Doctors examining the lungs of people killed by COVID-19 think they've figured out just what makes the disease so deadly, and why many survivors continue to suffer the effects for months afterwards.
And a separate research team has found COVID-19 can run riot throughout the body, raising a patient's risk of death for at least several months after they think they've gotten better.
The SARS-CoV-2 virus, which causes the disease, appears to trigger the immune system to overproduce a particular type of immune cell which sends inflammation into overdrive, preventing repair cells from doing their job and leaving the lungs permanently damaged.
"It's a devastating disease, but the picture we're getting of the COVID-19 lung is the first step towards identifying potential targets and therapies that disrupt some of the disease's vicious circuits," said Benjamin Izar, assistant professor of medicine at Columbia University, who led the first study.
The unique research had the lungs of 19 COVID-19 victims frozen instantly, preserving their exact state at time of death - including what microscopic cells and organisms were present.
"A normal lung will have many of the same cells we find in COVID, but in different proportions and different activation states," said Dr Izar. "In order to understand how COVID-19 is different compared to both control lungs and other forms of infectious pneumonias, we needed to look at thousands of cells, one by one."
Compared to the lungs of people without COVID-19, they found victims of the pandemic had lungs filled with macrophages - a type of immune cell which attacks intruders but also triggers inflammation.
"In COVID-19, we see expansion and uncontrolled activation of macrophages... They are completely out of balance and allow inflammation to ramp up unchecked.
"This results in a vicious cycle where more immune cells come in causing even more inflammation, which ultimately damages the lung tissue."
The doctors also found evidence the virus destroys a type of cell which helps oxygen and carbon dioxide get to where they need to be in the lungs. The remaining alveolar epithelial cells can't regenerate, kept in an "intermediate state" by a protein called IL-1beta, which is produced in abundance by the runaway inflammation.
Drugs used to "tamp down the effects of IL-1beta" are currently being trialled in treating COVID-19.
But that's not all they found. During all of this, "pathological fibroblasts" are filling the lungs with scar tissue, so there's less room for alveolar epithelial cells and making the damage essentially permanent. There are a number of existing drugs which could possibly prevent this, Dr Izar said.
It's estimated between 10 and 30 percent of all COVID-19 patients who fall ill never fully recover, even once the virus is out of their system. There are reportedly about 200 such 'long COVID' patients in New Zealand, despite only about 2600 recorded cases in New Zealand, symptomatic or not.
More than 40 people were involved in research, shrinking the time it would normally take to carry out such a detailed study from years to months.
"Our hope is that by sharing this analysis and massive data resource, other researchers and drug companies can begin to test and expand on these ideas and find treatments to not only treat critically ill patients, but also reduce complications in people who survive severe COVID-19," said Dr Ivar.
A separate recent study found anyone infected with the virus - even those who don't fall sick - have an increased chance of death in the following months.
Researchers at the Washington University School of Medicine in St Louis looked at medical data belonging to more than 87,000 COVID-19 survivors and found they had a 60 percent greater chance of dying in the six months afterwards than those who hadn't had the virus.
"These later deaths due to long-term complications of the infection are not necessarily recorded as deaths due to COVID-19," said senior author Ziyad Al-Aly, assistant professor of medicine. "As far as total pandemic death toll, these numbers suggest that the deaths we're counting due to the immediate viral infection are only the tip of the iceberg."
They also found the virus can cause damage to "nearly every organ system in the body", including the respiratory, nervous, gastrointestinal, cardiovascular and musculoskeletal systems, as well as impact on people's mental health, sleep, metabolism, kidneys and skin, cause blood clots and cause fatigue and amnesia.
The potential long-term effects are far worse than those of influenza, Dr Al-Aly said, with a 50 percent increased risk of death in the next six months compared to those who contracted the flu.
"Compared with flu, COVID-19 showed remarkably higher burden of disease, both in the magnitude of risk and the breadth of organ system involvement. Long COVID-19 is more than a typical post-viral syndrome. The size of the risk of disease and death and the extent of organ system involvement is far higher than what we see with other respiratory viruses, such as influenza."
As the first cases of COVID-19 were only detected in late 2019, the long-term prognosis for many COVID-19 patients remains unclear.
"We're only a little over a year into this pandemic, so there may be consequences of long COVID-19 that are not yet visible," said Dr Al-Aly.
Both studies were published in journal Nature.