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1. What is Long Covid?
A couple of months into the current SARS-CoV-2 pandemic it became clear that some people never seem to recover after being infected. This includes people of all ages (including children) and those with any severity of COVID-19, including a mild initial infection. The WHO estimates that about ten to twenty percent of the people who get COVID-19 develop what is officially called Post-Acute Sequela of COVID-19, or PASC. The condition is also known by the patient-coined term Long Covid, with patients calling themselves Long Haulers.
The symptoms vary widely from person to person, both in terms of which organs are affected and severity. Some patients may just have one symptom and others can have a collection of changing symptoms. The disease can be mild or severely disabling and can last for months, years or possibly, indefinitely. Common symptoms include brain fog, memory problems, heart rate dysregulation, shortness of breath, chest pain, headaches, muscle pains, exercise intolerance, ongoing exhaustion and many more.
2. There have been several different mechanisms proposed for what causes Long Covid (i.e. persistent virus, micro-clots, inflammation, auto-immunity and viral reactivation). How does this acidosis mechanism fit in with the other existing hypotheses?
There is very good evidence to support each of these mechanisms occurring in Long Covid patients. However, the results for most of them are inconsistent. Some patients will have micro-clots, some will have auto-antibodies and others will see reactivation of other viruses (e.g. Epstein-Barr virus). It is likely that all of these pathways are active to different levels in different individuals. As Long Covid varies a lot between people and over time, it’s possible that this is dependent on when the exams are done. It’s also possible that the different mechanisms depend on exactly where the SARS-CoV-2 virus went to in the body during the acute infection (i.e. it went throughout the whole body or it stayed in the lungs or it went to the brain) and how much damage it did there. It could also be affected by different underlying health conditions.
Regardless of the variation, we know that each of these pathways can interact with each other in multiple ways, including through alterations of the acid-base balance. Persistent SARS-CoV-2 virus can cause acidosis, as can clotting and inflammation. This acidosis can then further increase clotting and inflammation while also affecting the immune system, increasing auto-immunity and decreasing its ability to control infections (both SARS-CoV-2 and other viruses like EBV). Together this can create a reinforcing disease feedback loop where all the different mechanisms play a role, with acidosis serving as the underlying factor linking the different disease components together.
3. Some patients have only one or two symptoms, whilst others have many, why does that happen?
As we talk about in the question right above this one, there are likely several different disease pathways, or mechanisms, at play in Long Covid, all linked together by acidosis. However, the strength of each pathway and where in the body it is active can be affected by a lot of different factors. Where the virus got to during the acute infection, how much virus was there, how much damage it caused to the tissue, how healthy that tissue was to begin with, what other diseases or infections are going on in the body at the same time. All of these factors can influence the symptoms that a person experiences. For example, if the virus stays in the respiratory system during the acute infection, the patient may just have persistent shortness of breath or loss of smell/taste. Whereas if the virus also got to the muscles and the brain, the patient might also experience brain fog, fatigue, insomnia and PEM.
4. What is post-exertional malaise (PEM) or post-exertional system exacerbation (PESE)?
For some patients, any form of exertion (even something as simple as walking up a flight of stairs) can result in a dramatic worsening of symptoms (fatigue, pain/soreness, brain fog and others) that lasts hours, days, or even longer after the exertion. In Long Covid (like in myalgic encephalomyelitis), muscle usage seems to cause acidosis in and around the muscle. This is likely a consequence of SARS-CoV-2 infection of the muscle as well as a reduction of oxygen to the muscle from things like micro-clots and inflammation. This makes the muscles work more anaerobically (without oxygen), sort of like during normal strenuous exercise or weight lifting. Just like after strenuous exercise, muscles can be very sore and tired, this is because of the acid generated during the anaerobic use of the muscle. In Long Covid, this seems to occur with even mild muscle usage, can be much more intense, can affect more areas of the body and can take much longer to recover from, as the body does not seem to clear the acid from the muscle as quickly as it used to. This is most likely why PEM/PESE occurs.
5. What is the circadian clock and what does it mean if it’s disrupted?
Our bodies are very good at keeping time. The circadian clock regulates many processes in our body (like the sleep-wake cycle) on a 24 hour cycle (the circadian rhythm). Each of our cells also has a clock that regulates processes within the cell in a similar fashion and can affect many different things, like how our immune cells respond to viruses. We know that acidosis can disrupt the functioning of the clock within cells and so this disruption likely occurs during Long Covid. We don’t know for sure if the overall circadian rhythm is also disrupted in Long Covid patients, but that could be the reason why many patients suffer from disrupted sleep. The disruption of the circadian clocks can have a wide range of effects on our body and may also influence why symptoms sometimes change in Long Covid patients over the course of the day.
6. Some patients have had exams that show evidence of alkalosis (i.e. high bicarbonate or low CO2 levels in the blood), how does this fit with this acidosis mechanism?
Though it may seem contradictory, many patients with acute COVID-19 actually show indications of alkalosis, where the blood is too alkaline, not too acidic. Our bodies constantly try to maintain pH in a very narrow and specific range. We have several mechanisms that help to clear excess acid from the body, such as by producing a lot of bicarbonate (which neutralizes acid) or by changing breathing patterns. In the blood acid is often found in the form of carbonic acid. When we breathe, the carbonic acid converts into CO2 that we then exhale, effectively removing some of the acid from our blood. If we change our pattern of breathing, we can change how much acid we remove from the blood. Indeed some Long Covid patients experience hyperventilation and altered breathing. This may be a mechanism to counter the acidosis that may be occurring in the body. Normally, this would be a good thing, but it’s possible to over compensate, which could cause alkalosis. It’s possible that some patients shift between acidosis and alkalosis during the course of a day or week, but since most blood tests are only done once, we don’t see this changing pattern.
7. Some patients have had exams that don’t show any indications of acidosis, alkalosis or altered lactate levels, how does this fit with the acidosis mechanism?
As described in the answer to the question above, the body constantly tries to compensate for any alterations of the acid-base balance. Because of this a blood test at any one time may show indications of acidosis, alkalosis or a relatively normal balance. We believe though, that over time continual measurement of the acid-base balance would show indications of a disruption in Long Covid patients. The same is likely true with lactate. Lactate (or lactic acid) can be produced by any cells in the body, but can be produced in high amounts by muscles when they’re used anaerobically. However, the amount of lactate in the blood at any one time is dependent on how quickly the body can get the lactate out of the muscle and how long it stays in the blood. In a chronic disease such as Long Covid, lactate and the acid-base balance are best examined with multiple readings over the course of a day, week or month.
8. Based on this hypothesis, why do some experimental treatments seem to help Long Covid patients?
At present, we don’t have any proven treatments or cures for Long Covid; however, we do have a lot of experimental treatments, some of which have shown some promise in early clinical trials. Many of these experimental treatments modulate aspects of one of the different pathways proposed in Long Covid. For example, anticoagulants or HELP apheresis may reduce clotting, improving blood flow which would also reduce anaerobic respiration and thus acidosis. Similarly, hyperbaric oxygen treatment would increase the amount of oxygen that gets to the tissues (including the muscles) which would also help to reduce anaerobic respiration and acidosis. Anti-inflammatory drugs could reduce inflammation and help improve blood flow while also reducing the impact of auto-antibodies. SARS-CoV-2 vaccination or Paxlovid may help the body combat persistent virus, potentially reducing the ongoing virus stimulation of all of the disease pathways. However, each of these treatments can also have adverse consequences, such as is seen with SARS-CoV-2 vaccination in Long Covid patients. Vaccination can help improve symptoms in some patients, but in others it can worsen symptoms, sometimes significantly and we don’t yet understand why. In addition, most treatments, so far, seem to offer some level of temporary symptom improvement, but not a cure. It is possible that this is a matter of treatment optimization or could require a combination of treatments targeting multiple disease pathways, including acidosis. For all of these experimental treatments we are waiting on data from robust, large-scale, clinical trials to show how safe and effective the treatments are for different patients.
9. How can this acidosis hypothesis be tested and proven?
We’ve mentioned that because the body always tries to maintain a specific acid-base balance, a single blood test is likely not going to be able to prove if Long Covid patients have alterations in the acid-base balance. So, we have proposed two ways to prove this hypothesis. First, we can look at blood markers for the acid-base balance (pH, bicarbonate, CO2 and lactate) before, during and after exertion (such as the widely used 6-minute walk test). We suspect that compared to people that have never been infected with SARS-CoV-2, Long Covid patients will show significant changes in the blood markers during the course of the test. We can also look at the response in people that have been infected but have fully recovered and don’t have any persistent symptoms. It’s not clear though how these people will respond, as there is some research that says even fully recovered people have residual damage from the virus and so they may also show some alterations in the acid-base balance during the test.
A second way we can test the hypothesis is by continually monitoring the body over a period of a month. Over the past years several companies have made medical monitoring devices that look at how much oxygen gets to a muscle. These devices are often used by professional athletes during their training programs. By tracking muscle oxygenation we can get an idea of anaerobic vs aerobic muscle usage and use that to estimate the potential for acidosis. Similarly, there are devices in development that can continually measure blood lactate levels, again for professional athletes and again giving an estimation of the potential for acidosis. These devices can be used together with a smartwatch activity monitor and daily symptom and activity recording. Whilst this method won’t directly tell about the acid-base balance, it will give an estimate and will show how that dynamically changes over time and based on activity in Long Covid patients as compared to healthy uninfected control participants.
10. Is there anything that I can do now, based on this hypothesis?
We do not recommend acting on this hypothesis until we have robust clinical data proving the hypothesis and showing how it can be diagnosed and treated. However, we are aware that certain aspects can be examined at home using over-the-counter devices, such as the home muscle oxygen saturation or blood lactate measurements. Please note though, that while self-testing can be informative, it is not a substitute for a rigorous, controlled, clinical trial and individual measurements can not be used to confirm or disprove this hypothesis. Similarly, we do not recommend trying any experimental treatments for Long Covid until there is sufficient clinical trial data and under medical supervision. Several of us are Long Covid patients and so we understand the desperate need to do something to help; however, we have also seen the damage that can be caused by treatments that have not yet been proven. Research is progressing rapidly now and hopefully we will have some proven treatment options before too long. As we wait, we can recommend the simple but important advice of keeping as healthy as possible. Staying hydrated, eating healthy, reducing stress and staying mentally and physically active (as much as possible within your Long Covid energy envelope, not pushing it). All of these affect your health to some degree and in a disease such as Long Covid, we all need all the help we can get!
11. I have more questions, how can I get more information?
If you have any questions about acidosis or Long Covid, you can email us for more information: mail@researchaidnetworks.org. Any questions that we frequently receive, we’ll post back here for everyone to read. Please remember that we can not give out or address personal medical information. Depending on the demand, we may not be able to personally respond to all inquiries.
