Definition, inflammation and gut dysbiosis – there’s a lot to learn from long covid and maybe advice to share.
Rheumatologists may have a role in Australia’s response to long covid.
Respiratory physician Anthony Byrne, who is leading one of Australia’s first long-covid clinics at St Vincent’s Hospital, Sydney, says the complex, multi-system conditions experienced by most long-covid patients are similar to the kind of “nebulous” diseases rheumatologists are good at managing.
“Rheumatologists are skilled at taking care of complex, multi-system diseases and characterising and managing them,” Associate Professor Byrne said.
He added that long covid still needs to be more clearly defined but that a number of rheumatological conditions also once had vague definitions.
“I think we’d be looking for rheumatologists to help us a little bit with characterisation of long covid and coming up with an enhanced definition. For some of the diseases, like rheumatoid arthritis and systemic lupus erythematosus, there’s now a collection of blood tests, abnormalities and other findings that help characterise the disease,” Professor Byrne said.
The array of long-covid symptoms could include cognitive dysfunction, fatigue, chronic pain, sleep problems and compromised function of lungs, heart and other organs.
The World Health Organisation established a clinical case definition for long covid last year:
Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually three months from the onset of COVID-19 with symptoms and that last for at least two months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.
Professor Byrne said he was not that happy with the current definition, saying that it was a start but not an end.
“Although the definition covers some of the key features, it’s basically ‘pick a symptom’ and, if there’s not some other alternative explanation, that could be long covid. In order to work out what treatments are useful, it would be good to have clear definition,” he said.
One of the solutions to defining long covid more fully might come from Harvard University.
Professor Anthony L Komaroff, an expert in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at Harvard University medical school, has been asking why people remained feeling very sick for months and years after covid and other infectious diseases such as mononucleosis, Lyme disease and Ebola.
“I think there’s two possibilities. One is that the infection isn’t really fully gone. With covid, in particular, there’s growing evidence that the virus may leave the respiratory tract fully but still find harbour elsewhere in the body. There’s even some evidence that this RNA virus can integrate its genome into human cells and hide out there as a chronic infection,” Professor Komaroff said.
His second theory was that even if the SARS-CoV-2 virus was fully gone, it had already elicited a “vicious cycle” of inflammation.
“This inflammation leads to a state of chronic inflammation by all sorts of mechanisms, causing oxidative stress that damages tissue, that leads to an inflammatory response that causes more oxidative stress, that leads to more inflammation. Covid sets off a chronic cycle of inflammation,” Professor Komaroff said.
As in some rheumatological diseases, gut dysbiosis was also evident in long-covid patients.
“In particular, the species of bacteria that are pro-inflammatory are more common in the gut of long-covid patients. And the species of bacteria that are anti-inflammatory are less common in the gut, leading to a chronic, low grade, inflammation in the gut wall. This may well generate systemic inflammation and may even activate neuro inflammation in the brain,” Professor Komaroff said.
In the United States, a unique approach to diagnosis and treatment was being offered by IncellDx, a private company co-founded by Dr Bruce Patterson, the former head of virology at Stanford University. The therapy had not yet been taken up by other medical institutions in the US, but more than 20,000 long-covid patients were privately being treated by IncellDx.
The treatment followed Dr Patterson’s research on CCR5, a protein which was found on the surface of white blood cells. The research, published in the International Journal of Infectious Diseases indicates that CCR5 inhibition in critical covid patients decreases inflammatory cytokines, decreases the SARS-CoV2 RNA in plasma and increases CD8 T-cells, which are a type of T lymphocyte that destroys virus-infected cells and tumour cells.
IncellDx analyses a blood test for more than 150 biomarkers. Artificial intelligence helps define long covid and the various associated immune abnormalities. Drug treatment then targets, among other things, inhibition of the protein CCR5.
Dr Patterson said CCR5 was expressed on cells of the innate immune response, which is the early response in acute covid. However, Dr Patterson’s research also found residual CCR 5 protein of SARS-CoV-2 in long-covid patients up to two years after initial infection.
“Those cells migrate all over the body. But by using CCR5 antagonists, we can keep those cells from migrating and causing blood vessel inflammation, which we think is really the heart of long covid mechanistically,” he said.
The anti-cholesterol drug pravastatin and the antiretroviral maraviroc are the main drugs IncellDx uses for treating long covid. Dr Patterson said the treatment reduced the migration of the cells still carrying proteins from SARS-CoV-2, in the absence of replicating virus, and also prevented the cells from binding to the blood vessels.
“If they can’t bind to the blood vessels, they die off and then the inflammation slowly resolves. At the end of the day, it may be a vehicle by which we can modify the immune system and quiet down the immune system without immune suppressing,” Dr Patterson said.
Dr Patterson’s research on using pravastatin and maraviroc was in pre-print and not yet peer reviewed.
According to Dr Patterson, CCR5 antagonists had been proposed for use in treating cancers in combination with the PDL 1 inhibitors but it hadn’t been used to any great extent in rheumatology. However, IncellDx was also researching rheumatic diseases using proteomics – the large-scale study of proteins.
“We want to find if there a protein in lupus that’s causing this continuous immune activation, even if we can’t possibly find it; for instance, in an antecedent infectious agent. So, I think this is opening a door for a lot of new research,” Dr Patterson said.
