A transient flare-up of Long Covid symptoms triggered by cell stress

     A transient 2 hour to 3 day flare-up of Long Covid symptoms, typically strongest in the evening.  Any and all of the diverse Long Covid symptoms may increase a step or two in their severity during a flare-up. For example, a mild gut ache/bloated feeling may increase a step in severity to become a moderate gut ache.  Moderate head pressure may increase to serious head pressure.   Serious muscle aches and joint pains may become severe.   Sometimes old, mostly forgotten long covid symptoms reappear. For example, Long Covid associated tinnitus may only occur during the increased inflammation of a Verx.  Kidney pressure, heart aches, and gall bladder duct pains may also be felt by some long haulers during their Verx.  Neurocognitive issues such as brain fog, difficulty processing visual information, sensitivity to light and sound typically increase during a Verx.  Increased cranial nerve soreness as felt in various regions of the neck, throat, base of the skull, behind the eyes, and in the temples and scalp may also occur.

One long-hauler’s strong verx: “44 hours into my water fast, I had a flare up and it continued for several days afterwards. During the day, I had a full flare up; headache, dizziness, extreme fatigue, heart palpitations, headache etc. This flare-up was intense for 24 hours, then came in 6-8 hour waves over the next 3 days.”

     With a 36 hour water fast, one-third of long haulers report experiencing a Verx in the evening, while one-half experience a Verx the day of refeeding.  About 1 in 10 experience a more prolonged flare-up of symptoms following their first water fast, sometimes lasting as long as 2 or 3 days.  Besides fasting, many other things induce the Verx reaction in Covid long haulers.   Resveratrol is a well-known plant polyphenol found in the skin and seeds of red grapes.   Like fasting, it has been shown to induce the internal cellular “housecleaning” pathway known as autophagy in basic cell research(Park et al., 2016).  Just 600 mg, the standard dose for many Resveratrol supplements, taken in the morning will trigger an early evening Verx reaction in most long-haulers. Anecdotally, even certain foods, medicines, and medical procedures may trigger a Verx.   Dark chocolate, salmon, kefir, olive oil, statins, and MRIs with contrast dye (Gadolinium) have all been reported to cause symptom flare-ups in long haulers.

Similarities and differences from the Jarisch–Herxheimer reaction (aka Herx)

 “The Jarisch–Herxheimer reaction (JHR) is a transient immunological phenomenon seen commonly in patients during treatment for syphilis, and it manifests clinically with short-term constitutional symptoms such as fever, chills, headache and myalgias, besides exacerbation of existing cutaneous lesions. “(Belum et al., 2013)  The Jarisch-Herxheimer reaction is known colloquially as a Herx. The general public often use the term Herx, especially in the chronic Lyme disease community.  Interestingly, the Syphilis pathogen and the Lyme’s disease pathogen are both gram-negative bacteria in the spirochete class.  Both have immunostimulatory Lipopolysaccharide (LPS) cell walls.  Like the Herx, a Verx is also a transient immunological phenomenon normally resolving withing 24 hours.   The Herx is considered a transient strong immune reaction triggered by the sudden die-off of spirochete bacteria in response to treatment with antibiotics.   In contrast, I propose that the Verx is a transient strong antiviral immune reaction.  The Verx may be triggered by the increased antigen presentation of viral protein fragments on the surface of infected cells.  While the sudden increase in symptoms of the Herx reaction is thought to reflect activation of immune responses via extracellular pathogen sensors or PAMPs. The best studied pathogen sensor may be the TLR4 receptor which activates innate immunity in response to Lipopolysaccharides (LPS) of gram-negative bacteria.   Meanwhile, the Long Covid flare-up of the Verx may reflect increased degradation of SARS-CoV-2 viral proteins within infected cells and increased antigen presentation of viral fragments on the cell surface.   Natural Killer cells and Cytotoxic T Cells may then suddenly “see” virally infected cells and take appropriate antiviral actions.  In both the Herx and the Verx, the severity of the increased immune response likely reflects the severity of the infection in the body.  Anecdotally, as long haulers recover, the severity of their Verx reactions gradually decreases.  Certainly, that was my personal experience in the Fall of 2020 as I was self-treating with periodic dosing of Resveratrol, olive oil, short water fasts, molecular hydrogen, omega3 fish oil, niacinamide and other potential autophagy inducers.

Distinguishing between a Verx, normal fluctuations and Relapses

Of course, not every sudden increase in symptoms should be considered a Verx.   Many long haulers observe a daily fluctuation in the severity of their symptoms.   Some, such as joint pain or muscle aches may be consistently worse upon waking.  Others, such as brain fog and head pressure may consistently be worse in the evenings.   Attending a social event or cleaning house may trigger a severe increase in fatigue the next day… this “Post-exertional malaise” is common in long-haulers and should not be considered a Verx.  Changes in temperature or just the simple act of standing can sometimes make dysautonomia symptoms worse.   Finally, driving, watching TV or too much screen time may tax the visual processing systems of the brain causing neurocognitive symptoms to worsen. 

Significant relapses can also cause sudden increases in Long Covid symptoms.   Sometimes these have a likely cause such as severe emotional stress, other times, there is no apparent reason for the relapse.  In contrast with a Verx, the new symptoms or increased severity of symptoms during a relapse tend to persist for weeks or months.  I posit that relapses reflect increased viral replication or viral activation due to a decrease in antiviral immune containment.  Brand new symptoms may reflect viral infection of new cell types and tissue.   For example, I lost my sense of smell three months after my initial Covid-19 infection.   Certain physiological stresses, such as strenuous exercise may also cause relapses.    The increased oxidative stress associated with exercise may somehow signal latent virus to activate and replicate.   Other oxidative stressors such as drinking alcohol, consuming sugar in the form of birthday cake or eating a glazed donut have also been reported to cause a sudden increase in symptoms.

Hypothesis: 

The increased aches and pains during a Verx directly reflect sites of low-level persistent viral infection.

There is now strong evidence for low-level SARS-CoV-2 viral persistence in those with Long Covid.   This includes detection of SARS-CoV-2 mRNA and proteins in many tissues of the body via biopsy.  The gut or small bowel(Gaebler et al., 2021)

Autopsy studies further demonstrate viral persistence in the lungs of post-acute Covid patients  (Schwartz et al. 2022 preprint)   In the large NIH, University of Maryland Covid-19 autopsy study, Stein et al describe how the SARS-CoV-2 viral mRNAs and proteins can be detected at low levels in a tremendous variety of cell types and tissues outside of the lungs(Stein et al., 2022).  One of these autopsies was performed 126 days post initial infection.   Besides the lung, infected tissues include the gut, appendix, colon, liver, pancreas, heart, testis, ovary, uterus, adrenal gland, thyroid, muscle, skin, sciatic nerve, ocular tissue, optic nerve, olfactory nerve, cervical spinal cord, and many parts of the brain.  Another Covid-19 autopsy study also found SARS-CoV-2 in the blood vessels (Bhatnagar et al., 2021).  Not coincidentally, the biopsy and autopsy results generally correlate well with the known distribution of ACE2 receptors in the body. ACE2 is predominantly expressed in the small intestine, adipose tissue, kidney, heart, respiratory system, and, to a limited extent, in brain (Alifano et al., 2020). ACE2 is the main cell surface receptor that the SARS-CoV-2 spike proteins bind to gain access to the inside of cells.  Where do long-haulers feel their VERX symptoms?  That is variable from person to person, just like the locations of the virus are variable between individuals in the Covid-19 autopsy study (Stein et al., 2022). Common Long Covid flare-up symptoms include: worse head pressure, increased sensitivity to light and sound, increased brain-fog and decreased cognitive functions, heart pangs, chest pressure, joint and nerve pains, gut tightness and a bloated feeling, etc. These “verx” symptoms match known or suspected sites of viral persistence remarkably well.