X-ray technology creates clearer picture of lung changes that occur in long COVID
With advanced X-rays and blood biomarkers, researchers have found how lung tissue scarring in patients with COVID and pulmonary fibrosis forms a distinctive form of fibrotic interstitial lung disease, according to a study in eBioMedicine.
Further, this form of interstitial lung disease contributes to long COVID and understanding it may provide opportunities for early intervention, according to researchers.
“Our results suggest that treatments aiming at preventing microvascular thrombosis and tissue ischemia (such as early oxygen supplementation and anticoagulation) may be beneficial in patients with severe COVID-19 and avoid subsequent fibrotic remodeling,” Maximilian Ackermann, MD, lead study author from the University Medical Center Mainz, told Healio.
Lung imaging
Ackermann and colleagues evaluated 80 lungs — including 31 from COVID-19 autopsy samples, seven from influenza A autopsy samples, 18 from interstitial lung disease explants and 23 from healthy controls — to observe the pathophysiology of severe COVID-19 in comparison to other lung diseases, as well as to discover the blood biomarkers for disease severity and therapy response.
Imprecise predictions found through clinic imaging inspired Ackermann and colleagues to evaluate these lungs through Hierarchical Phase-Contrast Tomography (HiP-CT), the highest resolution 3D imaging technique created by the European Synchrotron Radiation Facility, and then compare them with the ones they obtained in clinic.
“Epidemiological data from patients with severe COVID-19 suggest that approximately 20% of hospitalized patients develop post-COVID pulmonary fibrosis, which varies greatly in its extent and progression and can only be predicted very imprecisely by routine clinical imaging,” Ackermann told Healio.
Through this advanced X-ray and imaging technology, Ackermann and colleagues discovered the mechanism behind the modification or scarring of connective tissue in severe COVID-19 lungs.
“We could observe a distinct, mosaic-like consolidation of individual secondary pulmonary lobules based on microvascular occlusion and secondary lobular microischemia, reflecting the prolonged effect of SARS-CoV-2 on the pulmonary vasculature,” Ackermann told Healio. “In comparison to other fibrotic lung diseases and to influenza A, changes in COVID-19 are driven by micro clots (medically termed secondary lobular microischemia) and new blood vessels formation via a specific mechanism, called intussusceptive angiogenesis.”
In addition to HiP-CT, Diamond Light Source also played a part in the team’s breakthroughs. According to a press release from the European Synchrotron Radiation Facility, this synchrotron light source allowed researchers to look at a smaller section of lung.
“These heterogeneously distributed, distinct changes in long COVID lungs at the level of the finest lung lobules cannot be detected via clinical imaging due to the lack of detail in current clinical technology,” Danny Jonigk, MD, FRCPath, director of the Institute of Pathology at University Hospital RWTH Aachen, said in the release. “With the new technology of HiP-CT, we were able to see, for the first time, that the scarring processes in post-COVID fibrosis are the result of generalized vascular damage caused by the SARS-CoV-2 virus.”
Liquid biomarkers
For observing liquid biomarkers, researchers obtained plasma samples from each lung disease group and analyzed them using validated enzyme linked immunosorbent assays, or ELISA.
The results of this analysis revealed new tissue and plasma biomarkers in COVID-19 and interstitial lungs that could be used to detect pulmonary fibrosis early.
“We noticed a significant increase in inflammatory markers and markers of new blood vessel formation, which are responsible for the clinical deterioration of affected patients,” Ackermann told Healio. “By comparing blood and tissue biomarkers in COVID-19 and in patients with other forms of pulmonary fibrosis, such as idiopathic pulmonary fibrosis, we could correlate early morphological and molecular features of the development of pulmonary fibrosis with increased levels of the involved proteins in the blood.”
Specifically, Ackermann said he and his team identified early matricellular markers in the blood serum that indicate the progress of the fibrotic remodeling that occurs in COVID-19 lungs and pulmonary fibrosis.
The fibrosis biomarkers TSP2, GDF15, IGFBP7 and Pro-C3 predicted fatal trajectory in COVID-19, researchers found.
“These ‘predictive serum biomarkers’ enable us to find new therapeutic approaches and to start therapy for the affected patients as early as possible, when the scarring processes can still be reversed via drug therapy,” Detlef Schuppan, MD, PhD, director of the Institute for Translational Immunology at the University Medical Center Mainz, said in the release.
When asked how future studies will be different, Ackermann said more research on matricellular biomarkers and HiP-CT would be beneficial because their study uncovered how these factors are significant in long COVID and pulmonary fibrosis lungs.
“Matricellular biomarkers could detect the early fibrotic remodeling,” Ackermann told Healio. “HiP-CT could help to understand how patterns of a disease are different across a whole organ, like the mosaic-pattern, helps us to decipher the mechanisms by which the damage is happening.”
For more information:
Maximilian Ackermann, MD, can be reached at maximilian.ackermann@uni-mainz.de.
Photo credits: University Medical Center Mainz and University Clinics Aachen
Reference:
Long COVID and pulmonary fibrosis better understood thanks to innovative techniques. https://www.esrf.fr/home/news/general/content-news/general/long-covid-and-pulmonary-fibrosis-better-understood-thanks-to-innovative-techniques.html. Published Nov. 1, 2022. Accessed Nov. 16, 2022.