The 1918 influenza pandemic, commonly referred to as the Spanish Flu, infected approximately one-third (500 million) of the world's population (then 1.8 billion) and killed an estimated 50 million. With such a high mortality rate, even among young and healthy individuals, this acute infectious disease took its toll, erasing from existence nearly 3% of all people on Earth. But the damage did not stop there: across the globe, survivors of the initial viral infection reported "long flu" symptoms — profound fatigue, brain fog, depression, tremors, sleeplessness, and a litany of neurological disorders.
While the initial pandemic forced governments to organize a response to the sudden crisis, an epidemic of chronic illness may not raise alarms that spur us into immediate action.
This "long flu," an echo of sorts of the Spanish Flu epidemic itself, has its parallel in long COVID today — a similar cluster of symptoms that persist in those who were previously infected with COVID-19. And the similarities suggest that what we think of as long COVID is not necessarily a novel condition, but merely one more instance of the medical aftermath that accompanies certain infections.
The medical establishment calls this condition post-acute infection syndrome (PAIS). Back in 1918, these mysteriously persistent long flu symptoms wreaked havoc on human health and local economies. For example, many claim that debilitating lethargy caused by this post-viral syndrome led to the "famine of corms" in the region that is Tanzania today, as farmers lacked the energy to plant, harvest, and shear months after getting sick.
Around the same time, cases of a new brain-attacking disease called encephalitis lethargica started to emerge, affecting up to one million people worldwide. The cause of encephalitis lethargica remains one of the largest medical mysteries of the 20th century, though some scientists contend that the Spanish Flu may have been the trigger. The condition was colloquially known as "sleeping sickness," as those infected developed extreme fatigue, neurocognitive impairments, psychiatric illness, and movement disorders. A subset of these individuals fell into a semi-comatose state that lasted for decades. About one-third of encephalitis lethargica patients eventually died from respiratory failure caused by neurological dysfunction, while many survivors continued to suffer from ongoing Parkinson's-disease-like (neurocognitive) symptoms.
In 1969, as chronicled in his book "Awakenings," the neurologist Oliver Sacks discovered that temporary remission of these chronic symptoms, coined post-encephalitic parkinsonism, could be achieved through the use of the Parkinson's drug L-DOPA. Like with Parkinson's disease itself, the benefits of the drug wore off over time, but the finding indicated that encephalitis lethargica impacted the substantia nigra (the part of the brain that helps control movement).
We now have a plethora of information suggesting that COVID-19 is the latest addition to the list of infections spawning post-acute infection syndrome.
Although the medical community has long known that acute infectious diseases are not always entirely self-limiting, chronic sequelae (meaning the secondary symptoms that appear after an infection) receive little attention, remain under-researched, and continue to be misdiagnosed and overlooked by doctors. According to a study published in the scientific journal Nature Medicine, post-acute infection syndrome is associated with a number of infections, including Epstein Barr virus, cytomegalovirus, Lyme disease, Q fever, West Nile virus, Dengue fever, and the aforementioned influenza. Often presenting well after the initial infection, post-acute infection syndrome manifests as a complex and variable disorder, typically entailing severe fatigue, gastrointestinal issues, confused sensory perception, and neurocognitive abnormalities.
Despite the growing pool of data from patients suffering from post-acute infection syndrome, a comprehensive explanation of the biological mechanisms by which the syndrome's symptoms arise has yet to be established. This lack of scientific understanding creates an untold degree of hardship for those dealing with severe and chronic sequelae of infections. Worse, when doctors cannot find a biological explanation for reported symptoms, patients are often left with little recourse and the feeling that their doctor believes the cause of their suffering is rooted in mental illness.
Years into our current pandemic, we now have a plethora of information suggesting that COVID-19 is the latest addition to the list of infections spawning post-acute infection syndrome; that is, "long COVID." Multinational surveys have been conducted, with thousands upon thousands of adult participants reporting that recovery from an initial COVID infection took more than 35 weeks. Some of these studies highlight the fact that new ailments are reported 6-12 months after an initial COVID infection, which most commonly include fatigue, post-exertional malaise, and cognitive dysfunction.
According to the CDC, in June 2022, almost one in five American adults who had COVID-19 still had long COVID. This statistic seems to be borne out by my anecdotal experience; I have met with and spoken to many people around the world who have lost their sense of smell, had to take medical leave, been fired from work, seen a drop in their focus during school, experienced overwhelming exhaustion and migraines, or become depressed after being infected with COVID. My home state's newspapers recently shared the sad medical saga of a man, Charlie Vallee, whom I grew up with in Vermont. After only mild respiratory symptoms during his initial bout of COVID-19, Vallee went on to develop such severe long COVID symptoms, including brain fog, that he left his job as an intelligence officer in D.C. and tragically took his own life. His family has set up a foundation to fund long COVID research in the hopes of one day understanding how this pernicious form of post-acute infection syndrome can cause an otherwise happy and healthy individual to die by suicide.
In other words, long COVID is affecting more people than we likely know. And it eerily parallels other post-acute infection syndrome scenarios throughout history, including those potentially linked to epidemics of parkinsonism. Hence, the threat of long COVID could lead to a future public health catastrophe, much as the "long" effects of the Spanish Flu did a hundred years ago. Unfortunately, the pharmaceutical and medical community are not approaching long COVID with the same fervor that they had for COVID-19. As a result, there is a real danger that a broad-scale investigation into the origin of long COVID is postponed or neglected by funding agencies and the medical establishment.
While the initial pandemic forced governments to organize a response to the sudden crisis, an epidemic of chronic illness may not raise alarms that spur us into immediate action. Like climate change, a gradually-evolving threat, especially one perceived to be far away, is much harder to address. But the threat here is not that far off, as emerging science reveals — which is why it is of grave importance that we push for an explanatory theory of long COVID (and post-acute infection syndrome) that can fully account for the totality of symptoms observed after an initial infection with SARS-CoV-2 despite no clinical findings of active infection.
The science behind long COVID
Multiple studies published in the journal Nature Communications (one published last year and one published in February of this year) explain how COVID-19 has the ability to trigger the aggregation of proteins within the human body. The research suggests that SARS-CoV-2 can cause normal proteins to abnormally misfold. These misfolded proteins are known as "amyloids," which are toxic to cells when they build up.
Specifically, amyloids occur when proteins misfold into twisted clumps and form long fibers, hindering cellular function. These so-called clumps can start stacking excessively, creating harmful deposits in the body — sort of like cholesterol in the bloodstream but at the cellular level. When misfolding of a protein named "alpha-synuclein" in the nervous system occurs, the amyloid buildup this causes in a neuron can lead to the formation of what is known as a "Lewy body," which is resistant to breakdown and clearance. Think of it as plaque buildup in the nervous system. Lewy bodies spread as pieces of these amyloids break away and seed the formation of new Lewy bodies in neighboring neurons.
The scariest thing about this? Misfolded alpha-synuclein is a hallmark of Parkinson's disease, Lewy body dementia, multiple system atrophy, and pure autonomic failure — all neurodegenerative diseases collectively known as synucleinopathies. And what can cause alpha-synuclein misfolding? Genetic mutations, exposure to certain toxins, and infections. COVID-19 may be one such infection — and that means long COVID symptoms may be a reflection of a developing neurological disorder.
Alarmingly, two studies published by the Mayo Clinic and the Medical University Innsbruck corroborate the findings in the Nature articles, recording signs of dream-enactment sleep disorder among one-third of patients after being infected with COVID-19. Over 80% of patients with dream-enactment sleep disorder go on to develop a Parkinson's-like disease within two decades.
So we need to ask the question: is the recent rise of dream-enactment sleep disorder after COVID related to neurodegeneration? Preliminary research from Stanford University and Beth Israel Deaconess Medical Center suggests that this may be the case, as disease-causing clumps of alpha-synuclein have been discovered in some long COVID patients.
So how does all of this connect? Basically, if dream-enactment sleep disorder is more common in those who have had COVID, and the vast majority of those who suffer from this kind of sleep disorder ultimately develop neurological diseases like Parkinson's, then COVID-19 could lead to an explosion of these diseases in the coming years.
This is not mere speculation; animal models further substantiate these claims. For example, a study of macaques demonstrated that SARS-CoV-2 induces Lewy body formation (a feature of Parkinson's disease), even after an asymptomatic infection. And, whether or not COVID is determined to be a direct cause of Parkinson's, it could also accelerate the disease course in patients who are predisposed. This was exemplified by a study performed by infecting mice with COVID-19, which found that the virus made the brain more susceptible to toxic compounds known to cause Parkinson's disease. The lead researcher on this study, Richard Smeyne, PhD, who serves as Chair of the Department of Neuroscience at Thomas Jefferson University and Director of the Jefferson Comprehensive Movement Disorder Center reviewed this article before publication, affirming what has been outlined and reiterating his study's findings: "Should the predicted risk from SARS-CoV-2 manifest, the diverse consequences would represent a substantial burden on patients, families, and society."
Dr. Smeyne elaborated on the seriousness of these findings, telling Salon, "Our studies in mice predict a 30-50% increase in Parkinson's risk for those moderately to severely infected with the Alpha variant. While on an individual basis this only changes a person's risk from 2% to 3% for developing Parkinson's, over the whole of the population we would expect to see millions more develop Parkinon's disease than would have if not for their COVID infection."
"We still have to examine if the newer strains of SARS-CoV-2 also have the potential to increase the risk for Parkinson's disease."
A prominent theory for explaining Parkinson's disease, put forth by Heiko Braak, a German doctor who studies Parkinson's, aligns well with all these long COVID findings. It states that Parkinson's is caused by a pathogen affecting either the nasal cavity or digestive system, thereby first initiating protein misfolding in the peripheral nervous system before spreading into the brain later on (sometimes decades later). This is why the onset of Parkinson's often entails autonomic dysfunction — which means involuntary processes like heart rate, blood pressure, respiration, etc. are compromised. As autonomic dysfunction is a common symptom of long COVID, it is thus possible that the post-acute infection syndrome mechanism responsible for long COVID progresses to the central nervous system over time and could eventually present as Parkinson's disease or a similar disorder.
In other words, while long COVID is not caused by the lingering viral remnants of COVID-19 per se, the initial infection could be precipitating amyloid buildup and Lewy body formation. If this is so, long COVID would mimic a chronic or slowly-evolving infection caused by the virus, similar to other post-acute infection syndrome cases, with the symptoms fluctuating and emerging unpredictably as the amyloids slowly spread throughout the nervous system.
Braak's hypothesis was based on autopsy data, which indicated a distinct pattern of aggregated alpha-synuclein in those who died from/with Parkinson's disease. However, according to Dr. Smeyne, "As of yet, there is no good non-invasive marker for alpha-synuclein aggregation in living patients, which is why The Michael J. Fox Foundation is offering a $2 million prize to any person or group that successfully develops such a marker."
The way forward
To investigate these claims, larger studies need to evaluate patients with long COVID for markers of Parkinson's-like diseases, such as misfolded alpha-synuclein. A clinical trial is currently underway to do just that — so that the history of post-encephalitic parkinsonism in the years following the Spanish Flu does not repeat itself. Considering the mounting evidence, it is crucial that we address the long COVID public health emergency promptly, to provide answers to those suffering from long COVID and prevent a potential increase in "post-COVID parkinsonism."
When asked about his outlook for the future, Dr. Smeyne said, "We are entering a period where we will have to learn to live with COVID being present as a fact of life. This means we still have to examine if the newer strains of SARS-CoV-2 also have the potential to increase the risk for Parkinson's disease and whether vaccination against this virus can reduce the increased Parkinson's risk, as has been shown following vaccination against influenza. Once we determine the answers to these questions, we can begin to look at other ways to interfere with the process."
Salon then asked what it will take to definitively prove whether COVID-19 can trigger a Parkinson's-like disease and whether long COVID is in fact the early stages of such a disease. Dr. Smeyne responded, "My best guess is we will need anywhere from five to ten years from the initial outbreak to see any statistically measurable effect."
Encouragingly, Dr. Smeyne went on to say, "One bright spot in these observations is that there is a considerable period, often about a decade, between viral exposure and the development of a neurological disease like Parkinson's. And there are currently scientists devoting their lives' efforts to find ways to solve this problem — the lag between exposure and disease gives me hope that we will find a way to stop the progression from infection to disease in its tracks."
There have been more than 760 million globally documented cases of COVID-19, with the real number of cases, including asymptomatic cases, presumably much higher. More than 750 million have survived, but, as reported, long COVID is occurring in 20-30% of these cases, meaning that hundreds of millions of people could be at higher risk of developing Parkinson's disease or other neurodegenerative issues later in life. If it comes to pass, the public health resources required to help will be astronomical. It behooves us to study long COVID now, lest we end up in such a crisis.
