COVID-19 lung failure: Why patients have to be ventilated for so long

Study shows pronounced scarring of the lungs due to impaired immune response

Berlin, 30.11.2021 – In the majority of patients with severe COVID-19, the lungs scar to an unusually high degree. This is shown by researchers from the Charité – Universitätsmedizin Berlin, the Helmholtz Institute for RNA-based Infection Research (HIRI), the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the RWTH Aachen University Hospital and the Robert Koch Institute in a recent study. As they describe in the scientific journal Cell*, phagocytes of the immune system play a central role. Some processes of COVID-19 lung failure are similar to those of idiopathic pulmonary fibrosis, a previously incurable form of lung scarring. The impaired scarring response could explain why the lung remains non-functional for a long time and requires prolonged ECMO therapy.

In patients with severe COVID-19, the lungs fail to function: they are so severely damaged that the body can no longer absorb enough oxygen from the air. Experts speak of Acute Respiratory Distress Syndrome, or ARDS for short. Only with the administration of oxygen, supportive ventilation or even the use of an artificial lung – the so-called ECMO – do those affected have a chance of surviving such an acute lung failure. Compared to other causes of lung failure, the lung damage in COVID-19 is particularly severe. “Patients with severe COVID-19 often have very severe lung failure,” says Prof. Dr. Leif Erik Sander from the Charité Medical Clinic with a focus on infectious diseases and pneumology, one of the two corresponding leaders of the study. “The extensive destruction of their lung structure requires invasive ventilation or even ECMO treatment over a longer period of time and is unfortunately associated with a very high mortality rate of about 50 percent.”

Among other things, the research team suspected that the reason for the long duration of the lung failure was a special form of ARDS in which the lung tissue becomes scarred, thickened and inelastic. Already relatively early in the pandemic, this type of tissue remodelling, known as fibrosis, had been noticed in individual patients. The current study of the interdisciplinary research consortium from all over Germany now confirms that severe COVID-19-related lung failure is indeed very often accompanied by pronounced scarring of the lung tissue. “A misdirected reaction of so-called macrophages, which are also known as scavenger cells of the immune system, could be partly responsible for this,” states Dr. Antoine-Emmanuel Saliba, working group leader at HIRI in Würzburg and second corresponding leader of the study.

For the study, the team examined the lungs of deceased COVID-19 patients using various microscopic images. “In almost all of those affected, we discovered enormous damage: the alveoli were largely destroyed, the walls clearly thickened. We also found pronounced deposits of collagen, which is a major component of scar tissue. All this is characteristic of severe fibrosis,” Prof. Dr. Peter Boor describes the findings. He led the study at the Institute of Pathology at the University Hospital RWTH Aachen. “These observations indicate that in COVID-19 lung failure we are dealing with a so-called fibroproliferative ARDS, i.e. a particularly severe form of lung failure. This could explain why we have to ventilate the affected patients for so long.”

The reason for this phenomenon was initially unclear. “With COVID-19, lung failure typically develops only in the second or third week after the onset of symptoms, when the viral load is actually already dropping again,” explains Prof. Sander. “This indicates that it is not uncontrolled viral replication that leads to lung failure, but downstream reactions, for example of the immune system, that play a role.” The scientists therefore analysed the composition and properties of the immune cells in lung lavage and tissue from severely ill or deceased COVID-19 patients. To do this, they used the most modern methods of single cell analysis. With these methods, it is possible to look at each individual cell in detail.

The team was thus able to show that macrophages in particular accumulate in large quantities in the lungs of COVID-19 sufferers who develop lung failure. These scavenger cells remove invading pathogens or cellular waste, for example, but are also involved in wound healing and tissue repair. “Surprisingly, macrophages in severe COVID-19 showed similar properties to those in a chronic form of lung scarring called idiopathic fibrosis,” Dr Saliba points out. In this incurable disease, the lungs scar inexorably until organ function is lost. The cause is unknown, and among all forms of pulmonary fibrosis, it has the worst prognosis. “In severe COVID-19, the macrophages come into contact with certain cells of the connective tissue that are responsible for the formation of scar tissue. These cells proliferate strongly and produce large amounts of collagen,” adds the single-cell research expert.

In cell culture, the scientists discovered that SARS-CoV-2 itself influences the phagocytes in such a way that they possibly fuel the fibrosis process. To do this, they isolated phagocyte precursors from the blood of healthy people and stimulated them with the virus. As an analysis of about 7,000 proteins showed, the immune cells then produced increased messenger substances that initiate scarring processes, much like in idiopathic pulmonary fibrosis. “SARS-CoV-2 is therefore at least one possible trigger for the misguided reaction of the phagocytes,” explains Prof. Dr. Matthias Selbach. The proteomics expert led the study at the MDC. “The virus apparently does not multiply in the immune cells, but reprograms them. Interestingly, we could not observe this effect when we stimulated the macrophages with an influenza virus. The influenza virus multiplied strongly in the immune cells. But it did not make them promote scarring processes.”

“So our data clearly show parallels between COVID-19 and chronic pulmonary fibrosis,” Dr Saliba sums up. “This may explain why some risk factors for COVID-19 are also risk factors for idiopathic pulmonary fibrosis – for example, underlying diseases, smoking, a male gender and an age over 60. However, there is a crucial difference between the two diseases: In COVID-19, the scarring is at least potentially repairable.” The research team was able to understand this using CT images. In COVID-19 sufferers treated with ECMO, the images initially showed typical milky-glass-like opacities that became denser and scarred as the disease progressed. In patients who were able to be weaned off ECMO treatment and who were gassing, the body was able to gradually dissolve the condensations – even though in some cases clear scarring residues remained.

The scientists now want to investigate in more detail which cellular processes lead to fibrosis regressing. “If we better understand the dissolution of scarred tissue, we will hopefully be able to help not only COVID-19 sufferers but also patients with previously incurable pulmonary fibrosis in the future,” says Prof. Sander. “The important role of macrophages in both diseases also suggests that inhibiting the cells could help prevent scarring.” At Charité, for example, research groups are investigating the effectiveness of blocking receptors that allow phagocytes to enter lung tissue.

*Wendisch D, Dietrich O, Mari T, von Stillfried S et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell (2021), doi: 10.1016/j.cell.2021.11.033

About the study

The study was conducted within the framework of a nationwide consortium, the “German COVID-19 OMICS Initiative” (DeCOI). The work was mainly funded by the German Research Foundation (DFG) and, within the framework of the Berlin proteomics research core MSTARS and various collaborative projects of the Network University Medicine (NUM), by the Federal Ministry of Education and Research (BMBF) and supported by the German Registry for COVID-19 Obductions (DeRegCOVID). The NUM was founded on the initiative of the Charité and is coordinated by it. It unites the forces of the 36 university hospitals in Germany. The basis for generating the data now published was the Pa-COVID-19 study platform, the central longitudinal register study for COVID-19 patients at the Charité. It aims to investigate COVID-19 patients clinically and molecularly quickly and comprehensively in order to identify individual risk factors for severe forms of progression as well as prognostic biomarkers and therapeutic approaches.

Links:

Originalpublikation
Medizinische Klinik mit Schwerpunkt Infektiologie und Pneumologie der Charité
Pressemitteilungen der Charité zum Coronavirus
Helmholtz-Institut für RNA-basierte Infektionsforschung (HIRI)
Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft (MDC)
Uniklinik RWTH Aachen
Robert Koch-Institut