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“This pandemic shone a very, very good light on the idea that there is really an intimate connection between infections and chronic disease. It was really hardwired into our medical training as doctors that most infections, when people get over the hump of the acute phase of the disease, it’s all behind them. I think long COVID has humbled us in many, many ways, but chief among those is the realization — the stark realization — that infections can cause chronic disease.”

 

“Looking at only acute illness from COVID is really only looking at the tip of the iceberg. Beneath that tip of the iceberg lies this hidden toll of disease that we don’t really talk about that much.”

 

Ziyad Al-Aly, chief of research at the VA St. Louis Healthcare System and clinical epidemiologist at Washington University in St. Louis

On the face of it, it doesn’t make sense. Once you get infected by a pathogen, your body should be better prepared to deal with it the next time it comes around. After all, now you have all these memory immune cells ready to alert the immune system to pounce on the invader and quickly wipe it out. Except it doesn’t appear to be working that way for many people. Instead of being better at fighting off the invader, they’re getting more hammered by it the second (or third or fourth) time around.

Pathogens

After an initial infection, our immune system should be primed to more effectively fight off a re-infection. That doesn’t appear to be happening with COVID.

Thus far, the study evidence is limited, but that’s the direction it’s pointing at and Ziyad Al-Aly’s Veteran’s Administration studies have been leading the way. While they focus more on a male, older, and not-as-healthy population they are large and rigorous and have made it into some of the top scientific journals in the world. His latest study, “Postacute sequelae of COVID-19 at 2 years“, found that the more times a person had been infected by the coronavirus, the worse off they tended to be.

Al-Aly spelled out his conclusions in a recent interview with Stat News:

“If you’ve had Covid previously and dodged a bullet and did not get long Covid the first time around and you’re getting another infection now, you’re pretty much trying your luck again. If you had long Covid before, upon reinfection there is a risk of worsening problems. You may have had brain fog and fatigue but not dysautonomia or other manifestations.”

Al-Aly’s findings were recently buttressed by a RECOVER preprint, “SARS-CoV-2 Reinfection is Preceded by Unique Biomarkers and Related to Initial Infection Timing and Severity: an N3C RECOVER EHR-Based Cohort Study“. This study, which focused on a younger and healthier population with more females, found that most of the people who were severely affected by the second infection had had a mild initial infection and that getting infected again was associated with an elevated risk of coming down with long COVID. (Note, though, that it’s also possible that doctors are assigning long-COVID diagnoses more).

A Liver Aside – Interestingly, given recent indications that the liver may play a role in ME/CFS, the study found that lower levels of albumin – a factor produced by the liver – were associated with reinfection. Albumin, interestingly, prevents fluid from leaking out of the blood vessels and leaky blood vessels could be contributing to the low blood volumes and low preload found in ME/CFS and long COVID.

AI to the Rescue? AI-Driven ME/CFS Project Unearths Clues Ahead of its Time

While these are long COVID studies, they suggest that the more times a person gets exposed to pathogens, the more likely they may be to come down with a post-viral illness or have their post-viral illness worsen.

The tendency to get re-infected; i.e. have a noticeable COVID-19 re-infection, or simply come down with more colds, suggests that an immune hole that predisposes one to long COVID, or ME/CFS, or other post-infectious diseases, may be present. Distinguishing that hole is a major goal of long-COVID research.

These findings, of course, also suggest that our population, in particular, should be as rigorous as ever about wearing masks as the most high-risk time of the year – the winter – is upon us.

Health Rising’s Re-Infection Poll

(We don’t know that everyone with ME/CFS has a post-infectious illness but given the findings indicating that people can get long COVID without ever experiencing a COVID-19 infection, for the purpose of this blog and others, I’m going to assume that everyone with ME/CFS has a post-infectious illness.)

Health Rising’s Re-Infection Poll builds on the findings thus far, to ask if the tendency to have more or less colds has any effect on these diseases. Do people who get these diseases tend to have more colds than usual prior to becoming ill? How about after becoming ill? After getting ill, are they affected more by immune events like colds? Also, is having more colds prior to becoming ill a risk factor for having a more severe illness?

Some other interesting tweaks to the long-COVID / post-infectious disease saga have recently shown up.

THE GIST

  • On the face of it, it doesn’t make sense. Once you get infected by a pathogen, your body should be better prepared to deal with it the next time it comes around, but instead of being better at fighting off the invader, people with long COVID are getting more hammered by it the second (or third or fourth) time around.
  • Al-Alym a Veteran Administration epidemiologist, wrote, “If you’ve had Covid previously and dodged a bullet and did not get long Covid the first time around and you’re getting another infection now, you’re pretty much trying your luck again. If you had long Covid before, upon reinfection there is a risk of worsening problems. You may have had brain fog and fatigue but not dysautonomia or other manifestations.”
  • These findings, of course, also suggest that our population, in particular, should be as rigorous as ever about wearing masks as the most high-risk time of the year – the winter – is upon us.
  • Health Rising’s Re-Infection Poll builds on the findings thus far, to ask if the tendency to have more or less colds has any effect on these diseases. Do people who get these diseases tend to have more colds than usual prior to becoming ill? How about after becoming ill? After getting ill, are they affected more by immune events like colds? Also, is having more colds prior to becoming ill a risk factor for having a more severe illness? (Check it out in the blog).
  • A study of over 2,000 college students found that most of the students (66%!) who developed long COVID were asymptomatic at the time they were infected; i.e. before they developed long COVID, they weren’t even aware they had been infected (!).
  • Plus, a recent small study suggests that many people who are barred from participating in long-COVID clinics because they lack a positive COVID test at the time of infection nevertheless have long COVID. The study, which assessed T-cell and antibody responses to the virus, found that 41% of the patients tested had been exposed to the virus.
  • These findings suggest that large numbers of people either don’t know they have long COVID and/or aren’t getting even minimal treatment for it.

The Pandemic Within the Pandemic

“Long Covid is really a pandemic within the pandemic,” Igor Koralnik, Division chief of neuroinfectious diseases and global neurology at Northwestern Medicine.

A study of over 2,000 college students found that most of the students (66%!) who developed long COVID were asymptomatic at the time they were infected. I don’t believe this kind of study has been replicated, but if validated, it indicates that many people with PEM, fatigue, sleep issues, brain fog, etc. who do not believe they had an infectious onset may have had one.

Plus, a recent small study suggests that many people who are barred from participating in long-COVID clinics or studies or have not received recognition from their doctors because they lack a positive COVID test at the time of infection nevertheless have long COVID. All it took was a bit deeper dive. The study, which assessed T-cell and antibody responses to the virus, found that 41% of the patients tested had been exposed to the virus.

Put these two factors together – an asymptomatic response to the virus that can result in long COVID – resulting in potentially hidden cases of long COVID – with the fact that many people without a positive COVID test but who have long COVID cannot get into a long-COVID clinic – uncovers a massive number of people who aren’t receiving even minimal care nor having their illness acknowledged by the medical system.

Koralnik, the author of the study, noted the distress caused by the medical system’s failure to correctly identify these people.

“They felt sometimes very disenfranchised or gaslighted even, because people told them, it’s all in your head, it’s stress, anxiety, it’s going to get better, you can do yoga and relaxation. But in fact we can show that at least 40% of this small sample were really exposed to the virus. So it would be vindicating for those people to know that one.”

Al-Aly – who with his VA studies has raised the visibility of long COVID considerably – stated that not having a diagnosis:

“doesn’t make the disease any less real. We have a crisis on our hands. But unfortunately, in a lot of ways it’s really invisible to the average person on the street, because a lot of these long Covid patients who are actually severely impacted are in bed or at home.”

 

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