The emergence of post-COVID syndrome shines new light on the old problem of post-viral syndromes
In Part 1, we discussed how the rise of long covid shines new light on chronic post-viral disorders long ignored by researchers and clinicians. But this issue didn’t just appear with the SARS-COV-2 COVID-19 pandemic. We hope post-COVID syndrome will spark sustained interest from the scientific medical community in this cluster of disorders with similar symptoms and histories of viral infection. These include autoimmune, autoinflammatory, chronic fatigue syndrome (CFS) and many undiagnosed chronic immuno-inflammatory disorders (CIIDs). Although these are not new diseases, they have been neglected and under-researched. Historically, they are practically invisible to public health, medical research and clinical practice.
It is increasingly clear that some people do not fully recover from certain infections. The medical community has recognized this in some cases for more than a century. For example, consider rheumatic fever (post-Streptococcus A syndrome) and rheumatic heart disease, both chronic post-infection disorders. More recently we’ve begun to see that many viral infections leave a subset of patients with symptoms lasting months or years. These generally include debilitating fatigue, “brain fog,” post-exertional exhaustion (exercise makes the fatigue worse) and mood disorders like anxiety and depression. Causes include an inability to clear the infection completely or other dysfunctional reactions by their innate or adaptive immune systems.
A call for awareness, research and funding for post-viral syndromes
Our scientific understanding of causes and pathways is seriously limited. But the biggest limitation is a lack of interest to research these diseases. This is despite that they have been around under various guises for many decades. This includes autoimmune and autoinflammatory conditions. For historical reasons, autoimmune diseases have been siloed by medical specialty and body part. Moreover, unlike oncology, immunology is not a united specialty prompting research to find common elements across chronic immuno-inflammatory disorders (CIIDs). We are trying to change that. This post puts post-viral syndromes in a historical context before long COVID emerged.
A note on definitions
Not surprisingly, the terminology is in flux. Since the pandemic is little more than a year old, and we expect a long-tail distribution of lingering symptoms, we have yet to see how many people will suffer longer-term disability. Patients calling themselves “long-haulers” first coined the term “long COVID” and shared it via social media. Recently (December, 2020), the UK NICE issued guidelines around long-term effects of COVID-19. According to their definitions, COVID-19 patients whose symptoms take more than 4 weeks but less than 12 to resolve have “ongoing symptomatic COVID-19.” Patients with unresolved symptoms more than 12 weeks after infection have “post-COVID syndrome.” The term “long covid” includes both groups.
The US CDC does not yet have specific terminology definitions around long-term effects of COVID-19, although they do discuss “late sequelae” and “persistent symptoms”. Nevertheless, in keeping with our mission, the name “post-COVID syndrome” places this phenomenon in a historical context that includes post-viral syndromes and autoimmune disease.
Post-viral syndromes are not new!
For more than a century, medical researchers have observed lingering symptoms, relapses or other long-term syndromes in patients after bacterial or viral infections. For decades, the clinical, research and immunology communities have been aware of other viral infections that may trigger long-term symptoms in a subset of patients.
In some cases, the host never clears the virus completely. Dormant viruses lurk in cellular reservoirs to re-emerge under stress or other triggers. In other cases, the patient’s own innate or adaptive immune response causes long-term dysfunction. These manifest as fatigue, brain fog, lingering hypersensitivity, tissue damage, even autoimmune diseases.
Read on for a brief history covering post-polio syndrome, shingles and postherpetic neuralgia, HSV flares, herpes and neurodegenerative disease, and the sad tale of Myalgic Encephalitis/Chronic Fatigue Syndrome/Systemic Exertion Intolerance Disease (ME/CFS/SEID), as well as post-infection syndromes after the 2003 SARS pandemic.
A nearly forgotten example is post-polio syndrome (PPS). In PPS, years or decades after the original poliovirus infection, patients suffer a recurrence of weakness in the same muscles affected by the original infection. This can cause severe disability or even death. There is no effective treatment. US polio cases peaked in 1952, just before mass vaccination started in 1955, which has since almost eradicated polio. As this older, polio-infected population cohort dies off, this condition is increasingly rare, so few have heard of it.
Herpesviruses: lifelong infection with occasional flares
Herpes Zoster: Shingles and postherpetic neuralgia
Compared to post-polio syndrome, many more people (including Bonnie) are familiar with shingles and its more severe manifestation as Postherpetic neuralgia. In shingles, latent Herpes zoster (chicken pox) viruses reactivate decades after the original infection, erupting in painful blistered skin along nerve pathways (see illustration). Postherpetic neuralgia, by definition, involves prolonged (>90 days) neuropathic pain along those dermatomes. It may also include general post-viral symptoms like fatigue, exhaustion, brain fog and mood disorders. Shingles responds to antiviral treatment (e.g., acyclovir or its prodrug valacyclovir). Postherpetic neuralgia may also be treated with tricyclic antidepressants and drugs for neuropathic pain, like gabapentin. Encouragingly, two shingles vaccines are now on the market that, while not 100% effective, can significantly shift the odds in your favor.
Herpes simplex (HSV): reactivation flares…
Herpes simplex (HSV) type 1 and 2 infections, oral and genital, are notorious for reactivation flares months, years or decades after initial infection. Fortunately, antiviral drugs are effective prophylactics with minimal side effects. Nevertheless, long-term HSV patients should also pay attention to diet (e.g., lysine/arginine ratios), sleep (sleep deprivation and jet lag are known triggers) and emotional stress. Also use prophylaxis when undergoing dental, especially invasive endodontic procedures, which may trigger severe oral outbreaks (Ellen’s very painful voice of experience).
We are pleased to find that long-term suppression management of HSV infection through antivirals is now offered to patients as a standard of care. When acyclovir first reached the market in the 1980s, patients had to aggressively pursue suppressive therapy against prevailing dogma that acyclovir only worked early in the course of infection. (This is also Ellen’s voice of experience). We likely have the AIDS community’s experience with long-term use of antivirals to thank for this. Valacyclovir is even more effective, see this older but not outdated article.
In some patients, acute HSV infection triggers autoimmune encephalitis, meningitis or meningoencephalitis which may cause long-term neurological damage. Chronic HSV infection may even be a factor in Alzheimer’s and other neurodegenerative diseases.
Other herpes viruses
Research suggests members of the herpes virus family may be triggers of Parkinson’s disease, and other neurodegenerative diseases. The mechanism is not direct, but probably involves the immune response. Since herpes infections are lifelong, their association with degenerative conditions is not too surprising. Herpes virus infections may be triggers of autoimmune disease as well, see paragraph below.
ME/CFS/SEID post-viral syndromes
Ellen frequented Incline Village, NV in the early 1980s, where a cluster of patients with chronic post-viral syndromes emerged. She recalls public health concerns that this was a communicable disease with potential for chronic morbidity. But also, media dubbed it as psychosomatic “Yuppie flu.” However, she had no idea at the time what a lengthy saga would unfold within the US CDC. This story illustrates how a federal government agency with enormous power and authority ineptly handled an emerging disease, wasting research money or diverting it to cronies. This balefully influenced clinical practice up to the present. Parallels with the COVID-19 pandemic spring to mind.
If there was ever a model of how not to research and treat post-COVID syndrome, it is the saga of Myalgic Encephalitis/Chronic Fatigue Syndrome/Systemic Exertion Intolerance Disease (ME/CFS/SEID). In this situation perverse incentives (no one wants to pay for treatment of these costly chronic diseases or care of their disabled victims) met regulatory capture in both the US CDC and UK NHS to underfund research, stigmatize the condition and sully the evidence base. Most of the detailed information about this history is not available via mainstream media sources, peer-reviewed included, because those media, too, were captured by medical groups promoting a psychogenic hypothesis. Even worse, this biopsychosocial theory reinforced clinicians’ tendencies to dismiss patients’ symptoms or define them away as psychosomatic.
In the UK a distressing example of regulatory capture and self-interested clinical researchers harmed ME/CFS sufferers. The promoters of the biopsychosocial hypothesis gained support from NHS and welfare policy stakeholders, who already had incentives to reduce payments to ME/CFS patients. The result was enshrining a treatment approach that not only was largely ineffective, even harmful, but also led to stigmatizing and gaslighting of patients, including limiting their treatment options and reducing their welfare benefits.
Lessons learned (or not) from history
These sagas are warnings about how well-connected groups can game evidence-based medicine against the best interests of patients. This is also a lesson about centralized healthcare. Special interests can easily capture centralized agencies, and once captured, it is slow going to force them to change course. ME/CFS/SEID patients, despite their disabilities, organized courageously to fight back, an effort that has taken decades to change practice guidelines and one which patients are still fighting.
Alas, we see some of the same mistakes emerging in the response to post-COVID syndrome. The ME/CFS/SEID community offers sobering advice to long-COVID patients about the possibility of being unwell for years. They also warn about what long COVID patients may not get from the medical system. This includes R&D as well as clinical practice. On a positive note, lessons learned from experiences of ME/CFS patients may improve post-COVID syndrome research and clinical practice.
Especially relevant to COVID-19 (SARS-CoV-2) are post-viral syndromes associated with other SARS virus infections. Here are two examples from more than a century apart.
The “Asiatic” or “Russian flu” pandemic of 1889-92, triggered serious neurological symptoms. It may not have been flu, but rather a SARS coronavirus (there was no way to distinguish back then!). Many anecdotes of patients report lingering fatigue and other symptoms that resemble ME/CFS and post-COVID syndrome.
Even more relevant is the 2003 SARS-CoV-1 pandemic. While SARS infected many more people in Asia than in North America, Toronto‘s severe outbreak prompted quarantines and stressed the hospital system. Healthcare workers (HCW) were particularly hard-hit, with 43% of cases occurring in HCW. (Aside–the sources all discuss droplet transmission, not aerosols! This is a foreshadowing of one of the biggest medico-scientific mistakes in the public health response to COVID-19).
Historically, long-term post-SARS symptoms have been described as PTSD or mental health morbidities. This framing is all too familiar to ME/CFS and autoimmune patients. But just because people are depressed or anxious doesn’t mean they aren’t sick! Some researchers have thought outside the mental illness/PTSD box and identified a post-SARS syndrome. Harvey Moldofsky’s study of Toronto healthcare workers so disabled post-SARS they could not return to work is most often cited. And here is a larger study of Hong Kong SARS survivors. At least it gives chronic fatigue co-billing with mental morbidities!
Autoimmune diseases and viral triggers
We also know that many autoimmune conditions are highly correlated with viral infections. For example, symptomatic Epstein-Barr Virus (EBV) infection, aka mononucleosis, may trigger several autoimmune diseases. The list includes cases of multiple sclerosis (MS) and systemic lupus erythematosus (SLE) aka lupus. Researchers have proposed additional viral and bacterial infections as triggers of SLE. More recently, research has identified human herpesvirus 6 (HHV6) as a risk factor for MS. The association of rheumatoid arthritis (RA) with periodontal disease likely follows bacterial, rather than viral infections. However, RA also follows Epstein-Barr and cytomegalovirus infection. Viral infections may trigger autoimmune flares as well, e.g., myasthenia gravis.
Viral diseases like COVID have been implicated as triggers for several autoimmune diseases, including Guillain-Barre syndrome, polyarteritis nodosa, and “dancing eye syndrome” (opsoclonus myoclonus syndrome).Aaron Abend, founder, The Autoimmune Registry
But, as with ME/CFS/SEID, research on viral triggers of autoimmune diseases and flares has been sporadic. Such research has focused on marquee diseases (Lupus, RA, MS). Contrast that with cancer where research on common mechanisms and patterns has helped understand many diseases. This is especially true because there are so many rare and currently unclassified CIIDs. We need much more research on viral infections, immunology & post-viral syndromes. Especially as they relate to chronic immunoinflammatory and autoimmune conditions. Perhaps post-COVID syndrome will finally attract scientific interest and public plus private funding to this area. Remember how AIDS/HIV inspired virology and immunology research at the end of the 20th Century? Could COVID-19 do the same for post-viral and similar CIIDs?
We should be looking at post-influenza as well as post-SARS syndrome?
This also raises the question of whether we have been overlooking other chronic post-viral infection syndromes. We know about herpes and shingles and post-polio syndrome, but post-influenza syndromes have been woefully understudied. Given the sheer number of influenza infections annually, it should be an obvious area of research.
We aren’t the only ones calling for this. See this article from Laura Spinney in Time Magazine on lingering post-infection effects of the 1918 influenza pandemic.
About DrBonnie360 & Ellen M Martin
We approach these thought leadership posts from our two different multi-lens perspectives.
- DrBonnie360: clinical dentist, Wall Street analyst, patient advocate, and digital health consultant.
- Ellen M Martin: evolutionary life science, finance & investor relations, marketing, communications and writing/editing.
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