emerging data Long-COVID aka Long-Haulers

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'Worst Hell You Could Ever Imagine': Study Hopes to Shed Light on Long-Haul COVID
Dr. Michael VanElzakker is leading a new study on why some people suffer from long-haul COVID-19, continuing to deal with symptoms longafter being diagnosed.

Colin Bennett can't shake Months after first getting COVID-19, he continues to grapple with symptoms.

"It is absolutely the worst hell you could ever imagine," Bennett said. "You wouldn't wish this upon anyone."

Bennett is part of a growing number of people suffering from long-haul COVID.

"What I am going through, I think of rare cancer patients. I have probably gone through 50 to 70 different symptoms by now," Bennett said.

Dr. Michael VanElzakker is the scientist leading a new study, looking to analyze if the brain can shed some light on what causes some people to keep dealing with symptoms so long after diagnosis. He notes that the brains of those suffering long-haul COVID look different than those who are not.

"I think a lot of us knew there would be long-term consequences," VanElzakker said.

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2 COVID Long-Haulers Open Up About Their Recovery

Inflammation, stress, memory issues, and other symptoms of "long haul" COVID-19 are still impacting Fiona Lowenstein and Chimére Smith. Smith tells LX News she developed occipital neuralgia after contracting the virus in March 2020. "It almost feels like I have a rubber band around my head, actually 20 of them at any given time."

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Pre print of a Yale study done on long-covid

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Abstract
Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection – without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Introduction
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2) has to date resulted in over 285 million documented COVID-19 cases worldwide. Neurological symptoms are emerging as relatively common sequelae of SARS-CoV-2 infection, with persistent cognitive impairment affecting approximately one in four COVID-19 survivors (Nasserie et al., 2021). While more common in individuals who had experienced severe COVID requiring hospitalization, even those with mild symptoms in the acute phase may experience lasting cognitive dysfunction (Becker et al., 2021; Nasserie et al., 2021). Colloquially known as "COVID-fog", this syndrome of COVID-associated cognitive impairment is characterized by impaired attention, concentration, speed of information processing, memory, and executive function (Becker et al., 2021; Nasserie et al., 2021). Together with increased rates of anxiety, depression, disordered sleep and fatigue, this syndrome of cognitive impairment contributes substantially to the morbidity of "long-COVID" and in many cases prevents people from returning to their previous level of occupational function (Davis et al., 2021; Tabacof et al., 2022). Given the scale of SARS-CoV-2 infection, this syndrome of persistent cognitive impairment represents a major public health crisis (Nath 2020).

The syndrome of cognitive symptoms that COVID survivors frequently experience closely resembles the syndrome of cancer therapy-related cognitive impairment (CRCI), commonly known as "chemo-brain". Neuroinflammation is central to the pathophysiology of cancer therapy- related cognitive impairment (for review, see (Gibson and Monje, 2021)), raising the possibility of shared pathophysiological mechanisms. Microglia, brain-resident macrophages, become persistently reactive following exposure to certain systemic chemotherapy drugs, after cranial radiation, or after systemic inflammatory challenge with low-dose lipopolysaccharide (Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2002; Monje et al., 2003; Monje et al., 2007). A distinct subpopulation of microglia that reside in white matter (Hammond et al., 2019) are selectively activated by systemic insults such as exposure to the chemotherapy drug methotrexate (Gibson et al., 2019). Reactive microglia impair mechanisms of cellular homeostasis and plasticity such as the ongoing generation of myelin-forming oligodendrocytes (Gibson et al., 2019), myelin plasticity (Geraghty et al., 2019) and new neuron generation in the hippocampus (Monje et al., 2002; Monje et al., 2003; Monje et al., 2007). Local microglial cytokine secretion contributes to at least part of this dysregulation (Monje et al., 2003). Elevated circulating cytokine/chemokine levels, particularly CCL11, can also limit neurogenesis and contribute to cognitive impairment (Villeda et al., 2011). In addition to these direct effects of inflammatory mediators on cellular plasticity in the brain, microglia also induce neurotoxic astrocyte reactivity through cytokine signaling (Liddelow et al., 2017). Astrocytes can assume a range of reactive states (Hasel et al., 2021) that can induce further pathophysiology, with certain states of reactive astrocytes inducing oligodendrocyte and neuronal cell death (Liddelow et al., 2017) through secretion of saturated lipids contained in lipoprotein particles (Guttenplan et al., 2021). This complex cellular dysregulation is thought to contribute importantly to cognitive impairment, and anti-inflammatory strategies correct such multicellular dysregulation and rescue cognition in disease states such as occurs after exposure to neurotoxic cancer therapies (Geraghty et al., 2019; Gibson et al., 2019; Monje et al., 2003) and in aging (Villeda et al., 2011).

While systemic and severe COVID can cause multi-organ disease and numerous potential mechanisms affecting the nervous system (Lee et al., 2021; Nath and Smith, 2021; Remsik et al., 2021), even mild COVID could result in an a detrimental neuroinflammatory response, including reactivity of these exquisitely sensitive white matter microglia. Given this context, we hypothesized that the inflammatory response to even mild COVID-19 may induce elevation in neurotoxic cytokines/chemokines, a pattern of white matter microglial reactivity, and consequent dysregulation of myelin-forming oligodendrocytes and hippocampal neural precursor cells.

Mild respiratory SARS-CoV-2 infection causes prominent neuroinflammation

To test the effects of mild COVID-19, we used a mouse model of mild SARS-CoV-2 infection limited to the respiratory system (Israelow et al., 2020; Song et al., 2021). SARS-CoV-2 infection requires expression of human ACE2. In this model, human ACE2 is delivered via AAV vector to the trachea and lungs. Two weeks following intra-tracheal ACE2-AAV delivery, SARS-CoV-2 is delivered intranasally (Figure 1A). Control mice received intra-tracheal AAV expressing human ACE2, but only mock infection intranasally. Mice exhibit no weight loss (Figure 1B) or observable sickness behavior; the challenges of working with a biosafetly level-3 mouse model limited the feasibility of further behavioral assessments. No virus was detected in brain (Figure 1C), unlike in the case of a neuroinvasive model of SARS-CoV-2 infection (Supplementary Figure 1). As expected, SARS-CoV-2 was present in the lungs of infected mice (Supplementary Figure 2). Despite the lack of evident symptoms/signs of illness in this respiratory infection model, we found prominently elevated cytokine profiles in serum and in cerebrospinal fluid (CSF) at 7-day and 7- week timepoints following respiratory infection, in comparison to control mice (Figure 1D-G). At 7-days post-infection, elevated CSF cytokines and chemokines include CXCL10, IL6, IFN-g, CCL7, CCL2, CCL11 and BAFF, among others (Figure 1F). Of these, CXCL10, CCL7 and CCL11 remain elevated in CSF at 7-weeks post-infection (Figure 1G). These results indicate that respiratory infection with SARS-CoV-2 results in profound changes in cytokines within the CSF.

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Yale researchers study long-term impacts even mild COVID can have

NEW HAVEN, Conn. — The long-term effects of COVID are not yet known, according to Yale researchers, but recently, they conducted a study to take a closer look.

The goal is to try to find out what's causing long COVID, which can affect multiple organ systems.

This study conducted by the Yale School of Medicine focused on mild respiratory infection with COVID.

"To see what the long-term impact of a mild infection with COVID might have on the brain of the host," said Dr. Akiko Iwasaki, an Immunobiologist with Yale Medicine.

They conducted the research on animals that were only infected in their lungs, which did not make the animals severely ill. That mimicked a mild case of COVID in humans.

"What we found is that after seven days and after several weeks of infection we found significant damage in the cells that are found in the brain," Iwasaki said.

This would lead to significant neurological consequences if similar things were to happen in humans with mild COVID.

"And in the future we will be testing various treatments to be able to block such an impact on the brain of someone with mild COVID-19 disease," Iwasaki added.

However, currently there is no therapy that is specifically targeted for either prevention or treatment of neurologic disease that happened as a consequence of infection with COVID.

"And this means that in addition to getting the vaccine and getting the booster, which would reduce the possibility of getting the virus, we would also want to practice measures such as proper ventilation indoor crowding," said Iwasaki.

As well as wearing a proper mask, like the KN95 or N95 to help prevent exposure.

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Mild COVID-19 Infections Can Lead to Long-Term Neurological Damage: Study

Neurological symptoms have been commonly reported in those suffering from post-COVID conditions - lingering symptoms experienced four or more weeks after an initial infection.

But a new study by researchers at Yale University found even those who contract mild infections can sustain neurological damage.

In an interview with NBC Connecticut, Dr. Akiko Iwasaki, who conducted the study, explained researchers intentionally gave mice a mild respiratory infection with SARS-CoV-2, the virus that causes COVID-19.

Over the course of seven days, they examined the infection's impact on the brain.

"And what we found is that even with a very mild infection, which we really cannot measure any disease phenotype in these mice, we still saw some significant damage in the cells of the brain," said Iwasaki, an immunologist with the Yale University School of Medicine. "This means that even a mild respiratory infection could lead to neurological symptoms; that's based on the damage that we see."

However, the doctor emphasized that those with severe illness are at higher risk for cognitive impairment.

Yale researchers cited a study that examined COVID patients in a New York City hospital system and determined the incidence of cognitive impairment was increased in hospitalized patients compared to those with mild COVID.

Persistent cognitive impairment is said to impact approximately one in four COVID survivors, according to a study about the frequency and variety of symptoms associated with the disease.

In regard to newer variants such as omicron, the incidence and severity of impairment remain unknown, researchers noted.

Post-COVID conditions overall are thought to affect a "high fraction" of people who have recovered from COVID-19, but what causes the lingering symptoms still remains unknown.

"Whether it be affecting the nervous system or the GI tract or the respiratory tract, the long COVID can affect so many multiple organ systems," Iwasaki said. "And currently, we don't understand how long COVID happens.

And if we don't understand that, we won't know how to treat these diseases better. So ultimately, we want to understand the underlying mechanism of disease, so we can come up with a therapy to treat these patients."

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Long COVID study: Boston researchers recruiting long haulers who are having trouble concentrating, experiencing strong fatigue
There are nearly 400,000 long haulers in Massachusetts, according to estimates.

As tens of millions of Americans continue to battle long-term coronavirus symptoms, Boston researchers are hoping to crack the mystery of Long COVID and what's sparking the debilitating condition for so many people.

Hub scientists are recruiting adults who had acute COVID-19 more than two months ago and are still experiencing symptoms, such as trouble concentrating and abnormally strong fatigue.

The brain scan study will be done in-person in Charlestown, so the long hauler study participants must be in the Boston area.

"We're looking to try to understand what's happening," neuroscience researcher Michael VanElzakker, with the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, told the Herald on Thursday.

Since VanElzakker put out the call for long haulers on social media, people have been "really appreciative," he said.

"Those who are dealing with this condition are really worried, and they're hoping they get studied," he added.

Nearly 20 million Americans are suffering from Long COVID, which is scientifically termed Post-Acute Sequelae of SARS-CoV-2 infection (PASC).

That 20 million American estimate is from the American Academy of Physical Medicine and Rehabilitation. Of those 20 million people, about 387,000 long haulers live in Massachusetts.

VanElzakker had been studying chronic fatigue syndrome before the pandemic. Many people with that disease initially have some type of viral infection.

"Studying that, I knew what was coming when COVID hit," VanElzakker said. "There would be a subset of people who wouldn't get better."

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VOX

Stuart Katz, a cardiologist at NYU Langone, got Covid-19 in December 2020, right before he was able to receive the Covid-19 vaccine as a health care professional. When we spoke for this article, more than a year since his infection, he told me excitedly that he just discovered he was able to eat honey again without it tasting awful. His extreme fatigue and brain fog had subsided after about six months, he says. Some aren't so lucky.

Strange and sometimes debilitating symptoms lasting long past the original bout of sickness are presenting in many people who've had Covid-19. The patient-coined term for this is long Covid, though experts often refer to it as post-Covid condition or PASC (for Post-Acute Sequelae of SARS-CoV-2 infection). Reports of how common long Covid is vary widely from study to study, but the WHO estimates that 10-20 percent of people are experiencing new or lingering symptoms three months after infection.

When we consider just how many people have been infected with Covid-19, that amounts to millions of people dealing with persistent, ongoing symptoms.

Unfortunately, there isn't much information on why this is happening and why only some people seem to be affected, though a recent preprint study out of Israel suggests that vaccinated people may have a lower risk of developing long Covid symptoms.

"Many people who have had Covid and who haven't recovered are starting to look very much like ME/CFS patients," says Lucinda Bateman, founder and medical director of the Bateman Horne Center, and an expert in the diagnosis and treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). As is often the case with long Covid, ME/CFS is characterized by chronic, debilitating symptoms such as fatigue, pain, and cognitive dysfunction — and ME/CFS often persists at least six months. The cause of ME/CFS is not well understood, but it's thought to possibly be triggered by a virus or another kind of infection. Bateman and other experts have been studying the parallels between long Covid and ME/CFS, hoping that this will give them a better understanding of both conditions.

While there's still so much we don't know about long Covid, it's possible to look to other chronic illnesses and post-viral syndromes for clues when it comes to managing the condition. There may not be a known cure for long Covid, but there are ways you can advocate for yourself and get care for your symptoms.

Know that symptoms can vary and may show up immediately after your infection ... or a few months later
One of the many frustrating realities of long Covid is that it doesn't look the same in everyone. In October 2021, the WHO released the following definition, which illustrates just how complex and varied long Covid actually is:

Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others ... which generally have an impact on everyday functioning. Symptoms may be new onset, following initial recovery from an acute COVID19 episode, or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable for children.

"Literally dozens and dozens of symptoms have been described, virtually touching on every single part of the body," Katz sayd. He also says that long Covid can crop up even in people who had a very mild case of the virus, so having a relatively easy bout of Covid-19 isn't a reason to discount your symptoms.

A systematic review published in November 2021 in the journal Frontiers in Medicine identified more than 100 possible symptoms that have been associated with long Covid. The most common ones noted in the research are those that are associated with the initial Covid-19 infection, such as loss of taste and smell, respiratory symptoms, chest pain, fever, and headaches. (The study authors did note that it's possible these are overrepresented in the research simply because they're the symptoms that were asked about most often.) Other common symptoms include cognitive dysfunction (like brain fog), nerve and muscle pain, sleep disturbances, mobility issues, and psychological symptoms.

Another major symptom is post-exertional malaise, which is a fancy way of saying that you are completely spent after doing even basic activities. "I personally experienced this where relatively minor things — things you would do without thinking, like run an errand to a store or do something that's really not exertional — would wipe you out not just for the day but for the next day too," says Katz.

These aren't the only possible symptoms that you might experience with long Covid; they're just the ones that have been mentioned most often in research.



Also, it's possible to be reinfected — especially with new variants popping up — so if you're suddenly experiencing new Covid-like symptoms after you've recovered from the initial infection, your first step should be getting tested to make sure it's not another round of Covid-19.

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At least 44 hospitals in the US have established post-Covid clinics as of August 2021, though there isn't an exhaustive list of these facilities. To find one in your area, try searching for "post-Covid clinic near me" or visiting the website of any large teaching hospitals nearby, which may have one or can refer you to one.

Give yourself a break (both physically and metaphorically.

"We tell people to pace their activity, meaning try to do the right amount of activity every day that doesn't escalate your symptoms but keeps you moving."

Despite the overwhelming fatigue that many people with long Covid experience, sleep disturbances are also frustratingly common. It's a vicious cycle in which the symptoms of long Covid can keep you up at night, and a lack of restorative sleep can make symptoms worse and healing harder.

"It's so easy to blame an illness like this on anxiety or depression or PTSD, which just isn't appropriate: This is a devastating, physical, post-viral, inflammatory, and neurologic illness."

There are really great patient advocacy groups that have given a voice to this and were a big part of the NIH paying attention and Congress providing appropriation of funds to study long Covid."

"Becoming part of that community is empowering and probably is the best thing that people should think about beyond talking with their doctors."
- Body Politic
- Long Covid Alliance
- Survivor Corps

[Anianna]

As awful as this is, I hope that this research sheds light on this myriad of symptoms because I've been living with this all of my life and, if what these people are experiencing as a result of Covid is in any way related, I and others like me who have been largely dismissed by doctors might finally get some answers.