A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression

Abstract

Since the outbreak of the COVID-19 pandemic, much has been learned regarding its clinical course, prognostic inflammatory markers, disease complications, and mechanical ventilation strategy. Clinically, three stages have been identified based on viral infection, pulmonary involvement with inflammation, and fibrosis. Moreover, low and high elastance phenotypes can be distinguished in mechanically ventilated patients, based on lung mechanics, ventilation-to-perfusion ratio, and CT scans; these two phenotypes have presumed differences in their underlying pathophysiology. Although essential for therapeutic guidance, the pathophysiology of COVID-19 is poorly understood. Here, we systematically reviewed published case reports and case series in order to increase our understanding of COVID-19 pathophysiology by constructing a timeline and correlating histopathological findings with clinical stages of COVID-19. Using PRISMA-IPD guidelines, 42 articles reporting 198 individual cases were included in our analysis. In lung samples (n = 131 cases), we identified three main histological patterns: epithelial (n = 110, 85%), with reactive epithelial changes and DAD; vascular (n = 76, 59%) with microvascular damage, (micro)thrombi, and acute fibrinous and organizing pneumonia; and fibrotic (n = 28, 22%) with interstitial fibrosis. The epithelial and vascular patterns can present in all stages of symptomatic COVID-19, whereas the fibrotic pattern presents starting at~3 weeks. Moreover, patients can present with more than one pattern, either simultaneously or consecutively. These findings are consistent with knowledge regarding clinical patterns of viral infection, development of hyperinflammation and hypercoagulability, and fibrosis. Close collaboration among medical staff is necessary in order to translate this knowledge and classification of pathophysiological mechanisms into clinical stages of disease in individual patients. Moreover, further research, including histopathological studies, is warranted in order to develop reliable, clinically relevant biomarkers by correlating these pathological findings with laboratory results and radiological findings, thus, increasing our understanding of COVID-19 and facilitating the move to precision medicine for treating patients.

A trimeric human angiotensin-converting enzyme 2 as an anti-SARS-CoV-2 agent in vitro

“…Finally, many new therapeutic candidates are in various stages of development (ref 13,14 ; https://www.bio.org/policy/human-health/vaccinesbiodefense/coronavirus/pipeline-tracker). While the infection resolves on its own in most asymptomatic and mild cases over time, COVID-19 in severe cases appears to progress in two phases -initial active viral replication in the respiratory system and subsequent excessive immune responses leading to multiple organ failure and possible death 15 . Thus, antivirals alone may be insufficient to change the course of disease progression for the population that needs intervention the most if administrated too late.…”

Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage. An autopsy study with clinical correlation and review of the literature.

“…Similarly, these reports describe general ndings and the presence of MKs is not further commented. In the remaining autopsy studies, including a review article there are no references to MKs [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]41]. Various reasons could explain this absence.…”

Corticosteroid use in COVID-19 patients: A systematic review and meta-analysis on clinical outcomes

“…On the one hand, there is the hyperin ammatory response, resulting in pulmonary thrombosis, extravasation of cell debris, and acute lung injury or even ARDS. [59] On the other hand there is a need to clear the viral infection itself. This primary phenomenon suggests a possible target for corticosteroids.…”