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Emerging theories of long COVID

A recent article in the online journal Science covers the growing focus on long COVID research and highlights the work of three scientists trying to uncover the biological mechanisms driving the illness.


Dr Danilo Buonsenso, a paediatric infectious disease physician at Gemelli University Hospital, Italy, witnessed first-hand how some children remained unwell for months after a mild SARS-CoV-2 infection. Their symptoms included being short of breath and experiencing crushing fatigue. Dr Buonsenso has since sought to find an explanation for the long COVID he has detected in his young patients.

He suspects there is damage to the blood vessels that carry oxygen and nutrients to cells around the body. Specifically, he believes that micro-clots (blockages of mostly small blood vessels) may be preventing blood from getting to all areas of the brain and body tissues. If so, this would result in ischaemic disease where cells in the brain and muscles are starved of blood.

Buonsenso is not alone. There is growing evidence for micro-clot formation in long COVID, which may result from a combination of factors:

  1. Activation of the immune system, which makes blood vessels more permeable and deformed.
  2. Activation of complement, which are proteins in the blood and on the surface of some cells that play a role in immunity by removing dead cells and fighting infections).
  3. Activation of platelets, which are cells in the blood that help form clots.
  4. Changes to blood pressure.

Viral reservoirs

In the USA, microbiologist Dr Amy Proal, working at the PolyBio Research Foundation, has also turned her attention to long COVID, in addition to her other work on ME/CFS. In a review of the literature on long COVID and other related post-viral illnesses, Dr Proal and Dr VanElzakker, at Harvard Medical School, published a paper on their ideas about the possible causes of long COVID.

They say that RNA viruses, including SARS-CoV-2, can initiate chronic illness in infected individuals, resulting in fatigue and a host of other symptoms that present similarly to ME/CFS.

They use a new term, post-acute sequelae of COVID-19 (PASC), to define long COVID. They suggest that if SARS-CoV-2 or remnants of the virus remain in organs or tissues, as persistent reservoirs, this might trigger an immune response. This would result in activation of immune cells that produce molecules to fight off the virus – a process that we experience as inflammation, swelling, heat and pain.

Dr Proal believes that if the viral reservoir is not removed, long-term immune activation can result in chronic illness, with lingering symptoms of fatigue, pain, sleep disturbance and so on.

Over time, the immune system (which works best by reacting swiftly to infections) may become weakened, leading to reactivation of latent viruses. These viruses lay relatively dormant in the human body, but begin replicating when immunity is suppressed (like how human herpes viruses cause cold sores when people are stressed).

The two researchers conclude that SARS-CoV-2 interacts with an infected individual’s microbiome/virome, leading to blood clotting, dysfunctional nerve signalling and hypersensitive immune cells. These immune cells react by attacking healthy cells in the body because the invading virus can sometimes look like parts of our own cells. These abnormalities all contribute to produce the symptoms we see in long COVID.

Immune system gone haywire

In Australia, immunologist Dr Chansavath Phetsouphanh of the University of New South Wales, Sydney, is searching the blood of long COVID patients for clues.

In a paper published in Nature Immunology, Dr Phetsouphanh and colleagues found that a proportion of patients surviving acute COVID-19 went on to develop post-acute COVID syndrome (PACS) lasting longer than 12 weeks.

They found that these long COVID patients had highly activated innate immune cells and lacked naïve T and B cells (white blood cells that have matured but are not yet activated). 

Long COVID patients also had increased expression of interferons, a type of immune cell that mediates immune activation, often in the presence of viral infections. When these are raised it indicates ongoing infection and an inflammatory response.

Using statistical modelling, Dr Phetsouphanh suggested that key inflammatory mediators (including interferons and interleukins) are associated with long COVID status, and can be used to identify long COVID patients with an accuracy of around 80%.

Treatment and the future

All of these scientists suggest that their work may help in the development of new treatments for long COVID, as well as the application of existing treatments such as off-the-shelf drugs. They believe that this emerging evidence will ultimately help to explain long COVID, but also other post-viral illnesses such as ME/CFS.

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