Long COVID Research 1

Review of the Long COVID Research

There is a considerable body of research on post-COVID conditions. But much of it is confusing. Rather than resolving issues, too many studies add information without contributing to a better understanding of the subject. In this chapter, I attempt to help answer this key question: What does the research mean for you if you have Long COVID?

In This Chapter:

Long COVID Is Not a Surprise

Long COVID Research - Viral Immunity

More than two decades ago, I recognized that the increasing frequency and growing severity of viral epidemics would define the twenty-first century. A pandemic loomed. Doctors were unprepared.

My book, Viral Immunity, was published in 2002. I followed SARS-CoV-1 when it emerged in Hong Kong and Guangdong Province, China 2003, but I didn’t write about it. Instead, I wrote Beating the Flu (2006), a book on protecting yourself from pandemic H5N1 bird flu.

In 2009, I traveled to Mexico City when the H1N1 swine flu pandemic broke out. I wanted to observe first-hand what it was like when a pandemic virus spread in a major city. That’s an eerie topic I’ll leave for another time. But one of the world’s most populous cities was like a ghost town.

Since the early stages of the COVID-19 pandemic in January 2020, I monitored the studies on post-COVID illness caused by the novel SARS-CoV-2 virus. Some acute cases recovered too slowly or incompletely in those early months, suggesting a chronic form. That was not unusual; it’s even expected, especially in those with severe infection. Long COVID is not a surprise, it was expected.

What Makes Long COVID Different

The overall number of cases is one reason Long COVID differs from other post-viral syndromes. The CDC estimates that 7.5% of American adults have lasting symptoms three or more months after their first SARS-CoV-2 infection. The US Census Bureau found that 28% developed Long COVID. Researchers haven’t been studying it long enough to get the percentages accurate, but both statistics add up to many sick people.

The US Department of Health & Human Services estimates up to 23 million cases of Long COVID. The global average rate of Long COVID is estimated at 10%. CIDRAP states at least 65 million people worldwide have this condition. That’s about the population of France.

“Worldwide, at least 65 million people have long COVID, and that is likely an underestimate, finds a review article published in Nature Reviews Microbiology.”

Another feature that defined the COVID-19 pandemic was the intensity of patient activists and some physicians who used social media to inform readers about recovery challenges and treatment options. Sorting through this much information on your own is daunting. This chapter lists some of the most significant resources to help you understand Long COVID.

Long COVID Research 2

Scientific Studies and Online Resources About Long COVID Research

There is a substantial body of scientific and clinical literature about Long COVID. Most of these studies focus on understanding the underlying causes of Long COVID. A few case studies explore the outcomes of various therapies and treatments on individual patients. I carefully examined the most promising research for this chapter, and here’s a summary of my findings as of mid-September 2023.

  • PubMed: 2,685 results of published peer-reviewed papers grouped in five areas.
    1. Pathophysiology
    2. Neurobiology
    3. Rheumatology
    4. Metabolic and endocrine
    5. Immunology
  • Google Scholar: 254,000 results
  • Science Direct: 207,325 results

Not only are there a lot of scientific papers about Long COVID research, but there’s conflicting information regarding what causes it, what makes it worse, and complications like getting reinfected while you have Long COVID.

Websites and Online Initiatives and Support

There are many online resources for patients. Here are some of the ones I used for my research:

  • RECOVERResearching COVID to Enhance Recovery is The National Institutes of Health (NIH) initiative to learn about the long-term effects of COVID. RECOVER aims to improve the understanding of and ability to predict, treat, and prevent PASC (post-acute sequelae of SARS-CoV-2), referred to by patients as Long COVID. Go to recovercovid.org for research papers and up-to-date events, including new trials. It’s from a conventional medicine viewpoint, but it’s thorough and informative.
  • INSPIREInnovative Support for Patients with SARS-CoV-2 Infectionsis an online COVID health study sponsored by eight universities. Participants complete an internet survey on how they’re feeling after SARS-CoV-2 infection. They also share their medical information through a secure cloud-based platform.
  • LONG-COVID EUROPE – The European view of Long COVID is of a pandemic within a pandemic. This group is concerned about the overconsumption of ineffective standard medical practices, inadequate diagnosis, and uncoordinated care. I’m also concerned, and that’s one of the main reasons I wrote extensively about this condition.
  • C-SUPPORTA foundation commissioned by the Dutch Ministry of Health, Welfare, and Sport, C-SUPPORT helps and advises people in the Netherlands who suffer from long-term coronavirus symptoms. They share learned experiences with healthcare professionals to improve the care and outcomes of Long COVID patients.
  • COVID CARE GROUP – A Facebook global community for long haulers offering advice about difficult symptoms. COVID CARE GROUP is considered the largest recovery resource worldwide, providing evidence-based research information and resources for recovery.

These are samples of the activity of patients and citizens, researchers, and governmental agencies attempting to understand and treat Long COVID. As a clinician, I attempt to raise awareness of Long COVID and encourage researchers to strive to discover effective therapies.

I advise patients to become knowledgeable about their condition. I remind them to be cautious about the overuse of pharmaceutical drugs and be mindful of alternative therapies that may not harm them but may not be effective.

Long COVID Research 3

Social Media

Patient-led evidence is invaluable in understanding a fast-moving infectious disease like COVID. Social media helped create the momentum needed to get more government and university involvement for Long COVID. Here are a couple that you may find helpful:

  • NIH Social Media Toolkit: Long COVID – Educates people about the symptoms and effects of Long COVID.
  • Prof. Akiko Iwasaki – Early in the COVID-19 pandemic, Dr. Iwasaki recognized the immensity of the problem before the rest of the world and launched a Twitter page to provide information on antiviral immunity and viral diseases. 

Dr. Iwasaki was not alone. There are many Twitter hashtags and account names associated with Long COVID, including:

Several British patients who were part of the Long Covid SOS advocacy group made a YouTube video, Message in a Bottle, which they uploaded in July 2020. It has since received more than 57,000 views.

The American teacher Amy Watson, coined the term “long-hauler” by posting a photo of herself in the cab of a semi wearing a trucker’s cap. She called her Facebook group Long Haul Covid Fighters.

Diana Berrent, who founded Survivor Corps as the Peace Corps of the COVID generation, established a strong presence on Facebook and YouTube.

YouTube Videos

Online virology and medical videos can help us understand Long COVID but watching them is time intensive. I’d like to see these videos include charts and summaries inserted at transition points. Here are a few about Long COVID and the experience of having this condition that I found useful:

  • THIS WEEK IN VIROLOGY (TWiV) – Hosted by Vincent Racaniello, Ph.D. of the microbiology department at Columbia University, along with other scientists and medical doctors, provides insights into aspects of viral infections.
  • DRBEEN MEDICAL LECTURES – Dr. Mobeen Syed is an MD who makes complicated medical conditions accessible. This video is an interview with Bruce Patterson, MD about IncellDx, a diagnostic laboratory that developed a test to differentiate acute from chronic COVID.
  • PBS NEWS – This edition provides sensible reporting on Long COVID—another broadcast interviews patients, explaining their symptoms and experiences.
Long COVID Research 4

Government Dysfunction and The Slow Pace of Long COVID Research

Academic researchers haven’t been idle. They are addressing the needs of Long COVID patients, as evidenced by the substantial funding allocated by governments worldwide and the number of papers listed on PubMed. Clinicians are dedicated to finding better ways to help patients manage symptoms and improve when possible. However, progress in generating effective patient outcomes has been slow and limited. Part of this is the need for wiser use of resources. Another is a lack of will to accept evidence-based and anecdotal papers when this form of clinical investigation could be the spark that sets off a flood of research.

For example, the National Institutes of Health (NIH) invested $1 billion into Long COVID research, but the outcomes have been modest. Most of the funding was directed towards observational research rather than ways to help patients directly. Esteemed physicians such as Ezekiel Emanual at the University of Pennsylvania and Eric Topol of Scripps Research Institute in San Diego have criticized the NIH for its misguided priorities and significant organizational challenges.

Unsurprisingly, the slow pace of the government’s efforts to address Long COVID is a source of ongoing frustration for patients and doctors. The substantial financial investment in this program has primarily been consumed by administrative expenses, leaving doctors and patients with limited knowledge about Long COVID and no consensus on how to treat it effectively.

Another significant obstacle for researchers is that Long COVID is a cluster of symptoms without a single cause. Modern medicine relies on a model that seeks a single cause for a disease and an effective and safe treatment or prevention method. Sometimes, it works extremely well. Here are some examples of smart research and effective intervention for three of the worst viral diseases of previous centuries.

Polio paralyzed hundreds of thousands of children in the early 20th century. But after the polio vaccine was introduced in the 1950s, this crippling disease was eradicated. Smallpox is caused by the variola virus that infects cells in the mouth, throat, and respiratory tract. A vigorous global vaccination campaign eradicated it. The last case of smallpox disease was recorded in Somalia in 1977.

Another example is the Human Immunodeficiency Virus (HIV), which causes AIDS.  Immunization is the accepted way to prevent viral spread, but we haven’t developed an effective vaccine to prevent AIDS. Instead, researchers developed antiretroviral drug therapy to control the disease. Though there is no vaccine or cure for AIDS, HIV drug treatment significantly lowers the viral load, allowing patients to live a normal life.

Different Biological Mechanisms Associated with Long COVID:

Immune system dysregulation
Gut microbiome dysfunction
Microvascular clotting
Hormone imbalances
Reactivation of EBV and HHV-
Reactivation of Lyme disease
Neurological impairment
Organ damage
Cognitive impairment patients refer to as brain fog.

The COVID Vaccine Controversy: Is The mRNA Vaccine One of the Causes of Long COVID?

Early in this pandemic, intense research efforts went towards COVID vaccines. One reason to emphasize a vaccine is that we didn’t have a specific and effective antiviral drug for SARS-CoV-1 or CoV-2. Another reason is that it’s highly profitable. So, the initial focus was developing vaccines to control the spread, a monumental effort to slow the global COVID-19 Pandemic and prevent economic collapse. COVID vaccinations began in the U.S. and Europe in December 2020 and are ongoing.

Vaccination skepticism is another topic, and I’ll discuss it later, especially concerning the cause of Long COVID. Overall, COVID vaccination helped slow the infection rate and reduce severe consequences of infection in immune-compromised and older people. But it also can cause Long COVID.

Some journalists and virologists argue that research on SARS coronavirus vaccines was already in process for several years. That’s why COVID vaccines were developed so quickly but without adequate safety evaluation. But I’ll leave that for a later discussion.

Image 5

Investigation That Addresses Systemwide Physiological Effects Confound Conventional Medical Thinking

Further complicating Long COVID research is the many body systems affected. What does a researcher focus on when it has a list of more than 200 symptoms?

Different Biological Causes of Long COVID

Immune dysregulation
Reactivation of EBV and HHV-6 herpes viruses
Disruption of the gut microbiome and persistent SARS-CoV-2 low-grade infection in the gut
Autoimmune activation and persistence
Blood clotting dysfunction
Impaired nerve signaling including dysfunction of the vagal nerve function

“Tests that return abnormal results in patients with ME/CFS and dysautonomia, such as total immunoglobulin tests, natural killer cell function tests, the tilt table or NASA lean test, the four-point salivary cortisol test, reactivated herpesvirus panels, small fiber neuropathy biopsy, and tests looking for abnormal brain perfusion should instead be prioritized.”

A 2023 paper outlines the many biological mechanisms that can cause Long COVID. The authors make a point that when COVID reaches a chronic stage without resolution, it’s better to evaluate more like ME/CFS than for acute SARS-CoV-2 illness.

Novel diseases, like COVID, have puzzling presentations. However, most of the research follows standard scientific thinking. Nothing new or creative. This is especially true when crossing traditional physiological boundaries requiring new thinking. It takes time for researchers trained in classical approaches to understanding diseases to catch up.

Here are some examples of leading Long COVID research in different areas of investigation that I consider helpful in understanding the different aspects of Long COVID. Remember, not all patients have the full array of systems and symptoms.

  • The Role of Immune Response During Acute Infection SARS-CoV-2 Invades the Lower Respiratory Tract
    Viruses that cause the common cold and the flu, including coronaviruses, mainly affect the respiratory system. A cold causes symptoms in the upper respiratory system, like sneezing, nasal congestion, and coughing. The flu affects both the upper and lower respiratory tracts. The flu can be life-threatening for older and immune-compromised people when it gets deep in the lungs and progresses to pneumonia. However, SARS-CoV-2 quickly enters the lower respiratory system, heading straight for the lungs. Studies found that the original SARS lesions in the lungs resulted in rapid loss of respiratory function.

  • How SARS-CoV-2 Affects the Central Nervous System
    Some researchers found that Long COVID is a neurological disorder affecting the brain and nervous system. They point to memory loss and foggy thinking, termed cognitive impairment, to support the cognitive dysfunction theory. The virus could linger in the brain for months after initial infection, triggering inflammation and an imbalanced immune response, keeping the immune system in an active response mode.

  • An Autoimmune Connection
    Doctors have long puzzled over why healthy immunity ends, and destructive immunity begins. This is the case with autoimmune diseases like rheumatoid arthritis and multiple sclerosis. It is also an essential question about Long COVID. Researchers found that acute COVID infection can trigger a diverse set of autoimmune conditions. The dysregulation of the immune response caused by SARS-CoV-2 presents a broad clinical spectrum, making it difficult to assess with standard laboratory tests.

  • Spike Protein Induced Thrombotic Vasculitis
    Several researchers, as well as clinicians, including Drs. Pierre Khoury and Voughn, believe COVID severity and Long COVID have a common cause. In a 2023 preprint, a team of researchers in the UK presented a case of debilitating symptoms after SARS-CoV-2 infection, noting the similarity of symptoms in some post-vaccination cases, both having persistent spike protein presence driving coagulopathy.
    “Considering the SARS-CoV-2 spike protein can independently induce fibrinaloid microclots, platelet activation, and endotheliitis, we predict that persistent spike protein will be a key mechanism driving the continued coagulopathy in Long COVID.”
    In the YouTube interview, Dr. Khoury describes using Ivermectin to treat acute COVID due to its anticoagulative properties.

  • Chronic Low-Grade Inflammation and Monocytes-Driver Hyperinflammation
    Persistent low-grade inflammation, like joint pain, is common in post-infectious illnesses and cardiovascular diseases. However, one type, the accumulation of monocytes, is unique to Long COVID. Researchers believe monocytosis promotes a pro-inflammatory environment in the lungs. Viral infections like Dengue also trigger inflammation, so this line of thinking is not new.
     A 2022 study found that monocytes cause an atypical cytokine storm in acute infection and may persist after the acute phase, prolonging recovery or causing chronic inflammation.

  • Innate Immune Cells Don’t Return to Normal
    Besides persistent monocytosis, natural killer (NK) cells remained elevated after the acute phase. Also, CD56, an archetype NK cell, remained higher than usual for several months after recovering from acute COVID. Eventually, CD56 cells falter, and levels may be below normal for at least three months after recovery.

  • Disrupted Serotonin Pathway
    Viral remnants could trigger the immune cells to produce more interferon. When low-grade inflammation persists, it interferes with the absorption of tryptophan, an amino acid used to make serotonin. Less serotonin impairs the vagus nerve, an integral part of the nervous system connecting the brain, gut microbiome, and other organ systems. Researchers believe that low serotonin is responsible for inadequate vagal signaling, causing system-wide dysfunction.
    A 2023 paper describes how viral infection reduces serotonin. The researchers found that viral infection with SARS-CoV-2 triggers type I interferon-driven inflammation that reduces serotonin through three mechanisms: (1) reduced intestinal absorption of the serotonin precursor tryptophan; (2) platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and (3) enhanced MAO-mediated serotonin turnover. 
    Serotonin deficiency is also associated with depression and chronic fatigue syndrome. One study demonstrated improved mood, sleep, and energy with prescription SSRIs. In our clinic, SSRIs helped a few Long COVID and ME/CFS patients a little but were far from a cure.

  • The Pain and Fatigue System
    Persistent fatigue is one of the most debilitating common symptoms of Long COVID (dry cough, loss of smell, stinging throat, muscle soreness, and joint aches). It’s not the same as being tired, like staying up too late or overworking. It doesn’t go away with more rest. Some doctors report that fatigue is the most common symptom with the current variants.
    No one understands it. Some researchers believe it’s because of mitochondria disruption. The mitochondria are organelles in cells that drive biochemical respiration and produce energy. Sleep disturbance can also contribute to chronic fatigue. But, in these cases, tiredness lessens with a good night’s sleep, not in Long COVID.
    Fibromyalgia and ME/CFS are other conditions that fit this model. In these chronic conditions, patients are tired all the time, don’t experience sound sleep, and don’t wake refreshed. They also have joint and muscle aches.
    A new way of framing the dynamics of chronic fatigue and ongoing pain is viewing pain and fatigue as a joint physiological system. Functional medicine physicians have known about this condition for some time. They term it “adrenal insufficiency.” The common occurrence among these patients is low normal morning cortisol, which can be tested in a morning blood sample or a saliva test.

  • Chronic Imbalance in Innate Immunity
    A robust immune response to acute SARS-CoV-2 exerts a lasting impact on innate and adaptive immunity. Inadequate immune response to SARS-CoV-2 may cause the inhibition of immune regulatory gene expression, favoring viral replication during the acute phase that does not return to normal after infection. In a sense, SARS-CoV-2 infection is two diseases: acute COVID infection and a chronic form, Long COVID.

  •  Long COVID Affects the Brain
    It’s clinically universal that Long COVID patients have some measure of cognitive impairment, along with other symptoms.
    “Expression of post-COVID symptoms was associated with specific affected cerebral networks, suggesting a pathophysiological basis of this syndrome…”
    A German study compared magnetic resonance imaging (MRI) images of patients with long COVID, fully recovered COVID-19 survivors, and healthy controls found microstructural changes in the images in different brain regions in the Long COVID patients. These findings are significant because they revealed viral-induced brain damage. That means healing brain tissue is a crucial element in the effective treatment of Long COVID.

Does The Virus Take Control of Our Bodies?

I don’t believe SARS-CoV-2 turns us into zombies like in pulp fiction and B-grade horror movies. But can it interfere with our body’s neurological messaging? Can it derail cellular metabolism?

A 2023 study found that SARS-CoV-2 can alter the structure of mitochondria, hampering energy generation. It can also affect genetic mechanism that damages mitochondria in organs, leading to more severe disease and to Long COVID.

The study’s authors weren’t surprised to see this activity but “were amazed at how sophisticated the virus is in achieving that goal.” The reach of the virus is astonishing. It disrupted mitochondrial genes in multiple organs in people with late-stage disease, especially in the heart, liver, and kidneys.

Mitochondrial disruption likely plays a crucial role in developing Long COVID, but it doesn’t turn patients into zombies.

Infectivity, Disability, and Mortality

Long COVID is not contagious. But take it seriously. Those with Long COVID have fewer healthy life years. The chance of hospitalization is increased. People with Long COVID have an increased risk of early death and serious illness.

“COVID-19 leaves its mark on the body in myriad ways, some of which last far longer—and are more serious—than a few days of  flu-like symptoms.”

Those with Long COVID are more likely to seek healthcare for a variety of other health concerns, including irregular heart rate, blood clots, and respiratory conditions. In 2022, the CDC published health statistics documenting more than 3,500 Americans who died from conditions associated with Long COVID.

Summary of Long COVID Research

Though there is considerable research and sizable funding for Long COVID investigation, it’s still elusive. So far, there’s no unifying theory. Maybe there isn’t one. The quest for a simple, elegant explanation may be too reductionistic for a complex condition like Long COVID. Instead, it requires an approach that strategically addresses multiple systems and disease processes at the same time. It requires enough flexibility to adjust therapy as the virus adapts to immune pressure and body systems respond. Treatment should evolve as symptoms change. Individualized therapy, rather than one pill for everyone, is likely our best approach to the treatment of Long COVID.

Selected References

Amruta, N., Chastain, et al (2021). SARS-CoV-2 mediated neuroinflammation and the impact of COVID-19 in neurological disorders. Cytokine & Growth Factor Reviews, 58, 1-15. https://doi.org/10.1016/j.cytogfr.2021.02.002

Balzanelli, M. G., et al (2021). Immunity Profiling of COVID-19 Infection, Dynamic Variations of Lymphocyte Subsets, a Comparative Analysis on Four Different Groups. Microorganisms, 9(10), 2036. https://doi.org/10.3390/microorganisms9102036

Chrousos GP, Kaltsas G. Post-SARS sickness syndrome manifestations and endocrinopathy: how, why, and so what? Clin Endocrinol (Oxf). 2005 Oct;63(4):363-5. doi: 10.1111/j.1365-2265.2005.02361.x. PMID: 16181227; PMCID: PMC7162060.v

Davis, H.E., McCorkell, L., Vogel, J.M. et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 21, 133–146 (2023). https://doi.org/10.1038/s41579-022-00846-2

DeVries A, Shambhu S, Sloop S, Overhage JM. One-Year Adverse Outcomes Among US Adults With Post–COVID-19 Condition vs Those Without COVID-19 in a Large Commercial Insurance Database. JAMA Health Forum. 2023;4(3):e230010. doi:10.1001/jamahealthforum.2023.0010 

Elham Dolatabadi, et al (2022) Using Social Media to Help Understand Long COVID Patient Reported Health Outcomes: A Natural Language Processing Approach

Elham Dolatabadi, et al. Using Social Media to Help Understand Long COVID Patient-Reported Health Outcomes: A Natural Language Processing Approach. medRxiv 2022.12.14.22283419; doi: https://doi.org/10.1101/2022.12.14.22283419

Goldstein, E. (2023). Mortality associated with Omicron and influenza infections in France before and during the COVID-19 pandemic. Epidemiology & Infection, 151, E148. doi:10.1017/S0950268823001358

Guarnieri, J. W., Dybas, J. M., Fazelinia, H., Kim, M. S., Frere, J., Zhang, Y., Soto Albrecht, Y., Murdock, D. G., Angelin, A., Singh, L. N., Weiss, S. L., Best, S. M., Lott, M. T., Zhang, S., Cope, H., Zaksas, V., Saravia-Butler, A., Meydan, C., Foox, J., . . . Wallace, D. C. (2023). Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. Science Translational Medicine. https://doi.org/abq1533

Kiho Son, Rameen Jamil, Abhiroop Chowdhury, et al. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms. European Respiratory Journal Jan 2023, 61 (1) 2200970; DOI: 10.1183/13993003.00970-2022       

Klein, J., Wood, J., Jaycox, J. et al. Distinguishing features of Long COVID identified through immune profiling. Nature (2023). https://doi.org/10.1038/s41586-023-06651-y

medRxiv 2022.12.14.22283419; doi: https://doi.org/10.1101/2022.12.14.22283419

Rezkalla SH, Kloner RA. Post-Acute Sequelae of SARS-COVID-2 Syndrome: Just the Beginning. Cardiol Res. 2021 Oct;12(5):279-285. doi: 10.14740/cr1290. Epub 2021 Aug 31. PMID: 34691325; PMCID: PMC8510656.

Robin Kerr, Harriet A. Carroll. Long COVID is Primarily a Spike Protein Induced Thrombotic Vasculitis, 18 May 2023, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-2939263/v1

Wong AC, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023 Oct 9:S0092-8674(23)01034-6. https://pubmed.ncbi.nlm.nih.gov/37848036/

Zhang, H., Zang, et al (2023). Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes. Nature Medicine, 29(1), 226-235. https://doi.org/10.1038/s41591-022-02116-3