Bradykinin Hypothesis Offers Two Explanations for Covid-19 “Long Haulers”

Thomas Smith by engin akyurt on Unsplash

One of the biggest mysteries of Covid-19 is why some patients seem to get better quickly after recovering from the virus, whereas others have symptoms that appear to linger for weeks or months. The latter group — those with lingering symptoms — are often called “Covid-19 Long Haulers.” According to a recent article in Nature, they can experience fatigue, lung damage and other symptoms for months after their initial Covid-19 infection clears.

Initially many such patients, The Atlantic reports in a story on the subject, were told that their symptoms were “all in their heads”, or the product of anxiety related to the disease and the pandemic. Unwilling to accept this explanation — or tolerate their ongoing symptoms — many Long Haulers began to form support groups and advocate for more study of their conditions.

Today, the phenomenon is much more widely recognized. And it’s more prevalent than originally anticipated — a physician quoted in Nature’s article estimates that up to 10% of Covid-19 patients experience lasting symptoms after their initial disease course is complete.

I’ve been sounding the alarm on Covid-19 morbidities since this Summer, as have other writers who cover Covid-19, like Nassim Nicholas Taleb. In reporting on the Covid-19 Bradykinin Hypothesis, I was pleased to hear that the Oak Ridge National Laboratory team behind the hypothesis is actively looking into the phenomenon of Covid-19 Long Haulers. The hypothesis provides at least two explanations for why the virus and its effects may linger in certain patients.

During an episode of the podcast Science on Tap in September, Dr. Daniel Jacobson, the lead researcher of the ORNL team behind the Bradykinin Hypothesis, said that “Many have probably heard of the Long Haulers phenomena; patients who, after they’ve had coronavirus and test negative, still continue on with symptoms — or even develop new symptoms. It appears there may be tens of thousands, if not hundreds of thousands of people, in the United States alone that are having these Long Hauler implications”.

Dr. Jacobson shared that ORNL has been working with Long Hauler groups, and that “It’s been a really amazing experience. There have been support groups that have really emerged online, often using social media to talk to each other. And they’ve organized in really interesting ways. They’re very interested in research, and they’re highly motivated people. There’s already survey data from a couple of these different groups. That’s giving an insight into what all those symptoms are, and in what order they are occurring.”

According to Jacobson, there are at least two possible explanations for the phenomenon, based on his group’s Bradykinin Hypothesis. The first is that bradykinin storms, and the downstream inflammatory responses— which Jacobson’s group has identified as a possible explanation for the disease’s effect — take a long time to subside in some people. In Jacobson’s words, “once bradykinin is out of whack — once you have a Bradykinin Storm — [it’s possible] that you need to reboot, you need to reset, or the Bradykinin Storm and inflammation will simply continue and propagate itself.”

Think of this like a traffic jam. A car accident happens on the freeway, and slows down traffic for several hours. There’s a long backup of cars, and travel grinds to a halt. Even once the accident is cleared, though, traffic won’t necessarily return to normal right away. It might take hours for the backup of cars to clear, and for normal speeds and traffic volumes to return. The original accident is gone, but its effects linger.

The same thing may be happening with Covid-19. Even once the virus itself has cleared, the Bradykinin Storm and inflammation that it created may persist in certain patients. As Jacobson suggests, the storms might even become self-propagating, continuing indefinitely after the initial infection is long gone.

If this is the case, it may be necessary to intervene and directly wind down Bradykinin Storms and inflammation in Covid-19 Long Haulers. This is the “reboot” which Jacobson suggests. More clinical research is needed, but it’s possible that this “reboot” could be achieved by using several of the pharmaceuticals mentioned in the team’s original paper. Several of these interfere with the formation or propagation of Bradykinin Storms, and could put a stop to a runaway storm and relieve Long Haulers’ symptoms. These would need to be tested in properly designed clinical trials.

Another explanation, according to Jacobson, is that “there’s still live virus in patients” even after they test negative for Covid-19. In Jacobson’s words, “We know for a fact that you can find virus elsewhere in the body, even when patients have tested negative in the nasal passages. So is there a reservoir for the virus? Is it still bouncing around the system and causing damage?”

Since March or earlier, reports have suggested that Covid-19 can still be found in fecal or sputum samples weeks after a negative nasal test. Other reports have indicated that the virus could potentially accumulate in reservoirs in the body, such as adipose (fat) tissue. It’s possible that even once patients start to test negative in a nasal swab, they’re still harboring virus in their bodies. Other viruses, such as HIV, are known to behave this way — it’s one of the reasons they’ve so far proven impossible to completely eradicate from the body.

The presence of viral reservoirs meshes well with the predictions of the Bradykinin Hypothesis, which suggests that Covid-19 is not primarily a respiratory illness. The virus enters through the nose, the hypothesis predicts, but once present in the body, it may spread to a variety of other organs — or spread into the blood or lymphatic system and travel throughout the body.

This explanation suggests a possible reason for why some patients may have Long Haul symptoms of Covid-19, and why others may recover fully after infection. The progression of Covid-19 within the body may be highly personal — based on a patient’s own biology, or on random factors. For some patients, the virus might remain confined to the upper respiratory system, like the nose and sinuses. For others, it may travel deeper — into the gut, lymphatic system, or other organs like the brain, heart, kidney, muscles, and the lungs.

Whether or not a patient suffers Long Haul symptoms, then, might be a product of where in their own body Covid-19 traveled when they were initially infected. If the virus reached an as-yet-unknown reservoir in their body, it might linger. If it stayed localized in the nose and upper respiratory system, their immune system may have fought it off completely, with no lingering long haul effects.

This explanation also raises a concerning question, which goes beyond those afflicted by long haul symptoms: if Covid-19 indeed travels throughout the body, why are we only testing for it in the nose?

Jacobson told me that “It is somewhat difficult to test in other tissues. The options for non-invasive tests are nose, oral cavity (sputum tests are available), urine and fecal sampling. Somewhat more invasive would be blood tests, but there are compounds in blood that inhibit PCR, and so make the standard testing approaches very difficult. Testing anywhere else would be very invasive and painful so raises lots of other challenges.”

If the virus can live deep in the body for weeks or months after a negative nasal test, could it return to the nose again at a later date, making patients infective weeks after they’ve tested negative? Could this be an explanation for why certain negative tests appear to turn positive later? Jacobson says that “This is possible” but that “this could also be due to false negatives” or patients “getting infected again, which we know is possible.”.

And even more concerning, could patients who test negative in the nose still pass on the virus in other ways?

As Jacobson says in Science on Tap:

“We clearly have both nasal and respiratory shedding. But we also know from a range of data sets that there are viral particles being shed in feces. We also know that when you flush a toilet, the part of the contents of that toilet aerosolizes. You will have this viral plume coming out of a toilet if somebody’s shedding the virus in their feces. Keeping in mind, the virus can live on plastic and metal surfaces for four days, and up to a day on fabric surfaces. That means we have to be thinking about bathrooms in hospitals as well as public places as possible sources of infections. And in fact, some studies have already been done, looking at doing swabs and aerosol testing in bathrooms and hospitals, and find that they’re really hotspots for viral particles in the bathroom. So that’s another mode of infection we need to be concerned about.”

Several papers have already described methods for testing for Covid-19 in feces. It’s possible that other routes of infection are being missed, too, because current tests focus primarily on finding virus in the nose. If this is the case, even those with a negative nasal test may still be infected — and may still be able to spread the virus to others through non-respiratory routes, such as fecal contamination.

If the viral reservoir theory were to pan out clinically, this could have important implications for long haulers. These patients might need treatments geared towards eliminating any remaining virus from their bodies, in order to fully alleviate their symptoms. But this theory — derived in part by studying Long Haulers — may have implications for others, too.

Again, if the virus is able to live deep within patients’ bodies — or to spread through fecal or other routes after nasal tests are negative — this could have profound implications for mitigation strategies based on frequent testing and the use of quarantine periods. If the virus can live elsewhere in the body for months — or be shed through non-respiratory routes — frequent nasal testing alone will not be enough to determine a patient’s Covid-19 status, nor will 14 days quarantines be enough to ensure that they’re no longer infective.

Jacobson cautions that “It looks like the majority of transmission is via droplets and aerosols and, likely to a lesser degree, contact transmission. These alternative routes of infection are important to be aware of, but are not as high on the list of our biggest concerns. Mask wearing has been shown to help in reducing transmission.”

As with many elements of the bradykinin hypothesis, all these possibilities require further study and clinical confirmation. The ORNL team is continuing to pursue them, using methods like explainable artificial intelligence to analyze data gathered from Covid-19 long haulers and other patients.

Their efforts — and the efforts of other researchers, as well as patient groups themselves — might lead to treatments that help long haulers. They may also lead to tests, treatments, and knowledge that benefit all Covid-19 patients, and guide public health efforts geared towards keeping the disease in check.

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Award-winning entrepreneur, and the co-founder and CEO of Gado Images. Thomas writes, speaks and consults about artificial intelligence, privacy, food, photography, tech, and the San Francisco Bay Area. As a professional photographer, Thomas' photographic work regularly appears in publications worldwide. Pitches/news tips:

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