What We Know - and Don’t Know - About the Drivers of Long COVID

Long COVID is a condition that continues to impact millions worldwide, long after the acute phase of COVID-19 has passed. Understanding the drivers behind this complex syndrome is valuable to developing treatments that help people get back to their lives. Katie is an economist and part of her training is about embracing complexity, finding themes and developing solutions and action plans based on available data. Andrea came out of high-performance athletics where it was important to leverage the knowledge and advantages you could give yourself to prepare for big sporting events like the Olympics and then perform on the world stage. We love and respect research, and are actively taking research forward, but we also want to confess that we are also always looking for practical application of available knowledge.  

To this end, we want to acknowledge the unknowns about Long COVID at the same time as we say it is possible to consider interventions now that target the body’s response to a COVID infection. This is the approach ThriveNinety takes with our programs. 

Alongside this, a large share of the Long COVID research is focused on supporting pharmaceutical interventions. These will no doubt be impactful and important in time, but are likely to take 5-10 years to be identified and approved for wide scale clinical use. In order to develop pharmaceutical interventions, researchers will need a better understanding of exactly how and why people’s bodies and brains are impacted. That will then allow drug interventions to be developed in focused ways that target the identified mechanisms.  

Researchers are hard at work analyzing samples and tissues taken as part of large-scale studies supported by NIH’s RECOVER work, and at the FNIH RECOVER - Treating Long COVID conference in September 2024 the NIH committed to continuing to support these efforts. Researchers working in this space attended in person or virtually to share their work and contribute to the conversation. They included Michael Peluso from University of California San Francisco, Dr. Ziyad Al-Aly from Washington University and Hannah Davis from the Patient Led Research Collaborative, among others. Their work and that of others offers us valuable insights into the potential mechanisms behind Long COVID. Let’s break down what might be driving these prolonged symptoms.

Long COVID can begin in a few different ways. Some people experience symptoms during an acute infection and find these symptoms stay with them for weeks, months or even years. Others seem to recover from an initial infection but suddenly start to feel symptoms weeks, or even a few months, later. Others may not have the common Long Covid symptoms listed above but find they have suddenly developed longer-term health conditions or see existing conditions worsen. This can include pre diabetics developing diabetes, people suddenly developing a heart condition, or existing (or previously undiagnosed) autoimmune issues becoming more prevalent. In Katie’s case, she experienced both a continuation of initial symptoms after a COVID infection and a worsening of symptoms after a second COVID infection.

The exact driver of Long Covid is not clear, and there may be more than one, including COVID-19 virus (or viral fragments) remaining in parts of the body; tissue damage caused by a COVID-19 infection; or the body mounting an immune response that does not moderate properly. Regardless of the underlying driver or drivers, evidence has shown that COVID-19 infections are associated with a narrowing of the blood vessels (endothelial dysfunction), inflammation in the body and brain, autoimmune issues and gut-microbiome disruption. This is linked to a heightened inflammatory response in the body and both an elevated and reduced immune response, with some elements of the immune system over-responding while others are less active than expected.

1. Viral Persistence

Even after people recover from acute COVID-19, fragments of the SARS-CoV-2 virus may remain hidden in certain parts of the body. This could lead to an ongoing immune response and inflammation, which may explain persistent symptoms like fatigue, brain fog, and gastrointestinal issues. Anecdotal, observations from pathologists suggest they are seeing viral presence in both people experiencing Long COVID as well as some who are not. So the mechanism is not clear, but is worth being aware of, and considering what you can do to support your immune system functioning. This issue is likely to be a major focus of pharmaceutical research going forward, and people are already considering (and testing) how existing antiviral drug treatments may be used to clear COVID-19 viral persistence.  

2. Immune System Overload

COVID-19 can cause lasting changes in the immune system, triggering an overactive or even misdirected immune response. This means the body could mistakenly attack itself, leading to conditions like chronic pain, cognitive issues, and cardiovascular problems. Both Peluso and Dr. Al-Aly have highlighted immune system dysregulation as a key driver of Long COVID symptoms. Evidence suggests that this is also connected with the presence of heightened inflammation levels in people with Long COVID. Pharmaceutical interventions here can be tricky to get right as suppressing the immune system will help limit issues and symptoms but leave someone vulnerable to other infections and health issues. Similarly, boosting the immune system may only make symptoms that are linked to an overactive immune system worse. As work in this space moves forward, we suggest three elements that can offer near term symptom management: Anti-inflammatory foods, limiting your exposure to environmental toxins (like chemicals, mold, etc.) and specific movements that support your body and its systems (nervous system, immune system, proprioceptive system, gut and more) to function well. These can be simple, but effective tools that can let you reduce symptoms in the near term.      

3. Blood Vessel Damage

COVID-19 doesn’t just affect the lungs—it can damage the lining of blood vessels, leading to circulation problems. When small blood vessels in the heart, brain, or other organs are impacted, it can cause dizziness, cognitive decline, and fatigue. Research points to endothelial (blood vessel) damage as a factor in Long COVID, contributing to widespread organ dysfunction and fatigue. We may not be able to impact this initial damage, but we can support our body’s ability to repair. More on this under Nervous System Dysregulation.  

4. Nervous System Dysregulation

For some people, Long COVID impacts the autonomic nervous system, which controls basic functions like heart rate, blood pressure, and digestion. This can lead to conditions like POTS (Postural Orthostatic Tachycardia Syndrome), where standing up becomes exhausting, causing dizziness and palpitations. There are simple and evidence-based techniques available to help regulate the nervous system. They help provide near-term symptom relief and also help your body systems to function more normally. When the nervous system isn’t stuck in overdrive it is able to move out of “flight or flight or freeze” mode, this creates a cycle of improvement in your body. When the autonomic nervous system moves out of fight or flight mode into a relaxed state it triggers important systems in your body that enable rest, repair and improved functioning. This means helping your nervous system function can help your body to reverse some of the damage it has sustained, helping you feel better and better over time. We encourage the NIH and others to not overlook the potential of low-tech solutions to have a big impact. It was great to see some of the success others were having using similar approaches to ours. At ThriveNinety we also believe that interventions in this space may have wider application for other complex and long term health issues - including Alzheimers, Parkinsons and where people have experienced significant physical trauma. 

5. Dormant Viruses Reactivating

Some experts believe that COVID-19 might weaken the immune system enough to reactivate dormant viruses like Epstein-Barr virus (EBV). When this happens, people may experience fatigue, inflammation, and other symptoms associated with viral reactivation. Therefore, it is important to do what you can to support your immune system functioning and help it from being overtaxed. Again, anti-inflammatory diet, limiting toxin exposure and the right movements to support system functioning all help limit symptoms and support the body to work better and gain back resilience over time. 

6. Energy System Breakdown

Mitochondria, often called the “powerhouses of the cell,” are responsible for producing energy. Some studies suggest that COVID-19 may damage mitochondria, leading to extreme fatigue and difficulty with physical activity. Anecdotally clinicians have seen mixed data about the links between mitochondrial damage and the severity of Long COVID symptoms. More work is needed in this space and we expect this to be one of the focuses of further support from the NIH and eventually pharmaceutical companies. 

7. The Impact of Stress

There are discussions about the impact of stress. It is clear that many of the Long COVID symptoms are consistent with an elevated and prolonged stress response in the body. This can be linked to the body feeling under threat from physical challenges and to the nervous system mounting a fight or flight response. The mental health challenges many face as part of their bundle of Long COVID symptoms, including anxiety and depression, are real. However, we feel there is much more work needed in this space to unpack the true drivers and mechanisms. For example, to what degree are these being driven by the body feeling under threat and sending signals to the brain to be cautious and reserve energy. Katie’s work on mental Health Policy in England found that people with ME/CFS were often channeled into taking therapy or other typical mental/behavioral health treatments, but do not benefit from them in the way that others with underlying mental ill health do. We may need to be open to considering that the presentation of mental ill health is due to physical health issues. Clinicians, academics and others should take care to avoid narratives around mental ill health without evidence as these may lead to people putting too much emphasis on psychological interventions like Cognitive Behavioural Therapy. In our experience, supporting people to tackle the physical systems leads to a reduction in anxiety and depression, suggesting the mechanisms may be body to brain vs brain to body. More work is needed to understand this further, but we encourage people to remain open about the mechanisms at play and to support further research to increase our understanding.    

Moving Forward

At ThriveNinety, we understand how debilitating Long COVID can be. Good work has taken place, and more is in the pipeline. In time we will have a better understanding of exactly how Long COVID impacts people, and how it may impact different people differently. This can help inform development and application of pharmaceutical treatments. However, all of this will take time. Drugs may also need to be coupled with elements of rehab to help people improve their nervous system function and regain functionality more quickly. 

By focusing on symptom management and addressing the body’s reaction to these underlying mechanisms, we aim to help people reclaim their energy and get back to feeling like themselves, in the near term. As more research unfolds, we remain committed to incorporating the latest evidence into our programs to support your journey to recovery. We also encourage people to use available data and evidence to help them manage symptoms and feel better in the near term.

Warmly,
Katie

Related Blog Posts:
Key Insights from the NIH RECOVER Conference: What’s Next for Long COVID?