Notice: I just now found an article, published 16 days before my article, which proposes the same idea: Does coronavirus linger in the body? What we know about how viruses in general hang on in the brain and testicles by Dr. William Petri, Professor of Medicine, University of Virginia. I am certain I did not read or see this article before writing my hypothesis. I will continue to write on this topic, but cannot take credit for it.

Introduction

Longhaulers are Covid-19 patients who continue to have symptoms long after most other Covid-19 patients have recovered. This is sometimes termed “longhauler syndrome”. The Longhaulers Hidden Virus Hypothesis proposes that longhauler syndrome is caused by the Covid-19 virus, SARS-CoV-2, hiding from the immune system in immune privileged cells (IPCs). Periodically, the virus multiplies outside of IPCs, causing the commonly-reported flare ups of symptoms. Then the immune system, which by then has antibodies and T-cells adapted to the virus, suppresses the flare up. In some patients with weaker immune systems, the flare ups may be longer and more severe; in others, the flare ups may be more quickly suppressed. SARS-CoV-2 has multiple ways to evade and strike at the immune system, allowing these flare ups to occur, despite the ability of the adaptive arm of the immune system to recognize and attack the virus.

See the update at the end of the article for a note about ME/CFS and PVFS.

The Hair Loss Symptom

Some Covid-19 longhaulers have noted a peculiar symptom of the syndrome: their hair is falling out. The COVID-19 “Long Hauler” Symptoms Survey Report (7/25/2020) found that hair loss is a common symptom among Covid-19 Survivors, who are also called Longhaulers [1]. Out of 1567 respondents, 423 reported hair loss as a symptom, which is 27% [1].

The loss of hair is a clue to the cause of longhauler syndrome. The “anagen” hair follicles are immune privileged cells (IPCs); they are protected from the immune system. In particular, the term “anagen” refers to the hair follicles when they are in the process of active growth. Suppose that the virus is hiding in these immune privileged cells, protected from the immune system. Then the presence of the virus would disruption the cells during this anagen stage, causing the hair loss.

What other cells are immune privileged? The Central Nervous System (CNS) cells are immune privileged. The virus could also, and actually primarily, hide there, in the CNS. And this is the hidden virus hypothesis — the disease Covid-19 continues long-term because the virus is hiding in IPCs.

CNS Symptoms

Central Nervous System (CNS) complaints are a common set of symptoms reported by longhaulers. The Covid-19 Symptoms Survey Report [1] included the following CNS symptoms, in order of frequency: difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness, partial or complete loss of sense of smell, blurry vision, confusion, and irritability [1, figure 2]. (The olfactory and optic nerves are considered part of the CNS.)

In fact, it would be nearly impossible to find a substantial number of longhaulers who do not have CNS symptoms. It is the most common feature of longhauler syndrome. And this means that the longhauler syndrome is essentially a CNS disease, with additional complications in multiple organ systems.

But isn’t Covid-19 a disease of the lungs? Actually, the ability of SARS-CoV-2 to directly infect neurons in the brain is well-established [12], and Covid-19 often includes severe CNS symptoms in Covid-19 [13].

Another survey of longhaulers — this one by the “Patient-Led Research Team,” which developed out of theBody Politic COVID-19 Support Group on Slack — also reported many CNS symptoms [2]. The report states the following:

“Neurological symptoms are being underreported in the media. These include brain fog, concentration challenges, memory loss, seizures, dizziness and problems with balance, various forms of insomnia, and others. Brain fog and concentration challenges were a more common symptom than cough during most weeks, as was insomnia.” [2, p. 4]

Longhauler syndrome differs from the ordinary type of Covid-19 in that CNS complaints dominate the pattern of symptoms. In Covid-19, that is, in persons who recover fairly quickly, the virus usually presents as an upper respiratory disease, with or without pneumonia, depending on severity. In some persons, Covid-19 may also present as a gastrointestinal disease, with vomiting, diarrhea, and abdominal pain as the main complaints. And this GI pattern of Covid-19 is sometimes devoid of major respiratory symptoms. But these different types of Covid-19 usually recover fairly soon.

By comparison, longhauler syndrome is a version of Covid-19 that affects the immune privileged cells (IPCs), mainly the CNS and often this also includes the anagen hair follicles. The reason that longhauler syndrome is primarily a CNS disease is that the virus is partially protected from the immune system there. The disease is able to continue for the long haul because the virus has established a stronghold in the IPCs.

Therefore, the hypothesis is proposed that Longhauler Syndrome is a version of Covid-19 that infects the immune privileged cells.

Fluctuating Symptoms

If longhauler syndrome is primarily of IPCs, especially the CNS, then why are there still many symptoms of the lungs and other organs outside of immune privileged cells, outside of the CNS. The virus uses the CNS as a stronghold, and from that hiding place, the virus multiplies and soon re-infects other areas of the body. This causes the wider range of symptoms that is seen in the syndrome.

But the symptoms most often show a pattern of fluctuations, a rising and falling of degree and type of symptoms over time. In the Symptoms Survey by Patient-Led Research Team, 89% of the respondents reported that “symptoms fluctuated in intensity and frequency” [2].

“A survey participant summarized the fluctuations of symptoms commonly shared by many
COVID-19 patients as follows: ‘The symptoms were like a game of whack-a-mole. Different ones would surge at different times and in different places in my body.’ ” [2, p. 17]

The LHV Hypothesis explains this feature of longhauler syndrome. The virus remains protected in the IPCs, and then it periodically multiplies and reaches into the non-protected areas of the body. But now the adaptive arm of the immune system has developed T-cells and antibodies that can recognize and fight the virus. Therefore, these forays outside of the CNS are temporary. There is a rise of symptoms, until the immune system suppresses the virus again, forcing it back into hiding, and causing a subsequent fall of symptoms. This pattern of a rise and fall of symptoms is mainly of the non-CNS (or more precisely, the non-IPC) symptoms.

The process continues over the long haul because of two factors. First, substantial protection is afforded by IPCs. Second, SARS-CoV-2 has a phenomenal ability to evade and disrupt the immune system, even after it has adapted its antibodies and T-cells to the virus. See the article “How Covid-19 Attacks your Immune System”.

In summary: The N-protein turns off the RNA silencing system inside cells [7]. The N-protein also suppresses Interferon type I (IFN), disrupting the response of the immune system to the viral infection [8]. In addition, the two viral proteases (Mpro, PLpro) cleave three immune system proteins (IRF3, NLRP12, TAB1), causing two effects. First, the response of the innate arm of the immune system is blunted. Second, the inflammatory response is increased, by enhanced production of Interleukin-6 [9]. Then, the Spike protein is covered in sugar chains (glycans) which shield the Spike from antibodies [10, 11]. The strong ability of the virus to fight against the immune system allows these repeated forays into non-protected regions of the body from its immune privileged hiding places.

Testing

Many respondents in the Patient-Led Survey reported not having been tested (47.8%), 25.5% because they were denied testing [2]. Of those who were tested, 54% were negative and 46% were positive [2, p. 12]. The explanation for the large percentage who tested negative is that the virus is hiding in the CNS, and is often not present in the throat, which is the source of the testing swab. Some patients do test positive, because the virus periodically flares up, and affects the upper and lower respiratory systems during that flare up.

Gender

It remains to be seen whether longhauler syndrome is found more often in men or in women. While 76.6% of the Patient-Led Survey respondents were women, this could be due to a bias in how likely women are to respond to a survey, especially one recruiting from social media longhaulers’ groups. It is worth noting, though, that one study of CNS symptoms found that “Female patients younger than 65 years old were more
likely to have neurological symptoms” [13]. That result in the study did not reach statistical significance. So further research is needed on this point. But it has been established that men are more likely to have a severe case of Covid-19 and are more likely to die from it. Thus, gender may be a factor. If men are more likely to have a severe case, women might be more likely to have a moderate case that continues indefinitely. Perhaps.

Why Some Persons and Not Others?

Why do some patients become longhaulers, while most others do not? It’s not a different strain of the virus, otherwise we’d see clusters of longhaulers in families or among co-workers. One person gets longhaulers, while those around him or her recover. Likely factors include high initial viral load, absence of early treatment, multiple changing treatments over time, and a weak immune system. There is also an element of chance, in that the virus must become established in certain cells before the immune system clears the body of the virus completely. Then it can hide, flare up, and hide again.

Final Thoughts

First, let me emphasize, this is only an hypothesis. It is not a proven fact, nor is it a theory with support from experimental evidence. The hypothesis is subject to criticism and possible revision or retraction. Second, further research is needed specifically on the phenomenon of “longhaulers”.

Third, if however the hypothesis turns out to be correct, it means that longhauler syndrome can be successfully treated. For if the cause is the virus hiding in immune privileged cells, then clearing the virus is likely to resolve the symptoms and bring the syndrome to an end.

Indeed, some physicians report working with Covid-19 patients and successfully treating longhaulers syndrome. So there is hope. I do not believe that longhaulers is caused by permanent damage to the body, such that it would be intractable. Rather, I believe it is merely a question of finding the right treatments, so as to attack the virus within the CNS. Such a treatment should be highly bioavailable, be able to cross the blood-brain barrier, and be able to enter cells so as attack the viral components within the cytoplasm.

I am planning an article of suggested treatments to be tested in clinical trials. I do not do clinical trials myself. I would simply propose a trial to test a suggested treatment, once I study the subject further.

“If I have Longhaulers Syndrome, what should I do?” Find a physician who is willing to work with you, to try various treatments, and figure out what works in your case. Steroids, natural viral inhibitors, and supporting the immune system with vitamins and minerals are among the options.

Peace and healing to everyone.

Edited on 8/17/2020 (4:15 pm ET) to add: the reason some treatments don’t work against longhaulers syndrome may be that the medications do not permeate the blood-brain barrier and/or do not reach the infected IPCs.

Edited on 8/17/2020 (7:51 pm ET) to add: So it seems that ME/CFS has many of the same symptoms as longhaulers syndrome, as many sufferers of ME/CFS are pointing out. “Why should we be concerned about ME/CFS after COVID-19? One reason is that prior studies of SARS, MERS, West Nile virus and even Ebola show long-term symptoms akin to those seen in ME/CFS in the aftermath of acute infection, ranging from 11%-90%.”[14] So Longhaulers syndrome has occurred before in the other SARS-type viruses, which cause SARS and MERS.

Given the many similarities, the cause might be the same, though with a different virus. The virus hides in immune privileged cells, so it can’t be cleared by the immune system, and any medications that don’t cross the blood-brain barrier, will not work on the disease. Use medications that cross the blood-brain barrier and which inhibit the virus within neurons and other CNS cells.

Edited on 8/18/2020 (7:11 am) to add: PVFS is also similar to Longhaulers Syndrome. Here’s a list of indications of Post-Viral Fatigue Syndrome (PVFS) quoted from HealthLine.com

  • “an unusual response to viruses that can remain latent within your body
  • increased levels of proinflammatory cytokines, which promote inflammation
  • nervous tissue inflammation”

“Other symptoms that can accompany post-viral fatigue include:

  • concentration or memory problems
  • sore throat
  • headache
  • swollen lymph nodes
  • unexplained muscle or joint pain”

The hypothesis is that Longhaulers Syndrome is a due to a virus remaining latent in the body. And we know that Covid-19 causes proinflammatory cytokines (which is the cause of the more severe respiratory symptoms). And now I have to add, based on the above information, that Longhaulers is also due to “nervous tissue inflammation”. Then the additional symptoms of PVFS also fit longhaulers syndrome, especially concentration and memory problems, muscle or joint pain, etc.

It fits perfectly. Covid-19 is largely an inflammatory disease, which is why steroids are used (See MATH+ Protocol, which recommended steroids before it was an accepted treatment by other doctors and health authorities.) This explains everything. Treatment must use meds that permeat the blood-brain barrier and reach the interior of nervous tissue and reduce inflammation there!

And why doesn’t the virus, when it infects neurons particularly, multiply as rapidly and destroy the neurons, as it does lung cells? The answer must have something to do with the fact that neurons do not replicate. The virus takes over the cellular machinery in order to replicate. Neurons have a somewhat different cellular system, as they don’t themselves replicate, and this must allow viruses, SARS-CoV-2 and others, to remain latent there, multiply at a low level without destroying the cells, and then periodically infect other types of cells where it can replicate at full speed.

* New article on Longhaulers looks at all the IPCs affected by Covid.

Article by Ronald L. Conte Jr.
Please note that I am neither a physician, nor a longhauler.

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Endnotes:

1. Lambert, N. J. & Survivor Corps., COVID-19 “Long Hauler” Symptoms Survey Report. Indiana University School of Medicine; 2020; Report Link (PDF)

2. “What Does COVID-19 Recovery Actually Look Like?”, Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team; Generated from survey data organized by decentralized team of COVID-19 patients; Report created and written by volunteers from the COVID-19 Body Politic Slack Group including: Gina Assaf, Hannah Davis, Lisa McCorkell, Hannah Wei., O’Neil Brooke, Athena Akrami, Ryan Low, Jared Mercier, and Adetutu A. Survey Authors and Contributors Include: Gina Assaf., Tina L., Annie C., Monica S., Jared Mercier, Lauren N., Noel H., JD Davids, and Susie. Report released on May 11th, 2020 by PatientResearchCovid19.com; Report Link (PDF)

3. Churchill, Melissa, and Avindra Nath. “Where does HIV hide? A focus on the central nervous system.” Current opinion in HIV and AIDS 8.3 (2013): 165. Study Link

4. Peterlin, B. Matija, and Didier Trono. “Hide, shield and strike back: how HIV-infected cells avoid immune eradication.” Nature Reviews Immunology 3.2 (2003): 97-107. Study Link

5. Te Velthuis, Aartjan JW, et al. “Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture.” PLoS pathogens 6.11 (2010): e1001176. Study Link (PDF)

6. Marik, P. “EVMS critical care COVID-19 management protocol.” (2020). Link to Latest MATH+ Protocol. Note: the MATH+ protocol recommends quercetin, a zinc ionophore, and zinc supplementation for Covid-19 prophylaxis, as well as at-home and in-hospital treatment.

7. Mu, Jingfang, et al. “SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells.” Science China Life Sciences (2020): 1-4.

8. Chen, Jidang, and Hinh Ly. “Immunosuppression by viral N proteins.” Oncotarget 8.31 (2017): 50331.

9. Moustaqil, Mehdi, et al. “SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts.” bioRxiv (2020).

10. Henderson, Rory, et al. “Glycans on the SARS-CoV-2 Spike Control the Receptor Binding Domain Conformation.” bioRxiv (2020).

11. Turoňová, Beata, et al. “In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges.” bioRxiv (2020).

12. Song, Eric, et al. “Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model.” bioRxiv (2020).

13. Agarwal, Pinky, et al. “Neurological manifestations in 404 COVID-19 patients in Washington State.” Journal of Neurology (2020): 1-3. Study Link

14. Hornig, Mady. “What does COVID-19 portend for ME/CFS?.” (2020).