Tracking the time course of pathological patterns of lung injury in severe COVID-19

Abstract

Background: Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARS-CoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics.

Methods: We analysed lung tissue from 41 COVID-19 patients that died in the period March-June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay.

Results: Patient´s age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0-8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression.

Conclusion: Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time.

Keywords: COVID-19; Diffuse alveolar damage; Lung pathology; Minimally invasive autopsy; Pulmonary thrombosis.

Fig. 1

Histopathological parameters. a Diffuse Alveolar Damage, exudative. Observe the septa with mixed inflammatory infiltrate, hyaline membranes, desquamated pneumocytes and macrophages in the alveolar lumen. b Diffuse Alveolar Damage, advanced. Pulmonary architecture is altered, with fibrotic bundles substituting the alveolar parenchyma and distortion of the wall of an airway. c and d Diffuse Alveolar Damage, intermediate. Alveolar spaces are diffusely filled with oedematous, myxoid connective tissue, indicating areas of early fibroproliferation. In d, one can observe the presence of hyaline membranes. e Alveolar haemorrhage. The alveolar spaces are filled with red blood cells and oedematous fluid. f Bronchopneumonia. Alveolar cells are filled with neutrophils and macrophages. There are no hyaline membranes. g Fibrinous, in organization thrombus in a pulmonary artery branch. h Multiple fibrin clots in alveolar capillaries (arrow). In the link https://pathpresenter.net/#/public/display?token=5a84d5d9 one has access to the scanned images of the examples above

Fig. 2

Distribution of the frequency of diffuse alveolar damage patterns in lung biopsies along time of hospital admission until death. 0 to 8 days: *Advanced DAD ≠ exudative DAD (p = 0.005); 9 to 16 days: **Advanced DAD ≠ exudative DAD (p = 0.002) and intermediate DAD (0.014). DAD diffuse alveolar damage

Fig. 3

Influence of age on the frequency of diffuse alveolar damage (DAD) patterns in patients that died within the 8 days of hospital admission

Fig. 4

Influence of weight on the frequency of diffuse alveolar damage patterns in the 41 patients that died of COVID-19. Normal: *Advanced DAD ≠ exudative DAD (p = 0.006) and intermediate DAD (p = 0.017); Obese: **Advanced DAD ≠ exudative DAD (p = 0.014). DAD diffuse alveolar damage

Fig. 5

Dendrogram showing that estimators of vascular pathology aggregated in the same cluster, but not the diffuse alveolar damage (DAD) patterns