [3], the global pandemic continues to progress, resulting in significant loss of life and the appearance of new SARS-CoV-2 variants of concern. SARS-CoV-2 infects the epithelium of the upper and lower airways and thereby causes COVID-19 disease [4]. The vast majority of COVID-19 patients are asymptomatic or mildly ill (approximately 80%), a still significant subset of patients shows a severe progression of. 5%) develop an acute respiratory distress syndrome (ARDS), septic shock, or multiorgan failure [5]. High quality ultrastructural correlates of the histopathological findings have been demonstrated only sporadically (e.g., by Ochs and colleagues [7])
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