Long COVID-19
Many questions remain, but some theories have emerged.
The lingering effects of COVID-19 continue to puzzle scientists and frustrate those experiencing its debilitating symptoms. While research is rapidly progressing, Long COVID presents unique challenges for researchers. Many symptoms, like fatigue and brain fog, overlap with other conditions, making it difficult to pinpoint who is specifically experiencing Long COVID and track its true impact.
In this newsletter, we delve into the latest findings on Long COVID:
Recent estimates on how common it might be
Promising research exploring its potential biological causes
New information on whether vaccines can reduce the risk of Long COVID
To those suffering from the long-term consequences of COVID-19, we acknowledge your struggle and the urgent need for understanding and solutions. We remain committed to sharing the latest science as it unfolds.
What is Long-COVID?
Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), refers to a condition where people experience a wide range of new, returning, or ongoing health problems weeks, months, or even years after first being infected with the SARS-CoV-2 virus (the virus that causes COVID-19).
Here are some key characteristics of Long COVID:
Symptoms: The symptoms of Long COVID can be very diverse and vary significantly from person to person. Some of the most common symptoms include:
Fatigue
Brain fog (difficulty concentrating)
Shortness of breath
Chest pain
Sleep problems
Muscle aches and pains
Loss of taste or smell
Anxiety and depression
Duration: The defining feature of Long COVID is that the symptoms persist for at least three months after the initial COVID-19 infection has resolved.
Challenges with Diagnosis: Because the symptoms of Long COVID are often non-specific and overlap with other conditions, diagnosis can be challenging. There is currently no single test for Long COVID, and diagnosis often relies on a doctor's evaluation of a patient's medical history and symptoms.
Impact: Long COVID can significantly impact a person's quality of life, affecting their ability to work, participate in daily activities, and maintain social connections.
The cause of Long COVID is still under investigation, but research suggests it may be linked to various factors, including persistent viral reservoirs, inflammation in the body, and damage to blood vessels or organs.
How many people have Long COVID?
Current estimates on the prevalence of Long COVID vary depending on the study definition and methodology used to define and measure it. Here's a breakdown of some estimates around the world:
World Health Organization (WHO): Estimates that 10-20% of people who contract COVID-19 experience at least one symptom lasting more than three months after the initial infection.
UK Office for National Statistics: Estimates are lower, suggesting around 2.7% of the population in the UK self-report Long COVID.
United States Centers for Disease Control and Prevention (CDC): Data from the National Health Interview Survey in 2022 suggests that 6.9% of U.S. adults reported ever experiencing Long COVID, while 3.4% reported currently having Long COVID.
Important Considerations:
These estimates are based on self-reported data or specific study criteria. The true prevalence of Long COVID might be higher or lower due to factors like:
Difficulty diagnosing due to non-specific symptoms
People not attributing lingering symptoms to COVID-19
Research is ongoing, and more accurate estimates may emerge as diagnostic tools and understanding of Long COVID improve.
What are the risk factors for Long COVID?
The exact reasons why some people develop Long COVID and others don't are still being unraveled by researchers. However, several factors have been identified as potentially increasing the risk of experiencing Long COVID but research is ongoing:
The severity of Initial COVID-19 Infection: People who experience a more severe case of COVID-19, requiring hospitalization or intensive care, seem to be at higher risk of developing Long COVID.
Age: While anyone can develop Long COVID, studies suggest a higher prevalence among middle-aged adults.
Pre-existing health conditions (e.g., autoimmune disorders)
Vaccination status (vaccination appears to reduce risk, but not eliminate it)
Sex: Some studies suggest women may be more susceptible to Long COVID than men.
Genetics: There might be a genetic component that influences susceptibility to Long COVID, but more research is needed in this area.
What are the current theories of pathogenesis (i.e., the process by which a disease or disorder develops) for Long COVID?
The root cause(s) of Long COVID continues to elude scientists, but several promising theories are under investigation. One theory suggests that even after the initial infection clears, traces of the virus might remain hidden within certain tissues. This could trigger ongoing inflammation and damage within the body. Another possibility is that the initial COVID-19 infection throws the immune system out of balance, leading it to become overactive or even attack healthy tissues. Researchers are also exploring the potential for damage to small blood vessels, which could disrupt blood flow and oxygen supply throughout the body. Finally, in some individuals, COVID-19 might trigger autoimmune reactions, where the immune system mistakenly starts attacking the body's own tissues. It's likely that Long COVID results from a combination of these factors, and researchers are working hard to unravel the complex mechanisms behind this condition. Some of the theories are summarized below:
Viral reservoirs (meaning viral proteins or viral RNA have found a home inside your body)
Reactivation of latent viruses, such as EBV.
Triggering autoimmunity
Gut microbiome dysbiosis
Chronic inflammation and immune dysregulation
Direct damage of the virus itself on organs
Dysfunctional signaling in the brainstem and vagus nerve
Microclotting and damage to blood vessels
Immune dysregulation*:
Complement dysregulation
Cross-talk between B and T cells impaired
Increase levels of circulating proinflammatory cytokines
Presence of autoantibodies
Increased proportions of exhausted T cells (by phenotype)
Gene expression changes in immune cells such as dendritic cell populations, monocytes, B cells, and T cells
Higher levels of antibodies to SARS-CoV-2 (spike-specific IgG) but also EBV, shingles, and chicken pox
*This is based on in vitro data, so we need more studies to see functional impacts in humans.
What are the impacts of Long COVID on cognitive abilities?
A recent study examined a large group of people to understand how Covid-19 affects cognitive abilities after infection (long Covid, defined as lasting symptoms for at least 12 weeks). They found that people with long Covid showed small to moderate declines in cognitive function, particularly in tasks that test memory, reasoning, and planning skills. These deficits were more pronounced in people who required hospitalization for Covid-19 and in those infected earlier in the pandemic, when the original strain of the virus was prevalent. Some key points are summarized below:
Study Design:
Type: Large-scale observational study
Population: Over 100,000 participants who completed online cognitive testing via the Cognitron platform
Data Collection: Researchers compared the cognitive function test results of individuals based on:
Self-reported COVID-19 infection at various time points
Whether they had ongoing symptoms
Severity of their infection (hospitalization vs. non-hospitalized)
Specific Results:
Key Finding: Participants who reported COVID-19 infection with symptoms continuing at least 3 months previously scored significantly lower on the cognitive tests. This suggests persistent cognitive impairment following COVID-19.
Severity Matters: Those hospitalized with COVID-19 showed greater deficits on cognitive tests compared to those with non-hospitalized cases.
Symptom Disconnect: Surprisingly, there was no direct link between poorer test performance and current symptoms like "brain fog."
Test Breakdown: Affected cognitive areas included:
Processing speed
Executive function (planning, reasoning)
Word finding
Has there been research on potential treatments for Long COVID?
Intensive research is currently underway to better understand the causes, potential treatments, and long-term impacts of long COVID. Although there's still no one-size-fits-all cure for Long COVID, researchers are making promising advancements in managing its various symptoms. There's significant overlap in treatments that help both Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. For example, carefully managing activity levels (known as "pacing") is a crucial strategy for both conditions.
Medications often target specific symptoms. Beta-blockers can help with POTS (a blood pressure condition), while low-dose naltrexone may address potential neuroinflammation. Additionally, intravenous immunoglobulin shows promise for those with immune system dysfunction.
Beyond medication, changes like increasing salt intake for POTS, managing cognitive workload for brain fog, and exploring elimination diets for gut problems can provide relief.
New treatment options are also on the horizon. Low-dose naltrexone, originally used for ME/CFS, could prove helpful for Long COVID. Antihistamines may alleviate certain symptoms, while the drug BC007 has the potential to address autoimmunity. Researchers are excited about the possibilities of anticoagulants to address abnormal blood clotting and apheresis, a blood filtration technique, to potentially remove microclots and reduce autoantibodies. Even some supplements, like Coenzyme Q10 and d-ribose, show promise for both Long COVID and ME/CFS and deserve further study. Some key takeaways are summarized below:
There is no single cure yet. Treatment focuses on managing symptoms and providing supportive care.
Some approaches being studied include antivirals, therapies targeting inflammation, and rehabilitation programs.
Scientists are turning to data from the ME/CFS community as long COVID shares many similarities.
Table 1: Summary of candidate treatments and supporting evidence
Notes: EBV, Epstein–Barr virus; HCMV, human cytomegalovirus; MCAS, mast cell activation syndrome; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; POTS, postural orthostatic tachycardia syndrome; VZV, varicella zoster virus.
Does getting vaccinated impact the likelihood of Long COVID?
The current picture on COVID vaccines and Long COVID risk reduction is promising, but still evolving. Several studies suggest that getting vaccinated against COVID-19 can significantly decrease your chances of developing Long COVID. Estimates vary, but some studies show reductions of up to 50% or more in the risk of Long COVID following vaccination compared to unvaccinated individuals.
It's important to note that these studies are observational, meaning they can't definitively prove that vaccines cause a reduction in Long COVID. However, the findings are consistent across multiple studies, suggesting a strong link between vaccination and a lower risk of experiencing long-term symptoms after COVID-19 infection.
Further research is ongoing to fully understand the protective mechanisms of vaccines against Long COVID. Getting vaccinated and staying up-to-date on boosters remains the most effective way to prevent severe illness, hospitalization, and potentially, Long COVID, according to the best available evidence.
Overall Impact:
Strong Evidence: Vaccination significantly reduces the risk of developing long COVID after an initial infection.
Varies by Study: Estimates range, but vaccines may reduce your risk by around 15-50% depending on the study and factors like the number of doses received.
Multiple doses of 3 or more are associated with the greatest decreased risk of about 70% in two studies for adults (here and here) and about 50% for kids (read more here).
How Vaccines Might Help:
Reduced Severity: Vaccines lower the risk of severe COVID-19, which correlates with a lower likelihood of long COVID.
Viral Load: Vaccines may help your body fight off the virus faster, reducing the amount of virus in your system, and potentially lessening the risk of lingering effects or damage to tissues or organs.
Immune Response: Some research suggests vaccines may help regulate the immune system, potentially preventing the dysregulation that may play a role in long COVID.
Other references:
Special thanks to Dr. Elisabeth Marnik and Dr. Yasmin Mohseni for co-authoring this newsletter!
Dr. Elisabeth Marnik is an Assistant Professor with a PhD in Immunology and Genetics. She used mouse models to understand how the immune system is altered in autoimmunity. You can follow her on Instagram at @sciencewhizliz and be sure to subscribe to her Substack
Dr. Yasmin Mohseni is an immunologist who holds a PhD in immunotherapy for solid organ transplant rejection and autoimmunity. She is now a scientist in cancer immunotherapy biotech. You can follow her on Instagram at @doctor.yas_
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