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“The penny dropped”: Why an NEJM lung study was a turning point in our understanding of COVID-19 and diabetes

12th March 2021

A study published last May in the New England Journal of Medicine (NEJM), which described morphological and molecular changes in the lungs of people who died from COVID-19, is now cited as a turning point in our understanding of why people with type 2 and type 1 diabetes are more vulnerable to severe infection.

In his presentation for the EASD e-Learning platform – part of e-Learning’s new series of tutorials on COVID-19 and diabetes – Professor Carel Le Roux commented: “Initially we did not understand why people with diabetes were disproportionately affected. It was really only when the New England Journal paper arrived showing us the histology of patients who died with COVID-19 that the penny dropped. That’s when we started to understand that this is a microvascular disease, affecting the small blood vessels on the outside of the lungs. Both type 1 and 2 diabetes affect the microvasculature and if you have a double whammy where COVID-19 does the same thing, unsurprisingly our patients run into trouble very quickly.”

To accompany Professor Le Roux’s presentation, we took a closer look at the paper and why it proved to be so groundbreaking.

A broad range of clinical respiratory syndromes have been associated with infection by SARS-CoV-2, and progressive respiratory failure in COVID-19 is the predominant cause of death. However, the morphological and molecular changes in the peripheral lung of patients who die from COVID-19 are not well-documented. In the May 2020 issue of the New England Journal of Medicine, Maximilian Ackermann, from the Helios University Clinic, Wuppertal in Germany, and colleagues from Belgium, Germany and Switzerland, published the results of an analysis in which they revealed the changed features of lungs from autopsies of patients who died from COVID-19, compared with lungs from patients who died from influenza and a control group.

What research methods were used?

Comprehensive analyses, including x-ray microtomography, histopathological and multiplexed immunohistochemical analysis, transmission and scanning electron microscopy, corrosion casting and direct multiplexed gene-expression analysis, were performed on pulmonary autopsy specimens from seven patients who died from respiratory failure caused by SARS-CoV-2 infection.

These specimens were compared to lungs from seven patients who died from pneumonia caused by influenza A virus subtype H1N1. Ten age-matched, uninfected lungs were used in the control group.

What features were revealed?

Diffuse alveolar damage with perivascular T-cell infiltration was observed in the lungs from patients who died from COVID-19 or influenza. There were three distinctive angiocentric features of COVID-19: severe endothelial injury, which was associated with the intracellular SARS-CoV-2 virus and disruption of endothelial cell membranes; widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries; and significant new vessel growth.

Compared with the patients who died secondary to influenza, the COVID-19 patients had 9 times the prevalence of capillary microthrombi and, primarily via intussusceptive angiogenesis, new vessel growth was 2.7 times as high in the lungs from patients who died with influenza.

Angiotensin-converting enzyme-2 (ACE2), the protein identified in earlier research as being the host-cell receptor for SARS-CoV-2, was identified in the lungs from patients who died from COVID-19 and influenza. “We found greater numbers of ACE2-positive endothelial cells and significant changes in endothelial morphology, a finding consistent with a central role of endothelial cells in the vascular phase of COVID-19,” commented Ackermann and colleagues.

What is the paper’s significance?

The small sample size was considered a major limitation of the study, given that the pandemic has claimed so many lives. Nevertheless, this study and observations have added significantly to the growing understanding of COVID-19 and demonstrated that vascular angiogenesis distinguishes the pulmonary pathobiology of COVID-19 from that of influenza virus infection.

The opinions expressed in this blog are those of the author, Dr Eleanor D Kennedy.

The full New England Journal of Medicine article can be accessed at:

Click here to watch Professor Le Roux’s film on COVID-19 and diabetes.