Three distinct differences in Covid-19 lungs vs lungs infected with H1N1

Death from Covid-19 marks the lungs in ways that are distinct from the lungs of persons whose death was caused by severe influenza infection, according to a small study that compared lungs from victims of each disease.

The findings, published online by The New England Journal of Medicine, add more pieces to the Covid-19 puzzle. A team of researchers from Boston, along with an international team from Belgium, Germany, and Switzerland joined to conduct an analysis comparing seven lungs of persons who died from acute respiratory distress syndrome (ARDS) secondary to infection with influenza A (H1N1) to seven lungs from Covid-19 victims in the hope that this examination would aid in the understanding of the disease that has killed close to 100,000 persons in the United States.

The lungs from the influenza patients were heavier, possibly due to more advanced alveolar damage than was seen in the lungs from the Covid-19 patients. But in general, both groups of patients “shared a common morphologic pattern of diffuse alveolar damage and infiltrating perivascular lymphocytes,” Maximilian Ackermann, MD, from the Institute of Pathology and Department of Molecular Pathology, Helios University Clinic Wuppertal, University of Witten–Herdecke, Wuppertal, Germany and colleagues wrote.

There were, however, “three distinctive angiocentric features of Covid-19.”

Those features of lungs taken from the Covid-19 patients were:

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

The researchers added that, “[A]lthough our sample was small, the vascular features we identified are consistent with the presence of distinctive pulmonary vascular pathobiologic features in some cases of Covid-19.”

They noted that previous research has identified a protein, ACE2, as the apparent host-cell receptor for SARS-CoV2. In their study, the lungs from Covid-19 patients as well as the lungs from the influenza patients had greater numbers of ACE2-positive cells than lungs of uninfected controls.

But they also “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,” they wrote. “Endothelial cells in the specimens from patients with Covid-19 showed disruption of intercellular junctions, cell swelling, and a loss of contact with the basal membrane. The presence of SARS-CoV-2 virus within the endothelial cells, a finding consistent with other studies, suggests that direct viral effects as well as perivascular inflammation may contribute to the endothelial injury.”

An unexpected finding was the presence of “enhanced intussusceptive angiogenesis in the lungs from patients with Covid-19 as compared with the lungs from patients with influenza… New vessel growth can occur by conventional sprouting or intussusceptive (nonsprouting) angiogenesis,” they found. “The characteristic feature of intussusceptive angiogenesis is the presence of a pillar or post spanning the lumen of the vessel. Typically referred to as an intussusceptive pillar, this endothelial-lined intravascular structure is not seen by light microscopy but is readily identifiable by corrosion casting and scanning electron microscopy. Although tissue hypoxia was probably a common feature in the lungs from both these groups of patients, we speculate that the greater degree of endothelialitis and thrombosis in the lungs from patients with Covid-19 may contribute to the relative frequency of sprouting and intussusceptive angiogenesis observed in these patients. The relationship of these findings to the clinical course of Covid-19 requires further research to elucidate.”

The small sample size, the authors wrote, is a major limitation of the study, especially when one considers that, globally, the pandemic has claimed more than 320,000 lives.

“On the basis of the available data, we cannot reconstruct the timing of death in the context of an evolving disease process. Moreover, there could be other factors that account for the differences we observed between patients with Covid-19 and those with influenza. For example, none of the patients in our study who died from Covid-19 had been treated with standard mechanical ventilation, whereas five of the seven patients who died from influenza had received pressure-controlled ventilation,” they wrote. “Similarly, it is possible that differences in detectable intussusceptive angiogenesis could be due to the different time courses of Covid-19 and influenza. These and other unknown factors must be considered when evaluating our data. Nonetheless, our analysis suggests that this possibility is unlikely, particularly since the degree of intussusceptive angiogenesis in the patients with Covid-19 increased significantly with increasing length of hospitalization, whereas in the patients with influenza it remained stable at a significantly lower level. Moreover, we have shown intussusceptive angiogenesis to be the predominant angiogenic mechanism even in late stages of chronic lung injury.”

In an editorial, Lida Hariri, MD, PhD, and C. Corey Hardin, MD, PhD, both of Massachusetts General Hospital, wrote Covid-19 has inspired new interest in ARDS, which is “remarkably heterogeneous, with not only a wide range of causes but also a broad spectrum of severity, abnormalities on imaging, and gas-exchange impairment. The form of ARDS that is associated with Covid-19 is no different.”

Hariri and Hardin point out that both sets of lungs had “evidence of diffuse alveolar damage, with widespread signs of thrombosis. Such injury to the alveoli is the pathognomonic histologic finding in ARDS, and both microthrombosis and macrothrombosis are also commonly observed. However, Ackermann and colleagues also analyzed the up-regulation of genes associated with inflammatory conditions and unique ’intussusceptive angiogenesis’ using some new techniques, including immunohistochemical assay, microcomputed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurements of gene expression. The results of these collective methods suggest the presence of increased levels of angiogenesis in human ARDS. The authors further report quantitatively more intussusceptive angiogenesis in the Covid-19 lungs than in the influenza samples and a corresponding differential up-regulation of angiogenesis-associated genes. These findings are intriguing, and it is tempting to ascribe this difference as being specific to SARS-CoV-2. Indeed, the novelty of the virus has led to a widespread attribution of many findings in patients with Covid-19 to the virus itself.”

But the limitations of the study gave the editorial writers pause. For example, “None of the patients with Covid-19 had been intubated (two had received noninvasive ventilation), whereas the majority of patients with influenza had been intubated and treated with ventilator settings that we would now consider not to be lung protective. The sample size of the study was also small, which is particularly problematic in a heterogeneous condition such as ARDS… These data are therefore unable to define differences specific to Covid-19 and H1N1 influenza. The investigators’ conclusion that ’vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection’ has to be considered speculative. It should also be noted that regulators of angiogenesis (e.g., angiopoietin-2) have long been acknowledged as ARDS biomarkers, even in the pre–Covid-19 era. Nevertheless, this observation of angiogenesis in an early stage of diffuse alveolar damage is important.”

  1. Be aware that the findings reported here are from a small cohort study and the findings need to be confirmed in larger clinical trials.
  2. Note that in this small sample, lungs from Covid-19 patients had significant new vessel growth through a mechanism of intussusceptive angiogenesis.

Peggy Peck, Editor-in-Chief, BreakingMED™

The study was funded by the National Institutes of Health.

Ackermann reported grants from NIH during the conduct of the study.

Hariri reported personal fees from Pliant Therapeutics, personal fees from Biogen Idec and grants and personal fees from Boehringer Ingelheim outside the submitted work.

Hardin reported grants from AstraZeneca outside the submitted work.


Cat ID: 195

Topic ID: 89,195,102,8,190,926,192,927,151,928,195,929,925,934