The researchers examined how common chronic viruses can “wake up” (reactivate) during and after severe COVID-19, and how this relates to illness severity and certain Long COVID symptoms.

Here is a patient-friendly overview of the key points.

Study Methods

The research used data from the IMPACC study (Immunophenotyping Assessment in a COVID-19 Cohort), a large, carefully designed project that followed 1,154 adults who were hospitalized with COVID-19 across 20 U.S. hospitals between May 2020 and March 2021. None of the participants had received a COVID-19 vaccine at the time of enrollment, as vaccines were not yet widely available.

Researchers collected samples repeatedly, up to 10 times over a full year after hospital admission.

These included:

• Blood (specifically immune cells called PBMCs)

• Nasal swabs

• Lung secretions (from patients who needed mechanical ventilation, called endotracheal aspirate)

They used multiple advanced laboratory techniques to look at:

• Viral genetic material (transcripts) showing active virus activity

• Immune cell profiles

• Inflammatory proteins (cytokines)

• Metabolic and protein changes in the blood

• Antibody levels to certain viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV)

This multi-layered (“multi-omic”) approach allowed them to track both the viruses and the body’s responses over time.

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They refer to this hypothesis as the “virtual hypoxia (low oxygen)” hypothesis.

We must first understand the relationship between energy production and oxygen levels before learning about their hypothesis in detail.

Background

Oxygen Consumption and Energy Production in the Brain

The cellular demand for oxygen is highest in the brain, which is only 2% of the body’s total mass yet consumes 20% of the body’s energy.

In general, this occurs using:

1. Glucose (dietary sugar)

2. Oxygen (O₂)

3. Mitochondria

These three ingredients enable your cells to efficiently produce adenosine triphosphate (ATP), the energy currency your enzymes use to supercharge catalytic reactions.

Energy Production With and Without Oxygen

What happens when one of these ingredients is missing, like oxygen or the mitochondria?

Well, ATP is still produced in the absence of oxygen. It can also be made without functional mitochondria. However, this form of sugar metabolism is a very inefficient way of making ATP and results in the production of a metabolic waste product called lactate.

Okay, back to the “virtual hypoxia (low oxygen)” hypothesis.

The ME/CFS Brain

If there is one buzzword every ME patient has heard along their patient journey, it’s the term mitochondrial dysfunction. This is (partly) what sparked the “virtual hypoxia (low oxygen)” hypothesis, which is the knowledge that:

1. The brain’s mitochondria consume a large amount of oxygen relative to other tissues in order to efficiently make energy.

2. The mitochondria in those with ME/CFS are dysfunctional.

Thus, the ME/CFS brain should behave as if they are chronically oxygen-starved, even when oxygen is readily available, due in part to mitochondrial dysfunction.

Lactate Levels in ME/CFS

We mentioned that converting sugar into energy without oxygen is not only highly inefficient (producing less ATP) but also produces lactate as a metabolic byproduct.

In healthy people, spikes in lactate are transient and occur only during exercise due to the increased oxygen demand from the muscles. However, in those with ME, blood lactate levels correlate with the severity of post-exertional malaise (PEM) even at rest.

This increase in lactate occurs when ample oxygen and glucose are present, suggesting the culprit is mitochondrial dysfunction. However, it’s unknown where in the brain metabolism is dysregulated, if at all. Therefore, the purpose of this featured study is to determine:

1. Is it also true in the brains of ME patients at rest?

2. If so, what brain regions are most affected?

Okay, now we can move on to the study.

The Study Details

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Continuous lactate monitoring, for example, could give patients with post-exertional malaise objective feedback on metabolic stress, such as mitochondrial dysfunction, helping them pace more effectively and potentially reduce the severity of crashes.

Yet many other molecules that are critical to our health remain invisible in real time. Molecules that:

1. Must be kept in a tight equilibrium

2. Lack clear signs that the equilibrium has become moderately dysregulated

3. (When dysregulated) lead to the progression of chronic disease

A perfect example is inflammation, specifically pro-inflammatory cytokines.

These molecules fine-tune inflammatory responses to protect us from pathogens and cancer. However, prolonged inflammation can be just as harmful as an insufficient inflammatory response. One can cause autoimmunity and other chronic inflammatory conditions, while the other can impair control of infections, especially latent infections, causing serious health complications.

Imagine if we could monitor inflammation in the body in real time. It could not only help patients understand which daily-life variables modify the inflammatory burden but also produce rich, frictionless datasets that would help researchers better understand the role of inflammation in our physical and mental health.

In this article, I will describe how Northwestern University researcher Shana O. Kelley and colleagues developed a molecular-pendulum biosensor that enables continuous, real-time monitoring of key pro-inflammatory cytokines. Their work demonstrated the capability to measure interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in living animals, marking the first time such continuous in-tissue tracking of these inflammatory markers was achieved with rapid sensor reset.

Here is how it works.

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However, what we didn’t reveal is that a subset of these cases can present as dementia without these classic AE symptoms. This suggests there is a separate category of dementia not caused by old age-driven neural degeneration. In 2010, Dr. Sean Pittock and colleagues at the Mayo Clinic coined the term autoimmune dementia to describe cognitive decline attributed to autoimmunity.

Here is the good news. The research suggests that early identification and treatment of autoimmune dementia can reverse the memory decline. The bad news is misdiagnosis is far too common.

In this article, we will teach you the signs and symptoms of autoimmune dementia to help you advocate for proper testing and better outcomes for yourself or a loved one.

How Common is Autoimmune Dementia?

Data describing the prevalence of this form of severe memory decline are still being collected. However, one Dutch nationwide observational cohort study assessing all AE cases between 1999 and 2019 found that 38% (67/175 cases) of patients with autoimmune encephalitis met clinical criteria for dementia without classic autoimmune encephalitis symptoms (at early disease onset).

Another study by a Swedish research group approached the question differently. They wanted to know how many individuals visiting a memory clinic were unknowingly suffering from autoimmune forms of dementia. After screening 1021 patients from the clinic for known brain-targeting autoantibodies, they found that 11 patients (1.07%) were positive.

Granted, it’s difficult to extrapolate how many people might have an autoimmune form of dementia based on this one study. But consider that researchers suspect “110 of every 100,000 people age 30 to 64 years, or about 200,000 Americans in total, have younger-onset dementia.” How many of these individuals actually have a misdiagnosed form of autoimmune dementia that is (partly) reversible when treated correctly?

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In this webinar, Dr. Hector Bonilla discusses current perspectives on Long COVID, including emerging evidence on viral persistence, immune dysregulation, the broad spectrum of clinical symptoms, and potential treatment strategies. We also highlight the launch of the Spanish-language version of the unhide® Platform, expanding opportunities for Spanish-speaking patients to track symptoms, contribute to research, and help shape the future of infection-associated chronic condition research.

Whether you are a patient, caregiver, clinician, or researcher, this conversation offers valuable insights into the current state of Long COVID research and why inclusive participation is critical to accelerating scientific discovery.

Watch the webinar below.

The culprit was an autoantibody in her blood that targeted a brain protein called CASPR2. She “got [her] life back” almost immediately after being treated with intravenous steroids.

There are more like Alina.

Take April Burrell, who lived in a psychiatric hospital for 20 years because her catatonic state left her immobile and unresponsive. Thankfully, after 2 decades, she suddenly woke up when clinicians began treating her for a previously unrecognized autoimmune disease.

How many more patients are trapped in psychiatric hospitals who actually have a treatable form of autoimmune encephalitis?

Autoimmune Encephalitis

Dozens of different neuropsychiatric diseases have been identified over the last 15 years, all triggered by an immune attack on the brain, known as autoimmune encephalitis. The consequences of autoantibodies targeting CNS tissue can lead to diverse neurological symptoms, and in some cases, psychosis.

But what if a patient has a brain-attacking autoantibody that is not known to science?

That is where PhIP-seq comes into play.

PhIP-Seq Can Help Researchers Discover Novel Autoantibodies

PhIP-seq technology was developed by Benjamin Larman and colleagues, in collaboration with Stephen J. Elledge’s lab at Harvard Medical School/Brigham and Women’s Hospital.

Years later, the DeRisi Lab at UCSF (including Michael Wilson, Joseph DeRisi, Caleigh Mandel-Brehm, Brian O’Donovan, and others) modified the method to identify novel neurological autoantibody targets in the brain.

Like fishing, this method uses autoantibodies from the patient’s cerebrospinal fluid (CSF) or serum to bind a vast library of over 700,000 human protein fragments localized to the outer surface of viruses that infect bacteria, known as bacteriophages.

What Is PhIP-Seq?

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In this webinar, neuroscientist Dr. Mara Kuvaldina discusses the science of brain fog and why taking a cross-condition approach is essential to advancing research. The conversation also introduces the Brain Fog Study, a collaboration between Columbia University and the Brain Inflammation Collaborative. The Brain Fog Questionnaire (BFQ) was developed to better understand this symptom across conditions, including Long COVID, ME/CFS, Lyme disease, autoimmune diseases, and others.

Whether you are a patient, caregiver, clinician, or researcher, this discussion offers valuable insights into one of the most common symptoms shared across neuroimmune conditions.

Watch the webinar below.