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The gel-like liquid that can form in the lungs of patients with severe COVID-19 infection appears to be glycosaminoglycan hyaluronan (HA), Swedish researchers have discovered in findings that could pave the way for novel therapies for the disease.
“We have for the first time demonstrated a striking presence of hyaluronan in alveolar spaces of the lungs in lethal cases of COVID-19,” say Urban Hellman, PhD, Department of Public Health and Clinical Medicine, Umeå University, Sweden, and colleagues, in research published recently in the Journal of Biological Chemistry.
They studied lung samples obtained at autopsy from severe COVID-19 victims and compared these with lung tissue from people undergoing thoracic surgery. They found that the alveolar spaces in patients with COVID-19 were filled with exudate that stained heavily for HA, which disappeared when it was exposed to an enzyme that breaks down the polysaccharide.
“There are already therapies that either slow down the body’s production of this jelly or break down the jelly through an enzyme,” said Hellman in a press release from Umeå University.
“Based on this novel finding, adjuvant treatment targeting hyaluronan may be a promising approach to reduce mortality in critically ill COVID-19 patients,” such as the antispasmodic hymecromone, which slows down the production of hyaluronan, the authors speculate.
They add, however, “Clinical randomized trials are warranted to evaluate the safety and efficacy of these substances in the case of severe COVID-19.”
Findings May Help Explain Why Steroids Work in Severe COVID-19
As previously reported by Medscape Medical News, a study of more than 530 patients with COVID-19 back in June showed that those with high levels of the steroid hormone cortisol on admission to hospital have a substantially increased risk of dying.
“It has previously been assumed that the promising preliminary results [of RECOVERY] would be linked to the general anti-inflammatory properties of cortisone,” Hellman said.
“But in addition…cortisone may also reduce the production of hyaluronan, which may reduce the amount of jelly in the lungs.”
Asked to comment, Venerino Poletti, MD, PhD, told Medscape Medical News that the current study “confirms what has already been shown in other settings in which we have acute alveolar damage…and was suspected in this context.”
However, the study relies on autopsy-derived material, “which means that we are dealing with, of course, very, very severe cases, and also cases in which other confounding factors are present,” including superinfections, Poletti noted.
Biopsies from living patients will be needed to help shed light on what happens in the early phases of interstitial pneumonia in patients with COVID-19, added Poletti, who is chair of the European Respiratory Society Interstitial Lung Diseases Group and professor in the Department of Respiratory Diseases and Allergy at Aarhus University Hospital, Denmark.
He nevertheless agrees with the Swedish researchers that the findings potentially shed some light on the role of steroids in treating COVID-19 infection.
However, it is not clear if these drugs can help to control hyaluronic acids “flooding into the alveolar spaces, or [whether they exert]…control of the inflammatory and vascular processes that are clearly found [as a] pathogenetic mechanism of this disease.”
Another aspect to consider is that there are “at least two phenotypes” of COVID-19 infection: one in which lung compliance is preserved and another in which compliance is impaired and lung weight is increased, Poletti explained.
He suggests that in the first phenotype HA “is not present in any great quantity until the late phase,” while in the second HA “plays a role in the pathogenesis.”
And although this has been examined in pathophysiological studies, again, there is still a lack of biopsy data, which would be “an important step in understanding the pathogenesis of the disease.”
Current Study Shows Exudate, HA Staining, in Lungs of COVID-19 Victims
For the current study, Swedish researchers examined lung tissue obtained at autopsy from three COVID-19 positive adults: two men, aged 47 and 48 years, and one woman aged 73 years.
These were compared with lung tissue from four patients undergoing thoracic surgery. The samples from all seven individuals were processed in an identical manner.
Two patients with COVID-19 had been in the exudative phase of the disease when they died, and the third was in the proliferation phase, with diffuse alveolar damage.
The alveolar spaces of all three patients with COVID-19 were filled with exudate and alveolar plugs that had pronounced HA staining. Moreover, the alveolar walls were damaged and hyperplastic, and HA staining was seen in the thickened alveolar interstitium.
The researchers say that, in contrast, the lung tissue from those undergoing thoracic surgery showed HA staining only in the alveolar walls and perivascular tissue.
Finally, they treated all the samples with hyaluronidase derived from bovine testes, which “effectively abolished the HA staining.”
“It is plausible that early in the disease, when hypoxemia is developing, inhalation of hyaluronidase could possibly clear the hygroscopic macromolecule from the lungs and facilitate respiration and oxygenation,” the team writes.
They also note that it “has been shown that intranasal administration of exogenous hyaluronidase can reduce lung HA content and restore lung function following influenza infection.”
They add that several publications from earlier this year have also reported that the lungs of patients with COVID-19 were filled with a “clear liquid jelly,” similar to that seen in “wet drowning,” leading to the suggestion that it could be due to HA.
Hyaluronan levels are generally increased in response to inflammation and injury, and the HA molecule is able to absorb water up to 1000 times its molecular weight, forming a “gel-like fluid with high viscosity.”
And in an editorial published earlier this year in the Nature journal Cell Death & Differentiation, Chinese researchers write: “Reducing the presence or inhibiting the production of HA holds a great promise in helping COVID-19 patients breathe. Doctors can simply provide patients medical grade hyaluronidase to reduce the accumulation of HA and thus to clear the jelly in the lung.”
And they agree with Hellman and colleagues that physicians “could also try a use a clinically approved bile therapy drug, hymecromone.”
The study was supported by the Swedish Heart-Lung Foundation. The authors have reported no relevant financial relationships.
J Biol Chem. Published online September 25, 2020. Full text