Dr. Daniel M. Altmann, one of the authors of an excellent new review of Long Covid immunology, and a professor of immunology at Imperial College School of Medicine
A BIG NEW SCIENCE REVIEW ON LONG COVID IMMUNOLOGY IS HERE
A new scientific review was published in the journal Nature July 11, 2023, and brings the world another step closer to understanding what might be causing Long Covid.
A scientific review is an article in a scientific journal, that analyzes existing research papers on a particular topic. “The immunology of long COVID” is a review, written by a group of professors and graduate students from the Imperial College School of Medicine in London.
One in ten people, according to this review, who get Covid-19 go on to develop Long Covid, a chronic illness. (Other studies put the number at anywhere from 2 in 10 to 7 in 10.) As with Covid-19, Long Covid can be mild or severe and everything in between. Symptoms can be numerous and changing, and might occur anywhere in the body.
The review (which I’ll refer to in this newletter as the Imperial College Review) gathered together an abundance of scientific evidence for the existence of Long Covid, confirming that Long Covid is a real biomechanical disease destroying hundreds of millions of lives.
The Imperial College Review organizes the scientific evidence of Long Covid into nine distinct areas. What follows are brief summaries and one big takeaway for each of these areas.
1 - ORGAN DAMAGE
There are long-term changes to organs in people with Long Covid, seen in X-rays, CT scans, MRIs and through other radiological tests. People who recovered quickly from Covid-19 did not have this kind of evidence of organ damage.
The most commonly effected organ is the heart, followed by the lungs.
Big Takeaway No. 1: Long Covid is primarily a cardiovascular disease that has the potential to damage every organ in the body.
2 - PERSISTENT SARS-CoV-2 VIRAL RESERVOIRS
Before Covid-19, most scientists believed coronaviruses couldn’t remain in the body after the acute phase, the way other kinds of viruses, like HIV, do. They were wrong, and there’s now ample evidence to prove it.
In some people with Long Covid, symptoms are associated with persistent SARS-Cov-2 infections in the body’s tissues, sometimes for years. These ongoing infections are not detectable by current widely-available testing methods. The viral reservoirs seem to be small, but they’re powerful enough to prompt an ongoing immune and autoimmune response.
Big Takeaway No. 2: People with Long Covid still have active SARS-CoV-2 in their bodies long after the acute phase of the infection, triggering ongoing autoimmune and autoinflammatory disease.
3 - ABNORMAL INNATE IMMUNITY
Your body has two main systems that help keep you healthy and fight off germs and disease: the innate immune system and the adaptive immune system.
The innate immune system is your body’s first line of defense and works the same way every time.
In people with Long Covid, there is evidence that the innate immune system is not working properly. We do not yet know why.
Big Takeaway No. 3: In people with Long Covid, something is malfunctioning in the innate immune system, resulting in persistent low-level infections.
4 - REACTIVATION OF OTHER VIRUSES
Most of us have dormant living viruses in our bodies all the time, kept in check by our immune systems. For many people with Long Covid, something happens in the body’s fight against SAR-CoV-2 that starts production of measurable active antibodies against those other viruses again.
There is an especially strong association between Long Covid and reactivated Epstein Barr Virus virus. This association was strongest in people whose Long Covid symptons included fever, headache, myalgia, neurological disorders and pulmonary disorders.
Big Takeaway No. 4: Many people with Long Covid have evidence of viral reactivation in the wake of their infection with SARS-CoV-2, and EBV reactivation is strongly associated with certain Long Covid symptoms.
5 - ABNORMAL ADAPTIVE IMMUNITY
The adaptive immune system learns and remembers how to fight off specific pathogens and works differently every time by creating pathogen-specific antibodies. These antibodies stay in your system to recognize pathogens if they ever show up again. This part of the immune system is often referred to as T cell immunity.
Medical science, prior to SARS-CoV-2, did not believe a coronavirus could cause immunodeficiency similar to the way HIV does. The evidence is now clear that this thinking needs to change.
SARS-CoV-2 does cause measurable changes to the adaptive immune system. These changes might be temporary in some people, and long-lasting in others. People with Long Covid show similar and lasting perturbations in the adaptive immune systems.
Big Takeaway No. 5: SARS-CoV-2 leads to lasting changes to the adaptive immune system in people with Long Covid.
6 - AUTOANTIBODIES
Antibodies are special proteins that the immune system produces to fight infections. Autoantibodies are special proteins made by the immune system that attack the body’s own cells.
When autoantibodies attack healthy cells, it can lead to autoimmune diseases, such as Lupus, Rheumatoid Arthritis, Psoriasis, Sjögren syndrome, Myasthenia gravis, vasculitis and more.
Many people with Long Covid present with symptoms of these and other autotimmune diseases. When tested, people with Long Covid have many different kinds of autoantibodies circulating in their bodies that people without Long Covid do not, with marked similarities to lupus.
Autoantibodies that attack the body’s neurons have been found in the cerebrospinal fluid of Covid-19 patients, as have autoantibodies that attack the lining of the body’s blood vessels.
The Imperial College Review suggests that people who already had autoimmune diseases or issues before getting Covid-19 might be at higher risk of developing Long Covid. It says there is likely a shared “aetiology” (cause) among Long Covid and other autoimmune diseases.
For instance, many people with Long Covid develop an autoimmune disease called Postural Orthostatic Tachycardic Syndrome (POTS), which has previously been connected to the production of autoantibodies against G protein-coupled receptors (GPCRs). These same autoantibodies targeting GPCRs are commonly seen in Long Covid patients.
Big Takeaway No. 6: Long Covid is now causing new autoimmune disease in many people, and prior autoimmune issues might be a risk factor for developing Long Covid.
7 - BRAIN AND NERVOUS SYSTEM DAMAGE
There is a measurable amount of brain damage in people with Covid-19 and Long Covid that was not there before they contracted SARS-CoV-2. This damage impairs thinking, remembering, sensing, and focus and can cause tingling, tremors, seizures and many other symptoms.
Long Covid brain damage appears to come mostly from autoantibodies and inflammatory molecules rather than the virus itself, according to the Imperial College Review.
Cytokines are pro-inlammatory molecules. The cytokines TNF, IL-1α and IL-1β are frequently found in the brains of people who’d had Covid-19. Another inflammatory cytokine, CCL11, is found in the blood plasma of people with Long Covid who report having “brain fog” as a symptom.
Though the reviewers were careful not to suggest many treatment options throughout most of this review, they did make an exception for CCL11, saying it is “an important therapeutic target for the treatment of neurocognitive long COVID symptoms.”
Big Takeaway No. 7: Autoantibodies and inflammatory cytokines are likely the main cause of brain damage and nervous system damage seen in Long Covid. Targeting CCL11 could help.
8 - BLOOD VESSEL DAMAGE AND MICROCLOTS IN THE BLOOD
While SARS-CoV-2 most frequently enters the body through the air we breathe, it can also enter through the eyes. Once it’s in the body, the virus begins attacking the lining of the blood vessels.
The lining of the blood vessels is called the endothelium, and the Imperial College Review defines SARS-CoV-2 as an infectious endotheliopathy rather than just a respiratory disease.
The average adult human body has 60,000 miles of endothelium in it. The endothelium is made up of endothelial cells and is one cell thick, and helps blood to flow smoothly. It also regulates heart rate and blood pressure, among other important jobs.
Damage to the endothelium leads to blood clots in the blood vessels. These clots can be large, or they can be tiny.
Very tiny clots (“microclots”) are dangerous. They can clog the tiniest blood vessels of the body, where many important functions take place - such as the exchange of oxygen and carbon dioxide in the lungs, or the absorption of nutrients into the bloodstream from the intestines.
While clotting is a problem for everyone with acute Covid-19, this issue continues indefinitely for those who develop Long Covid. Many Long Covid symptoms are likely related to microclots found in the capillaries.
Long Covid microclots are different from the usual blood clots doctors see, because they contain fibrin, a fibrous substance the body and most anticoagulants can’t dissolve.
These stubborn tiny clots seem to inspire autoantibody production, raising levels of inflammatory cytokines. One such cytokine is especially troublesome: IL-6. The Imperial College Review suggests a drug targeting IL-6, called tocilizumab, be trialed in Long Covid patients to interrupt the endothelial-damage-clot-inflammatory cycle. Tocilizumab is currently used as a treatment in other autoimmune diseases and some cancers.
Big Takeaway No. 8: Long Covid patients have ongoing blood vessel damage and widespread fibrin microclots clogging their smallest blood vessels. Tocilizumab might help.
9 - DYSBIOSIS
Dysbiosis is when the balance of good and bad bacteria in our body gets disrupted. Normally, we have helpful bacteria that help us to stay healthy, but when there's dysbiosis, the bad bacteria can take over and cause health issues.
In people with Long Covid, there is consistent and quantifiable dysbiosis. Some researchers have even developed a Long Covid diagnostic test that looks for too much Ruminococcus gnavus and Bacteroides vulgatus, and too little Faecalibacterium prausnitzii.
The reviewers found a strong association with Long Covid and a form of dysbiosis that leads to less production in the gut of a molecule called butyrate. Butyrate is a short-chain fatty acid produced when good bacteria in the gut break down fiber. Butyrate has an important role in regulating how the immune system works.
The Imperial College Review notes that dysbiosis leading to reduced levels of butyrate is also strongly associated with ME/CFS, another disease that shares so many symptoms with Long Covid many people believe they’re the same disease.
The review does not speculate about what is causing the ongoing specific and measurable dysbiosis in Long Covid patients, but did suggest that developing treatments that enrich the body’s supply of short-chain fatty acids is of interest.
Big Takeaway No. 9: The balance of good and bad bacteria in the gut and elsewhere is disrupted in people with Long Covid, leading to reduced levels of butyrate, an immunomodulatory molecule needed to control inflammation.
The review concludes by stating very clearly that while much is known about Long Covid, much remains unknown. We need more studies and we desperately need clinical trials for treatments.
The reviewers express frustration about the lack of attention given to Long Covid in public discourse, and closes with a most remarkable paragraph that I’ll share with you here:
“The oncoming burden of long COVID faced by patients, health-care providers, governments and economies is so large as to be unfathomable, which is possibly why minimal high-level planning is currently allocated to it. If 10% of acute infections lead to persistent symptoms, it could be predicted that ~400 million individuals globally are in need of support for long COVID. The biggest unknowns remain the joined-up scheme of its pathogenesis and thus the best candidate therapeutics to be trialled in randomized controlled trials, along with a better understanding of the kinetics of recovery and the factors influencing this. Some countries have invested in first-round funding for the pilot investigations. From the above, far more will be needed.”