Could COVID-19 studies already be providing clues about what went wrong with the long haulers and people with post-infectious chronic fatigue syndrome (ME/CFS), fibromyalgia and other diseases?
Two articles in the New York Times – a feature length one, “How Covid Sends Some Bodies to War With Themselves“, and “Scientists Uncover Biological Signatures of the Worst Covid-19 Cases” – present the possibility it is.
Cytokine storms (a very imprecise term) and a tricky immune system are at the heart of it. The feature New York Times piece starts with Dr. Iris Navarro-Millán, a New York rheumatologist who had just watched the health of a 61-year-old COVID-19 patient with mild shortness of breath suddenly plummet. Despite being given oxygen, he’d ended up on a ventilator and requiring dialysis for two months.
Navarro-Millán concluded that a cytokine storm had wiped his lungs and kidneys out. She’d seen this kind of thing before in autoimmune patients experiencing a sudden flare. The proper response was simple – knock the immune system down with steroids or other drugs.
COVID-19 patients, though, were fighting off an infection. The accepted wisdom was that tamping down the immune system during an infection would make things worse. Nevertheless, Navarro-Millán tried something different in the next COVID-19 patient showing signs of a rapid decline – a quick-acting immune-suppressing drug called Anakinra.
The patient rapidly got better. In June, Navarro-Millán published a small (n=14) case series report suggesting that Anakinra may have helped prevent mechanical ventilation in about half of the patients. Anecdotal reports from Italy and from several hospitals in the U.S, suggest that glucocorticoids and other immune-suppressing drugs have been helpful. As soon as they see oxygen levels drop, they provide them. Clinical trials are needed, however, to validate her findings.
(An Anakinra ME/CFS study unfortunately failed but in that study Anakinra was given long after initial infectious event occurred.)
If Navarro-Millán is correct, though, antiviral drugs like Remdesevir, that one would intuitively think would be beneficial, will have limited effects in some patients. Studies suggest that Remdesevir does accelerate recovery times, but does not significantly affect mortality; i.e. if you were going to be able to fight off the virus, Remdesivir could help you do that more quickly.
If, on the other hand, if your immune system had turned on you and a “cytokine storm” was the problem, it doesn’t significantly help.
The studies suggest that the people who are dying from COVID-19 may not be dying from the virus – they’re dying from the cytokine storm their bodies have initiated in an attempt to fight off the virus.
If that’s true – and it’s still a hypothesis – effective COVID-19 treatment will depend on identifying just what kind of COVID-19 patient you are – do you need pathogen suppression (or immune enhancement) or immune suppression?
One major study of almost 6,500 patients provided hard evidence that immune suppression was the ticket for some. It found that low to moderate doses of a steroidal, immune-suppressing drug called dexamethasone reduced death rates by a third. Here was solid evidence that in some cases, immune suppression worked.
Of course, it wasn’t as simple as giving everyone the drug.
“Timing is Everything”
After noting that dexamethasone was cheap, widely available and safe, a published comment on that study, titled “After 62 years of regulating immunity, dexamethasone meets COVID-19“, concluded that “timing was everything” with the drug.
The “cytokine storms” don’t happen with everyone. People who are able to mount a strong early immune response to the virus may never experience one. Oddly enough, it’s the people who can’t amount a strong early immune response who may get plastered by a cytokine storm later. At that point – apparently alarmed by all the damage present – they go into overdrive.
The authors believe that the appearance of substances called “alarmins”, which are associated with cell damage caused by the pathogen, sends the immune system into hyperdrive, resulting in inflammation and even more cell damage. An uncontrolled, positive feedback loop then occurs as inflammation-induced damage triggers more inflammation, leaving the COVID-19 patient in real trouble.
The authors proposed that the best course before the alarmins show up is to try and fight the virus off. After they show up, though, immune suppression is needed.
It gets more complicated. Many types of immune responses may show up – each with an optimal treatment protocol.
In “Scientists Uncover Biological Signatures of the Worst Covid-19 Cases“, Katherine Wu of the New York Times reports that the immune systems of some people with COVID-19 appear to have trouble marshaling the right kind of immune response. In a massive, but largely fruitless effort, their immune systems are spraying bullets all over the place – but missing the target. (A similar process has been suggested in ME/CFS).
In fact, one study suggests that these dysfunctional immune systems appear to have been tricked into mounting an immune defense more suited to bacteria and fungi than viruses. The immune system’s misguided efforts leave the virus intact and a long-term immune response stuck on the on-button.
Adequate early immune response to the virus – Interestingly, the dexamethasone study found that the drug actually made people with mild cases of COVID-19 worse but did not increase their mortality rates. This suggests that if your immune system is already successfully fighting off the virus, you don’t need dexamethasone.
Poor early immune response to the virus – People with an insufficient early innate immune response (people who are older or who have immune issues) may suffer later when their immune system finally gets into gear and then compensates by going into hyperdrive – flooding the body with cytokines and causing a vicious cycle of inflammation-induced damage to occur.
These people may need to get their immune or antiviral response boosted early in order to avoid a cytokine storm that comes later. Because immune responses will vary, identifying and then boosting the specific immune deficiency they have would be the most effective.
People in the throes of a cytokine storm – these people need immune suppression. Broad spectrum immune suppressants such as dexamethasone can be helpful, but a more precise reading of the immune system could allow doctors to target the specific part of the immune system that has overheated and tamp that down.
The inability to distinguish immune subsets may explain why immune suppression appeared to fail to work with the first coronavirus that appeared in 2003, or in sepsis. In two cases, researchers who have gone back and re-analyzed old trial results have found that immune suppression did work – but only in those patients whose test results suggested they had high levels of inflammation.
Clues for ME/CFS and the Long Haulers?
With many immune drug trials underway, we should learn much more about their impact on COVID-19. Early into the pandemic, though, without the results of any long-hauler studies published, we may be getting some clues as to what may have gone wrong very early in the disease process in ME/CFS and the long haulers.
People with initial poor responses to the virus may have set themselves up for a devastating cytokine storm later – which could then set the stage for a prolonged illness. Ron Davis has said that he believes the damage that sets ME/CFS in motion probably begins very early – hence his desire to get a hold of coronavirus patients very early in the game.
While the Dubbo studies may not have tested their participants early enough to catch that, they represent a landmark effort to understand what happens in post-infectious illness. They tracked an extensive cohort of people (n=253) who’d experienced various infectious events (Ross River virus, Epstein-Barr virus, Q fever (Coxiella burnetii ) over the course of year in the mid-2000’s. All appeared to have been successfully treated for the pathogen they’d encountered; i.e. testing suggested it had been vanquished.
They found, though, that 35% of people still had “post-infectious illness” (e.g. chronic fatigue syndrome) at 6 weeks, 27% did so at three months, and 9% were still sick at 12 months. The studies also found that while the initial symptom set was different in all three infections, it evolved over time to a general pattern characterized by fatigue, musculoskeletal pain, and neurocognitive issues.
The study found that more severe symptoms early were associated with an increased risk of coming down with a post-infectious illness. That could suggest a hyperactive immune response (cytokine storm?), which set off a strong case of “sickness behavior”.
That finding was buttressed a bit by a genetic study which found that small changes (single nucleotide polymorphisms (SNPs)) in two immune genes involved in the early immune response were associated with a 8-fold increase in a person’s chance of having a “severe illness response”; i.e. ME/CFS.
Increased incidence of a SNP which boosts interferon gamma (IFN-y) was especially intriguing because IFN-y administration has been show to produce the array of symptoms associated with an infection; i.e. “sickness behavior”. Similarly, the over-representation of an IL-10 SNP, which muffles it’s anti-inflammatory effects, might set the stage for an early heightened immune response.
While the study never found direct evidence on increased cytokine levels, cell cultures confirmed that people with these SNPs did indeed produce more pro-inflammatory cytokines. That finding sent the authors were looking not to the body but to the brain. They believed that an active cytokine response early in the illness tweaked the microglia to sensitize central nervous system pathways and produce ME/CFS.
That’s an interesting conclusion given that some COVID-19 researchers are already tentatively linking cytokine storms to central nervous system dysfunction. They believe it may be possible to identify cytokine profiles that are likely result in long term central nervous system issues and use anti-inflammatories or other drugs to knock them down.
The fact that the genetic polymorphisms identified appeared to have the same effect on each of the infections was striking and left the authors wondering they’d identified something that could be applied to many post-infectious illnesses.
“Because of the highly varied characteristics of the pathogens studied here, these findings may plausibly be generalized to the host response to many infectious agents.”
If they’re right, some of the COVID-19 long haulers might have the same immune genetic predispositions that this study suggested people with ME/CFS do.
It’s important to note that COVID-19 studies published thus far have not assessed long haulers – they’re focused exclusively on what’s happening early in the illness.
- Rheumatologists experienced in treating “cytokine storms” began successfully using immune suppressants like Anakinrin and dexamethasone in COVID-19 patients who’s oxygen levels were falling.
- Studies and anecdotal reports suggest that immune suppressants work when the virus has caused so much tissue damage that an inflammatory positive feedback loop has formed. When people with COVID-19 die, it appears it’s the immune system that is killing them.
- Before that inflammatory process has gotten started – when the body is focused on fighting off the pathogen – antivirals and immune enhancing drugs appear to be more helpful.
- The Dubbo studies in Australia did not test their subjects early but found evidence suggesting that ME/CFS patients are predisposed to produce a very active immune in response to an infection. That response could have produced the more severe symptoms that most people who came down with ME/CFS experienced.
- The Dubbo authors hypothesized that this hyperactive immune response activated microglial cells in the brain which then produced the symptoms found in ME/CFS. They noted that all the symptoms in ME/CFS could be produced by the brain.
- The COVID-19 studies have already opened up several possibilities. 1) a poor early response to the virus results in a cytokine storm later. The bigger the cytokine storm the more likely one is to be hospitalized and suffer from organ damage.
- Smaller cytokine storms, on the other hand, in non-hospitalized patients, could have triggered several outcomes: an autoimmune process, neuroinflammation, herpesvirus reactivation. It’s also possible that the virus had not been completely vanquished.
- COVID-10 is already illuminating the different immune responses to the virus that are occurring it’s critical for the ME/CFS community, as well as for the non-hospitalized long haulers, that they be represented in studies so that we can learn what exactly went wrong with them.
While few long hauler studies have been published thus far, think how easy it would be so easy to turn these early COVID-19 studies into long hauler studies. All the researchers need to do would be to follow the progress of the patients in the study – and then look back and see if they can identify what was happening in people who turned out to be long haulers.
Several scenarios have been presented. All involve some period of strong immune activation
- Poor early immune response leads to a massive cytokine storm later that damages the lungs and other organs and causes hospitalization. Researchers focused on hospitalized patients may, however, conclude that the fatigue, PEM, etc. that is present is the result of organ damage.
- Poor early immune response leads to a smaller cytokine storm later. The patient is able to fight off the virus while at home but has trouble recovering. Various hypotheses have been presented: the cytokine storm has triggered an autoimmune reaction (Nath), it has altered central nervous system functioning, or the virus has not been completely neutralized, or it has reactivated herpesviruses.
- A strong early immune response causes a smaller but still potent cytokine storm. In the Dubbo hypothesis the patient is able to fight off the virus but the cytokine storm it triggered causes the microglia to go on to hyperalert – producing all the symptoms of ME/CFS, FM and others. We don’t know if this strong early immune response actually occurred but it might have given that stronger symptoms were a risk factor for coming down with ME/CFS.
The Dicey Drug Issue
Thus far some studies and observations suggest that a poor early immune response in some COVID-19 patients may set up them up for a scorching immune response later (cytokine storm) that produces a dangerous positive inflammatory feedback loop. These patients appear to respond to immune suppressants. On the other hand, giving immune suppressants too early – or to people whose immune systems are fighting off the pathogen – is not beneficial.
Depending on where they are in their illness, people with COVID-19 could benefit from antivirals or immune suppressants. These drug studies are providing invaluable insights into the different ways the immune system responds to pathogens. If we can identify which immune mistakes have occurred in the long haulers we will have likely come a long way.
It’s clearly critical for us that long-haulers- particularly non-hospitalized long haulers – get into studies. “Cytokine storms”, for instance, appear to play a major role in sending COVID-19 patients to the hospital – but we don’t know if they’re occurring in non-hospitalized patients. With many COVID-19 studies naturally focusing on hospitalized and more severely ill patients we need more data on non-hospitalized patients.
It’s clear that studies embracing the immune system, genetics, the brain, autonomic nervous system, etc. are needed to study the long haulers. Dr. Nath’s, Ron Davis’s – if it can get the funding – and the Swedish ME/CFS Center study will – and hopefully more will pop up.