What If POTS, ME/CFS and Long COVID Are Neuroimmune Disorders?

What if conditions medicine once dismissed as 'all in the head' are, in fact, about the conversation between the brain and the immune system?

For decades, people living with postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and, more recently, Long COVID were told their tests were 'normal' and that their symptoms must be psychological. A 2026 narrative review by neurologist Svetlana Blitshteyn, immunologist Taylor Doherty and neuroimmunologist Lawrence Steinman argues for a different framing: these three conditions overlap biologically, and they belong under the umbrella of neuroimmunology, alongside multiple sclerosis (Blitshteyn et al., 2026).

This article translates that review for a general audience. We separate what the research supports from what is still a bold hypothesis, so you can see both the evidence and the open questions.

One overlap, three names

POTS and ME/CFS are the two most common phenotypes of Long COVID, and many patients meet criteria for more than one condition. In a large community survey, at least 20% of people with POTS also satisfied the diagnostic criteria for ME/CFS (Shaw et al., 2019). The shared mechanisms below are what lead the authors to argue these are neighbors, not strangers.

Six threads in the evidence

The review pulls together six mechanisms that keep appearing across all three conditions. None works alone, and researchers are still mapping how they interact.

The numbers behind the argument

A few figures from the review help show how strongly the immune system appears in these conditions. They come from different studies and populations, so they are not meant to be compared with each other.

Sources: Blitshteyn et al. (2026); Larsen et al. (2022); Konstantinov et al. (1996); Shaw et al. (2019).

What if...

This is where the review looks forward. The following ideas are supported by early evidence but are not settled science.

What if the brainstem is a shared control room?

Using 7 Tesla MRI, researchers found structural abnormalities in the dorsolateral medulla of people with Long COVID, and these correlated with symptoms (Rua et al., 2024). This region houses vagal nuclei and vestibular pathways. Blitshteyn (2025) proposes it could also be where POTS originates, whether or not a COVID infection triggered it. This is a hypothesis awaiting confirmation.

What if the nervous system can read threat and call the immune system into action?

The vagus nerve is the core of the inflammatory reflex, a circuit linking the nervous system to immune responses (Pavlov & Tracey, 2012). Insular cortex neurons in mice can store and retrieve specific immune responses (Koren et al., 2021). In humans, simply anticipating infection in virtual reality triggered an immune response, even without physical contact (Trabanelli et al., 2025). What if, in some chronic conditions, this brain-immune dialogue gets stuck in the wrong gear?

What if some patients have an immune phenotype that responds to immunotherapy?

The authors call for studies that test for T-cell exhaustion and other immune signatures in POTS, so researchers can identify subgroups who might benefit from immunotherapies. For now, this remains a research priority rather than a proven treatment (Blitshteyn et al., 2026).

What if energy metabolism is part of the answer?

In a small open-label pilot of 20 people with POTS, six months of time-restricted eating was linked with improvements in upright heart rate, energy and mitochondrial function (Dzotsi et al., 2025). With no control group, this is a signal worth testing, not a recommendation.

Evidence at a glance

The stigma story, and why labels matter

The authors point to a historical parallel. Multiple sclerosis was once labeled hysterical paralysis, until its biological basis was uncovered and it became a recognized neuroimmune disease. They argue that POTS, ME/CFS and Long COVID have traveled a similar road, with patients often misdiagnosed with anxiety, somatization or functional disorders because routine tests came back normal (Blitshteyn et al., 2024; Davenport et al., 2024). Their proposal is that the first step is to stop assuming a psychological cause, and to build neuroimmunology training, consensus guidance and care pathways for these patients.

It is worth noting what this does not say. Recognizing a biological basis does not mean psychological support has no place. It means that suffering should not be dismissed as purely psychological while the biology is still being mapped.

What would change if this view takes hold?

• Diagnosis: a 10-minute standing test instead of a seated vital-sign check, with tilt-table and autonomic testing where available.
• Research: advanced imaging, immune profiling and autonomic testing becoming routine tools rather than rare ones.
• Treatment: new and repurposed immune-modulating or anti-inflammatory therapies tested in well-defined subgroups.
• Training: neurologists and neuroimmunologists equipped to recognize and treat these conditions.

The question is no longer whether the brain and the immune system talk to each other. It is what happens to people when that conversation breaks down, and whether medicine is ready to listen.

This article is an educational summary of a narrative review, not medical advice. If you have symptoms such as a racing heart on standing, lightheadedness or persistent fatigue, a clinician familiar with autonomic disorders can help you explore the options.

References

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Blitshteyn, S., Doherty, T. A., & Steinman, L. (2026). Postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and Long COVID as neuroimmune disorders. ImmunoTargets and Therapy, 15, 581262. https://doi.org/10.2147/ITT.S581262

Blitshteyn, S., Treisman, G. J., Ruhoy, I. S., et al. (2024). Postural orthostatic tachycardia syndrome and other common autonomic disorders are not functional neurologic disorders. Frontiers in Neurology, 15, 1490744. https://doi.org/10.3389/fneur.2024.1490744

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— HeartLabs Team