Autopsies show how COVID-19 damages lungs more than flu

1 June 2020. Related: COVID-19: pathogenesis, COVID-19.

Mark Mascolini for NATAP.org

COVID-19 wreaks more havoc in the lung than influenza A(H1N1), according to an autopsy comparison by German researchers. [1]

The greater damage with COVID-19 included widespread thrombosis with microangiopathy, 9-fold more prevalent alveolar capillary microthrombi, and almost 3-fold more aberrant angiogenesis (new blood vessel growth) than seen with influenza A.

Researchers at the University of Witten-Herdecke and colleagues at other centers note that respiratory disease is the hallmark of infection with SARS-CoV-2, the virus that causes COVID-19, but the precise morphologic (structural) and molecular changes remain poorly defined. To address that gap, they compared 3 sets of lung biopsies from (1) 7 people who died from COVID-19 respiratory failure, (2) 7 people who died from acute respiratory distress syndrome (ARDS) caused by influenza A(H1N1), and 10 age-matched uninfected control lungs. They used several methods to analyse lung biopsies: 7-color immunohistochemical analysis, microcomputed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.

In people who died from COVID-19 or influenza A, the peripheral lung histologic (microscopic anatomy) pattern was diffuse alveolar damage and perivascular T-cell infiltration. In people with COVID-19, the researchers characterised alveolar damage as necrosis of alveolar lining cells, pneumocyte type 2 hyperplasia, and linear intraalveolar fibrin deposition. In flu patients, “florid diffuse” alveolar damage was marked by “massive interstitial edema and extensive fibrin deposition.” 

The researchers found no angiotensin-converting enzyme 2 (ACE2)-positive lymphocytes in perivascular tissue or alveoli of uninfected control lungs, but they did find ACE2-positive lymphocytes in the COVID-19 group and the influenza A group. CD4 T cells proved more numerous in COVID-19 lungs than in flu lungs (average 13.6 versus 5.8 within a 200-μm radius of precapillary and postcapillary vessel walls in 20 fields of examination per patient, p=0.04). But COVID-19 lung had significantly fewer CD8 T cells than flu lungs (average 5.3 versus 11.6, p=0.008).

Alveolar capillary microthrombi proved more than 9 times more prevalent with COVID-19 than with influenza A (average 159 versus 16 thrombi per square centimeter of vascular lumen area, p=0.002). But in postcapillary venules less than 1 mm in diameter, COVID-19 lungs had fewer thrombi than flu lungs (average 12 versus 35, p=0.02). Three-dimensional microCT showed that lung in both groups had “nearly total occlusions of precapillary and postcapillary vessels.”

Imaging showed structurally deformed capillaries in COVID-19 lung, marked by “sudden changes in caliber and the presence of intussusceptive pillars* in capillaries.” In the COVID-19 group, transmission electron microscopy showed ultrastructural damage to the endothelium and both intracellular and extracellular SARS-CoV-2. 

The researchers found 2.7-fold greater density of intussusceptive angiogenic features* in COVID-19 lungs (average 60.7 features per field) than in flu lungs (average 22.5) or uninfected control lungs (average 2.1) (p<0.001 for both comparisons). In people with COVID-19, degree of intussusceptive angiogenesis increased significantly with longer time in the hospital (p<0.001). In contrast, flu patients had no increase in intussusceptive angiogenesis over time.

The investigators summarised three features that distinguished COVID-19 lungs from influenza A lungs:

1. Severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes,”
2. Widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries, and
3. Significant new vessel growth through a mechanism of intussusceptive angiogenesis.

The authors call this last finding unexpected and suggest that more endothelialitis and thrombosis may contribute to the intussusceptive angiogenesis documented in COVID-19 lungs. They caution that how their findings affect the clinical course of COVID-19 remains to be defined.

*Compared with normal sprouting angiogenesis, intussusceptive angiogenesis is a “splitting process” marked by invasion of existing blood vessels by other tissues, forming damaging “tissue pillars”. [2]

References

1. Ackermann  M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020 May 21. doi: 10.1056/NEJMoa2015432.
   https://www.nejm.org/doi/full/10.1056/NEJMoa2015432
2. Adair TH, Montani JP. Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences. 2010. 
   https://www.ncbi.nlm.nih.gov/books/NBK53238