In DepthCOVID-19

Blood vessel injury may spur disease's fatal second phase

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Science  05 Jun 2020:
Vol. 368, Issue 6495, pp. 1039-1040
DOI: 10.1126/science.368.6495.1039

Science's COVID-19 coverage is supported by the Pulitzer Center.

Frank Ruschitzka told his pathologist to be ready before the first COVID-19 patient died. In early March, Ruschitzka, who leads the cardiology department at University Hospital Zürich, noticed that patients with the disease had strange symptoms for what was then thought to be chiefly a respiratory infection. Many patients had acute kidney failure, organ damage, and mysterious blood clots. Several weeks later, the first body was autopsied: Tiny clots and dead cells littered the capillaries of the lungs, and inflammation had distended blood vessels supplying every organ in the body.

The pathologist had never seen anything like it. But the results showed Ruschitzka why his patients were suffering so much: The virus had targeted their blood vessels.

Since the Zürich team's findings were published in mid-April, dozens of studies have revealed similar patterns of vascular damage in people who died of COVID-19. For example, a 21 May paper in The New England Journal of Medicine showed that the lungs of COVID-19 victims had nine times as many clots as those who died of the H1N1 flu. Other studies have noted inflammatory symptoms in children (Science, 29 May, p. 923) and strokes in otherwise healthy young adults. Now, researchers have woven these findings into a new hypothesis explaining why some patients slip into a fatal “second phase” of COVID-19, 1 week or so after hospitalization.

The key is direct and indirect damage to the endothelial cells that line the blood vessels, particularly in the lungs, explains Peter Carmeliet, a vascular biologist at the Belgian research institute VIB and co-author of a 21 May paper in Nature Reviews Immunology. By attacking those cells, COVID-19 infection causes vessels to leak and blood to clot. Those changes in turn spark inflammation throughout the body and fuel the acute respiratory distress syndrome (ARDS) responsible for most patient deaths.

“It's a vicious cycle,” says Nilam Mangalmurti, a pulmonary intensivist at the Hospital of the University of Pennsylvania, who was not involved in the new research.

This mechanism could explain why the disease pummels some patients who have obesity, diabetes, and cardiovascular conditions: The cells lining their blood vessels are already compromised. If so, drugs used to treat these conditions might help prevent other COVID-19 patients from sliding into serious disease. “[A vaccine] would be terrific,” says Richard Becker, a cardiologist at the University of Cincinnati College of Medicine who outlined a similar cardiovascular cascade in a 15 May review in the Journal of Thrombosis and Thrombolytis. But until a safe, effective vaccine is available, he says, such therapeutics might be “a good start.”

In healthy individuals, endothelial cells help regulate blood pressure, prevent inflammation, and inhibit clotting, in part through the continual production of nitric oxide (NO); they also serve as gatekeepers for molecules passing in and out of the bloodstream. When injured, they send out a complex array of signals to immune cells and clotting factors, which rush to repair the site. And they warn their fellow endothelial cells to be on alert for invaders.

Based on autopsy reports like those from the Zürich hospital, the epidemiology of the disease, and how the new coronavirus behaves in cells in the lab, Carmeliet and colleagues believe the virus can send that system spinning out of control.

When SARS-CoV-2 enters the lungs, it invades cells in the air sacs that transfer oxygen to the blood. Surrounding those sacs are capillaries lined like bricks with endothelial cells. The virus directly invades some of those cells; others become “activated,” likely in response to signals from the invading virus and other damaged cells. Some infected cells likely commit suicide. “It's not a quiet death where the cell just dies,” Mangalmurti says. “All the contents leak out.”

Carmeliet and colleagues suggest damage and other changes in the activated cells trigger vascular leakage, flooding the air sacs with fluid, a hallmark of ARDS. White blood cells swarm to the lungs and NO production likely plummets. Together with the activated endothelial cells, the immune cells release a host of signaling molecules, including interleukins, which raise local blood pressure and weaken cell junctions. Damage to the endothelial cells also exposes the membrane underneath them.

That exposed membrane in turn triggers uncontrolled clotting. The endothelial and immune cells add fuel to the fire, recruiting additional clotting factors and platelets, which help form clots. Those clots degrade into the key biomarker D-dimer, creating the sky-high levels that alert clinicians to patients in trouble (see graphic, below). Eventually, such clotting spreads throughout the body and blocks the blood supply within vital organs.

GRAPHIC: TEUWEN ET AL., NAT. REV. IMMUNOL. (2020), ADAPTED BY V. ALTOUNIAN/SCIENCE

These chain reactions culminate in a final, destructive phase of inflammation. Like clotting, inflammation is an essential defense, sending a diverse army of cells and messenger molecules called cytokines to fight invaders and mop up the debris of battle. But in COVID-19, this reaction spirals out of control in a deadly cytokine storm and plunges patients' bodies into shock.

Ruschitzka says the three-step hypothesis “makes perfect sense” of what he saw in his patients; he's already sending the Carmeliet paper to colleagues. He says the array of pathways may also explain why some young people without known risk factors for COVID-19 become seriously ill: They might have undiagnosed clotting or autoimmune disorders, such as rheumatoid arthritis, that amplify the effects of SARS-CoV-2 infection.

This emerging view of the key role of endothelial cells suggests that a number of existing drugs might dampen or even arrest the fatal second phase of the disease, Becker says. Already, evidence that inflammation and clotting play a role in COVID-19 has inspired dozens of trials in the United States and Europe of anticlotting, anti-inflammatory, and antiplatelet drugs.

Ruschitzka thinks another commonly prescribed drug might help: statins. Typically taken to lower cholesterol, they also reduce inflammation and improve endothelial cell function.

Mangalmurti welcomes such trials, but cautions that patients may respond differently depending on how healthy their endothelial cells are to start. “One size does not fit all.”

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