I have my first case of Covid. I tested positive just a few hours after I thought “uh oh.” Rapid antigen tests miss real infections disturbingly often, but they don’t hallucinate Covid. A positive RAT is almost never wrong.1
And it’s just clearly not a normal cold or flu. As of the fifth day, my illness has been 90% pain, malaise, fatigue, and only about 10% typical cold symptoms — and I’m wondering if Covid’s notorious sore throat and cough might still come for me. Covid stories are amazingly diverse. It seems like almost anything is possible.
And yet, predictably, my SARS-CoV-2 infection began with the aching. What’s that about? Seems like there might be something there for a pain science blog to look into …
Most of the infections I have ever had have begun with that nasty aching. It’s like a biological tradition for me, as predictable as Old Faithful, or Elon Musk screwing up Twitter in strange new ways. It is roughly proportionate to the overall severity of the infection. So for years now I have been dreading how it might go with Covid.
Badly. It’s going badly. The aching has been severe.
It has also been eerily similar to the chronic pain I usually suffer from, without any infection at all (or none that I know of). So this is a good opportunity to talk about the overlap between the phenomenon of infection aches and other kinds of chronic pain, and what they probably have in common: the mechanism of neuroinflammation.
But I am too sick write an entire fresh post in my current condition, so how about a relevant re-run instead? What I’m experiencing right now with Covid is a dramatic example of neuroinflammatory-powered sensitization, a topic I first explored in 2019. Not many current subscribers will have seen this content in the first place … plus I’ve done some updating (of course).
Overlap between infection aches and chronic pain
Not everyone gets the infection aches — something I was very surprised to learn at some point many years ago. But most of us have had the displeasure, and almost everyone lives through it eventually. It’s a distinctive sensation, and strikingly similar to post-exercise muscle soreness, and to the widespread aching routinely suffered by many people with fibromyalgia and other puzzling chronic pain.
I know it all too well from my own years of struggling with chronic pain. I haven’t had even one infection since before the pandemic, so it has been four years since my last chance to compare infection aches to my every day pain … and I am amazed all over again by the strength of the resemblance. My acute Covid pain over the last few days has been qualitatively identical to my chronic pain. The Covid version is stronger, but not by all that much.
What do they have in common? Why does the aching that often precedes infections feel exactly like some other common kinds of chronic pain?
It’s probably not a coincidence. They are likely powered by the same thing: neuroinflammation. An inflamed nervous system! Which sounds like sensationalistic nonsense preceding a sales pitch for something that puts out the fire, but bear with me (and there’s nothing for sale). The nervous system gets inflamed for many reasons, but the result is similar, and neuroinflammation is probably a major shared mechanism of misery in several kinds of puzzling chronic pain and illness.
An uncomfortable feature, not a bug
That gross feeling of exhausted fragility causes sickness behaviour, a constellation of disabling symptoms that happen in all animals as a normal response to threats to our overall health.2 It is a highly “conserved” trait, which is a biologist’s way of saying that it’s too important for any organism to evolve away from. Critters have probably been getting neuroinflamed for as long as there have been critters (about 600 million years).
Just like a fever, sickness behaviour is a defensive reaction imposed on us by our immune system for our own good. It’s not a random side effect. That feeling has a functional purpose: it forces rest and isolation. “No foraging this week!”
In modern medicine, sickness behaviour has traditionally been defined as a response to major infections, but it’s clearly not limited to that. It also fires up after major injuries, for instance. After my wife’s terrible accident in 2010 — a major brain injury and spinal fracture, plus several other less serious fractures and lacerations — a doctor warned her not to underestimate how profound and prolonged her fatigue would be, and indeed she was utterly exhausted for a good year. Healing is metabolically expensive, and so we need rest after major injuries.
Neuroinflammation is specifically how our bodies guarantee that the resting happens.
Recent research is revealing that neuroinflammation is kind of a big deal, an elaborate generalized response to almost any kind of major biological stress.
A response that can get out of hand, much like pain.
When neuroinflammation goes wrong
The most obvious examples of sickness behaviour are probably not the only examples. They are almost certainly the tip of an iceberg of subtler examples. Neuroinflammation probably has many forms and triggers, and may go wrong in sneakier ways than is generally appreciated.
Neuroinflammation is a driver of “sensitization” — lowering the pain threshold — which is specifically how it produces that “fragile” feeling. This has an obvious role to play in sickness behaviour, a fine example of “how the body says no.”3 This link has not been firmly established yet, but science is closing in, and we already know for sure that chronic widespread pain is closely linked to sensitization. So sensitization bridges the gap between the clinical problem of chronic widespread pain and the biological mechanism of neuroinflammation, and so “neuroinflammation drives widespread chronic pain via central sensitization.”4
Why chronic, though? The most obvious way that neuroinflammation can go wrong is to drag on. Once it starts, it might be somewhat self-sustaining, a perpetual malaise machine, obnoxiously persisting even without an ongoing threat. This is actually one of the top Long Covid theories: the neuroinflammatory process spins out of control (“immune dysregulation”), and just won’t wind down when the infection is over.5 It’s a strong hypothesis.
If that’s what’s going on with Long Covid, then it’s probably also what’s happening with a lot of ME/CFS and fibromyalgia.6
It’s not too surprising that a fierce viral infection might knock the immune system off kilter. But sickness behaviour may also have some dysfunctional triggers…
For instance, in humans, neuroinflammation could be caused just by perceived threats to health — by psychological stress. Humans are much better at imagining threats than cats or capybaras (or zebras, which is “Why Zebras Don’t Get Ulcers”7). And certainly psychological distress is linked to inflammation. The most relevant example is that people with PTSD have more neuroinflammation.8 Since PTSD is defined by the inability to stop perceiving, remembering, and re-living serious threats, it’s a particularly good place to look for signs that it drives neuroinflammation.
That is all highly speculative, and there are some serious problems with blaming the mind for neuroinflammation.9 But it remains a disturbing and intriguing possibility.
- Soni A, Herbert C, Lin H, et al. Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection : A Prospective Cohort Study. Ann Intern Med. 2023 Jul;176(7):975–982. PubMed 37399548 ❐ PainSci Bibliography 51627 ❐
This study compared the results of both rapid antigen tests and PCR tests in many people from the middle of the pandemic, late 2021. Subject were asked to do both kinds of tests if they felt sick, or just suspected exposure. For symptomatic patients testing a single time, the widely available RATs were positive for about 60% of COVID infections, as confirmed by more sensitive PCR test. A second RAT (2 days later) bumped that up to about 92%, and a third RAT (another 2 days later) pushed the sensitivity slightly higher to 94% — which sounds pretty good, but even three tests spread out over a week missed 6% of actual infections.
That’s one in sixteen cases of COVID that never turned up on any of three RATs — several study participants, and probably millions of people in the wild.
For asymptomatic infections, RAT sensitivity of a single test was comparable, but it improved much less with repeated testing, maxing out at 79% — leaving more than 20% of actual infections undetected. So you just can’t use a RAT to be sure that you don’t have a sneaky infection (but you can confirm one).
As fully expected, false positives just don’t happen: they didn’t pick up a single one.
- Lyon P, Cohen M, Quintner J. An evolutionary stress-response hypothesis for chronic widespread pain (fibromyalgia syndrome). Pain Med. 2011 Aug;12(8):1167–78. PubMed 21692974 ❐
- I am using the phrase “how the body says no” more literally here than its traditional meaning. It is usually deployed to emphasize the connections between minds and bodies, specifically how stress and emotional repression manifest a refusal to continue functioning properly (illness). This perpetually popular notion surely has some seeds of truth in it … which keeps it alive and abused by alternative medicine, constantly suggesting to sick people that they are the authors of their own poor health. But I’m talking about how effectively neuroinflammation *shuts us down*, preventing normal behaviour and literally creating the *feeling of sickness* in response to major physiological stresses.
- Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology. 2018 08;129(2):343–366. PubMed 29462012 ❐ PainSci Bibliography 52332 ❐
- Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023 Mar;21(3):133–146. PubMed 36639608 ❐ PainSci Bibliography 51215 ❐ One of the major outstanding mysteries is whether it’s truly “dysregulation” — excessive and unnecessary — or whether there’s actually still a good reason for the neuroinflammation, such as viral persistence, or even just subtle but extensive damage. Maybe people with Long Covid still feel sick because they *are* still sick.
- Albrecht DS, Forsberg A, Sandström A, et al. Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation. Brain Behav Immun. 2019 Jan;75:72–83. PubMed 30223011 ❐ PainSci Bibliography 52325 ❐
- Sapolsky RM. Why Zebras Don’t Get Ulcers. 3rd ed ed. New York: Times Books; 2004.
- Lee DH, Lee JY, Hong DY, et al. Neuroinflammation in Post-Traumatic Stress Disorder. Biomedicines. 2022 Apr;10(5). PubMed 35625690 ❐ PainSci Bibliography 51625 ❐
- Woodburn SC, Bollinger JL, Wohleb ES. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation. 2021 Nov;18(1):258. PubMed 34742308 ❐ PainSci Bibliography 52006 ❐
True, full-blown neuroinflammation is defined by some well-known physiological characteristics, and it is unlikely to occur even with severe psychological stress, if at all. Even if stress can provoke partial neuroinflammation or something similar-but-different, it might be a bit ridiculous to call it “neuroinflammation,” in the same way that rusting metal is technically “combusting” but it is not “on fire.” No stress that most people will ever deal with is likely to to cause the same degree (and maybe not the same kind either) of total immune system freakout that we see in people who are nearly killed by injury or illness. Woodburn et al:
“Preclinical research demonstrates that neuro-immune responses to stress are distinct from CNS disease, injury, or infection and should not be characterized as neuroinflammation.”