A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression
Open accessAbstract
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.
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The major reported lung pathologies of severe COVID-19 include diffuse alveolar damage, organizing pneumonia, and chronic interstitial pneumonia.
“The major reported lung pathologies of severe COVID-19 include diffuse alveolar damage (DAD), organizing pneumonia, and chronic interstitial pneumonia (1–3, 5).”
From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [3]
Viral infection is mediated mainly by the binding of SARS-CoV-2 to the ACE2 receptor expressed on the surface of lung epithelial cells, endothelium, pericytes, and other cell types.
“Viral infection is mediated mainly by the binding of SARS-CoV-2 to the angiotensin–converting enzyme 2 (ACE2) receptor expressed on the surface of lung epithelial cells, endothelium, pericytes, and other cell types (1–4).”
From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [3]
DAD and alveolar-capillary barrier breakdown are prominent pathological features of severe COVID-19.
“DAD and alveolar-capillary barrier breakdown are prominent pathological features of severe COVID-19 (1–4).”
From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [3]
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- Authors
- Polak, S. B., Van Gool, I. C., Cohen, D., von der Thüsen, J. H., & van Paassen, J.
- Affiliations
- Leiden University Medical Center (NL)
- Venue
- Modern Pathology
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 33
- Issue
- 11
- Pages
- 2128-2138
- ISSN
- 0893-3952 (ISSN-L)
- PMC
- PMC7306927
- OpenAlex
- W3036853141
- Cited by
- 481
- References
- 71
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 30 · 2023: 76 · 2022: 115 · 2021: 172 · 2020: 57
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Modern Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Keywords
- COVID-19 pandemic, SARS-CoV-2, lung histopathology, disease progression, pulmonary fibrosis, acute fibrinous and organizing pneumonia, diffuse alveolar damage, microvascular damage, blood clots, hyperinflammation, hypercoagulability, mechanical ventilation, disease staging, biomarkers, precision medicine
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Humans, Pneumonia, Viral, Coronavirus Infections, Disease Progression, Pandemics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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