What Makes Long COVID So Difficult to Understand?

What Makes Long COVID So Difficult to Understand?

Long COVID is not just one disease. It’s not even a medical term or official diagnosis.

Long COVID is an umbrella term coined by Elisa Perego, PhD, in May 2020. Perego, an archaeologist at University College London, used the hashtag #longcovid on Twitter to describe unrelenting symptoms after her initial infection. Her term challenged World Health Organization (WHO) experts focused on acute infection, and she was proven right. 

In This Chapter: 

During the early stages of the pandemic, Perego and other patients found that those with severe or even mild SARS-CoV-2 infection could have long-lasting symptoms. SARS-CoV-2 can infect multiple organs at the same time, each with a different set of symptoms, and it has both acute and long tail stages. COVID is a complicated disease that disturbs multiple body systems and can linger long after the initial infection, giving rise to Long COVID syndrome. 

Long COVID is perplexing because it presents as a cluster of persistent symptoms in individuals who were infected with SARS-CoV-2 and don’t fully recover. Despite more than three years of the COVID-19 pandemic, “Long COVID” still retains the stigma of a mystery disease. But is it mysterious, or is it simply a complex syndrome not uncommon in other post-infectious conditions? 

In this chapter, you’ll learn that Long COVID is not an unexpected mystery disease; many other infections cause similar symptoms. In a Vox article by Dylan Scott, the author states that most scientists agree there is no single cause of Long COVID. However, that’s not technically true. SARS-CoV-2 is the causative viral infection, the source of many symptoms, much like other post-viral illnesses discussed in Chapter One

What Is Post-Acute Infectious Syndrome? 

SARS-CoV-2 is not unique in triggering post-acute chronic symptoms. Post-acute infectious syndrome (PAIS) occurs in some individuals after infection by viruses, bacteria, or spirochetes like Lyme disease. At least ten unexplained PAISs have been associated with documented viral infections. Besides SARS-CoV-2, other viral infections that can trigger chronic illness include SARS, Ebola, Polio, Chikungunya, Epstein-Bar Virus, and Dengue.

Dengue is frightening. Like COVID, the spectrum of symptom severity in Dengue ranges from mild to life-threatening, including Dengue shock syndrome. Dengue can infect various organs, such as the liver, brain, heart, and intestines. Both viruses can infect a wide range of body cells. 

At least a third of Dengue patients report fatigue and other symptoms persisting for two months after their initial infection. Post-dengue fatigue syndrome (PDFS) includes symptoms of extreme fatigue, severe muscle weakness and pain, joint pain, “brain fog,” and neurological complaints, much like symptoms of Long COVID, only more severe. PDFS symptoms often begin abruptly with severe headaches, pain behind the eyes, muscle aches, loss of appetite, and fever. PDFS can last for months or become chronic. These symptoms bear a striking resemblance to those of Long COVID because they have common pathways in the body and have similar effects on viral immunity. 

We Should Have Learned from The Original SARS

Similar post-infectious symptoms occurred after the original SARS epidemics. SARS-CoV-1 emerged in 2003 from Foshan, Guangdong region in China, next to Hong Kong, and another coronavirus, MERS, emerged in Saudi Arabia in 2012. Both had a higher death rate and led to more severe acute illness compared to SARS-CoV-2. However, neither of them escalated into a global pandemic. 

Follow-up studies found that nearly 50% of survivors experienced chronic fatigue up to a year after recovering from the acute phase. This was even more severe than what we see with Long COVID. At the time, we didn’t have the medical will or academic curiosity to learn more. Though, in hindsight, we should have. 

What Can We Learn from Other PAISs?

All PAISs, including Long COVID, are characterized by a failure of the body to fully recover from an acute infection. Like with Long COVID, the pathogen is no longer detectable by standard laboratory methods. However, a blood sample often reveals immune markers such as elevated Immunoglobulin G (IgG). In some cases, Inflammation markers like C-reactive protein may be somewhat elevated, although this is not a consistent finding.

Body System Pathways Lead to Long COVID

In a review article published in Nature Reviews Microbiology, the authors suggest a pathway of body systems most likely to become part of a patient’s Long COVID presentation. This biological map aligns with my understanding of viral infections, which I previously wrote about in Viral Immunity and Beating the Flu, a book on the H5NI pandemic avian influenza, the “bird flu.” 

SARS-CoV-2 can breach the blood-brain barrier and infiltrate the hypothalamus, triggering low-grade inflammation that reduces nervous system function. One of the prominent symptoms is sleep disturbance, which results in persistent daytime fatigue and a feeling of restlessness. It disrupts the hypothalamic-pituitary-adrenal (HPA) axis, causing low-grade adrenal insufficiency. Cortisol levels in a blood test may be low or hover at the lower end of the normal reference range, leading to weakness, tiredness, and a lack of motivation. 

Causes, Triggers, Vaccines, and Other Associations of Long COVID

Causes, Triggers, Vaccines, and Other Associations of Long COVID

Though considered uncommon, the occurrence of Long COVID symptoms after vaccination is a genuine concern. It’s essential to clarify that not everyone vaccinated for SARS-CoV2 develops Long COVID, and not all Long COVID patients were vaccinated. COVID-19 vaccines have saved lives and prevented countless complications in vulnerable individuals. However, they are not without risks.

Vaccination may prevent Long COVID, but like all vaccines, those targeting SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, can cause reactions and complications in some people. It might even be one of the causes of Long COVID.

Although rare, a cluster of cases has emerged after vaccination, with post-vaccine symptoms including severe fatigue, headaches, abnormal heart rate, and blood pressure issues. Some individuals with varicose veins have also reported superficial blood clots and phlebitis. An article in Science indicates that some people may be susceptible to experiencing symptoms similar to Long COVID. 

Paradoxically, a review of 16 observational studies in the British Medical Journal found that Long COVID patients may benefit from an immune boost through vaccination. 

Genetic Predisposition: The COVID-19 Host Genetics Initiative (HGI) is a bottom-up collaborative effort among genetic researchers with the goal of working together to learn the genetic determinants of COVID susceptibility, severity, and outcomes. The aim is to enhance the understanding of the biology of SARS-CoV-2 infection, and HGI members have identified 51 distinct genome-wide links associated with SARS-CoV-2 infection. 

A meta-analysis found that individuals carrying the FOXP4 gene were at higher risk for Long COVID. FOXP4 is present in alveolar lung cells that help promote respiratory health. If SARS-CoV-2 infections weaken lung function, it can contribute to developing Long COVID. 

Inflammation Biomarkers: Long COVID patients may or may not exhibit biomarkers of inflammation, such as C-reactive protein (CRP), in a blood sample. The three most common markers are Interleukin-6 (IL-6), CRP, and Tumor Necrosis Factor Alpha (TNF-α). These tests are available from Quest Diagnostics and Labcorp. However, on average, they are present in less than 20% of Long COVID patients. This low percentage doesn’t make for a universal test to diagnose Long COVID. However, a diagnosis is more likely if one or more of these markers are present. 

Long COVID Is a Multisystem Syndrome

I prefer using Long COVID Syndrome (LCS) instead of Long COVID. A syndrome is a cluster of symptoms frequently occurring together, characterizing a particular health condition. 

Long COVID is a multisystem condition with over 200 symptoms extending beyond the respiratory tract. These symptoms include profound, unrelenting fatigue, weakness, irregular heart rate, numbness of the extremities, and liver or bladder malfunctions. But the number of symptoms can be overwhelming, as doctors and researchers often become too engrossed in the details to see the big picture.

Long COVID’s Impact on Organ Systems

   · HEART: chest pain, palpitations, functional impairment, irregular heart rate, inflammation (including myocarditis)
   · BLOOD VESSELS: abnormal clotting, thrombosis, micro clots, pulmonary embolism, stroke
   · LUNGS: cough, difficulty breathing
   · PANCREAS: diabetes, pancreatic insufficiency, pancreatic organ failure
   · GASTROINTESTINAL TRACT: abdominal pain, gas, bloating, nausea, diarrhea, vomiting, constipation, dysbiosis
   · KIDNEYS: renal failure
   · BRAIN and NERVOUS SYSTEM: depression, anxiety, sleep disturbance, memory loss
   · MUSCULOSKELETAL SYSTEM: muscle weakness, joint pain
   · REPRODUCTIVE SYSTEM: irregular menses, increased severity of PMS, erectile dysfunction, low sperm count

What Happens When You Get a Viral Infection and Symptoms Linger?

After initial exposure, the body’s immune system responds. Either it clears the virus, leading to recovery, or the virus bypasses some of the immune barriers and goes deeper into tissues and cells. This can cause several days or a few weeks, of acute symptoms. Most of the time, the immune system prevails, and you get better. But when non-specific immune imbalances occur, reactivation of dormant herpes viruses like Epstein-Barr virus (HIV-4) and HIV-6 can trigger symptoms of PAISs. 

COVID differs from other common viruses, like Epstein-Barr, in that it affects many body systems at the same time. Diarrhea and other gastrointestinal symptoms are common due to the impact of SARS-CoV-2 on the gut microbiome. The viral dysbiosis caused by SARS-CoV-2 can contribute to many of the symptoms associated with Long COVID. 

Virally infected tissue triggers an autoimmune response, not directed at the virus itself but at the tissue where it resides, like the joints or blood vessels. The immune response can lead to clotting and endothelial changes, resulting in spontaneous bruising. Neurological impairment may occur due to dysfunctional nerve signaling in the brainstem and vagus nerve, causing chronic fatigue and postural tachycardia syndrome (POTS). 

These symptoms make sense because dysregulation of these five body systems can cause all the symptoms linked to Long COVID. Similar immunological responses cause symptoms seen in ME/CFS and dysautonomia. 

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The Pandemic Will End, But Long COVID Will Not Go Away

Long COVID differs from post-COVID, when recovery is delayed by 2-4 weeks. Slow healing is typical for severe respiratory viral infections in less healthy individuals. But Long COVID is unique. It’s a syndrome characterized by a cluster of symptoms that vary from patient to patient and can persist for months or years. The NIH defines Long COVID as symptoms persisting for more than three months. 

Once it becomes chronic, Long COVID resembles myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and a type of dysautonomia called “postural orthostatic tachycardia syndrome” (POTS). Dysautonomia, according to The Dysautonomia Project, is an umbrella term for autonomic nervous system disorders. 

Researchers report that 10%-20% of those infected with COVID-19 develop Long COVID, with the most common age group being between 36 and 50 years old. In comparison, the worst outcomes for acute COVID-19 are observed in those over 50 years old. The occurrence of Long COVID is highest in hospitalized cases, affecting 50%-70% of patients compared to 10%-30% of patients who were not hospitalized. 

Children can also experience Long COVID. A 2022 systematic review paper revealed that about 25% of children and adolescents with acute COVID-19 developed chronic fatigue, mood changes, and sleep disturbances consistent with Long COVID.

What Are Your Chances of Getting Better if You Have Long COVID? 

Medical doctors are unfamiliar with treating ME/CFS and dysautonomia. They prescribe drugs to treat symptoms but may not address the underlying complexity of these conditions. So, it’s not surprising that no specific, effective treatments for ME/CFS or POTS exist. The average clinician expects Long COVID patients to share the same fate. But could we do better? I think so. 

Getting Better

I’ve treated ME/CFS and POTS patients over many decades, and at our integrative medical center, we treat chronic Lyme disease patients. The majority improve, and many get better as their condition gradually goes into remission. I know it’s oversimplifying to equate Long COVID with ME/CFS, but there are similarities. Both lack a specific cure, yet that doesn’t mean they can’t be treated safely and effectively. 

Antibiotics are crucial in Lyme disease, and antivirals can benefit COVID patients. However, relying solely on antimicrobials isn’t the solution in the chronic stage, like Long COVID. Most of the time, they don’t work. I know the answer is complicated, but it’s not impossible to understand Long COVID and treat it safely and effectively.

Most Long COVID patients suffer on their own, but it doesn’t have to be that way. Some patients take a more proactive approach. The health and fitness guru Oz Garcia hits the mark in his book, After Covid: Optimize Your Health in a Changing World. His natural health recommendations can aid in the recovery from acute and post-COVID symptoms and may even help prevent Long COVID.

Recovering from Long COVID is challenging. Overly simple treatments often fail, while high-cost drug therapies offer short-term symptom management with a risk of side effects and little chance of long-term cure. 

A simple, safe, and effective solution doesn’t exist for complex, multifaceted conditions like Long COVID. 

However, that doesn’t mean we don’t have ways to manage the effects of the illness or treatments that can alter the course of the disease, bending the curve toward healing and complete recovery. In the following chapters, I’ll discuss ways to beat Long COVID. 

Selected References 

Choutka, J., Jansari, V., Hornig, M. et al. Unexplained post-acute infection syndromes. Nat Med 28, 911–923 (2022). https://doi.org/10.1038/s41591-022-01810-6 

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 

Iqbal, P., Ata, F., Chaudhry, H., Muthanna, B., Younas, H. W., Sharma, R., Fadah, K., Elazzazy, S., Hamad, A., Abu Tabar, O. S., & Omar, N. E. (2023). Post‐COVID‐19‐associated multiorgan complications or “long COVID” with literature review and management strategy discussion: A meta‐analysis. Health Science Reports, 6(4). https://doi.org/10.1002/hsr2.1211 

Jensterle M, Herman R, Janež A, et al. The Relationship between COVID-19 and Hypothalamic-Pituitary-Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess-The CAPISCO International Expert Panel. Int J Mol Sci. 2022 Jun 30;23(13):7326. doi: 10.3390/ijms23137326

Lai, J., Liu, H., Manachevakul, S., Lee, A., Kuo, T., & Bello, D. (2023). Biomarkers in long COVID-19: A systematic review. Frontiers in Medicine, 10. https://doi.org/10.3389/fmed.2023.1085988 

Lopez-Leon, S., Wegman-Ostrosky, T., Ayuzo del Valle, N.C. et al. Long-COVID in children and adolescents: a systematic review and meta-analyses. Sci Rep 12, 9950 (2022). https://doi.org/10.1038/s41598-022-13495-5 

Malavige, G.N., Jeewandara, C. & Ogg, G.S. Dengue and COVID-19: two sides of the same coin. J Biomed Sci 29, 48 (2022). https://doi.org/10.1186/s12929-022-00833-y 

Oliver O’Sullivan. Long-term sequelae following previous coronavirus epidemics. Clinical Medicine Jan 2021, 21 (1) e68-e70; https://www.rcpjournals.org/content/clinmedicine/21/1/e68 

Rocchi G, Giovanetti M, Benedetti F, Borsetti A, Ceccarelli G, Zella D, Altomare A, Ciccozzi M, Guarino MPL. Gut Microbiota and COVID-19: Potential Implications for Disease Severity. Pathogens. 2022;11(9): 1050. https://doi.org/10.3390/pathogens11091050  

Sigera PC, Rajapakse S, Weeratunga P, De Silva NL, Gomes L, Malavige GN, Rodrigo C, Fernando SD. Dengue and post-infection fatigue: findings from a prospective cohort-the Colombo Dengue Study. Trans R Soc Trop Med Hyg. 2021 Jun 2;115(6):669-676. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115379/ 

TranV-T, Perrodeau E, SaldanhaJ, et al. Efficacy of first dose of covid-19 vaccine versus no vaccination on symptoms of patients with longcovid-19: BMJMed 2023; 2: e000229 https://doi:10.1136/bmjmed-2022-000229     

Umakanth, M. (2018) Post Dengue Fatigue Syndrome (PDFS) among Dengue IgMAntibody Positive Patients at Batticaloa Teaching Hospital, Sri Lanka. Open Access Library Journal, 5: e4798. https://doi.org/10.4236/oalib.1104798 

Whiteley MS, Holdstock JM. Non-thrombotic superficial venous phlebitis secondary to Covid-19 vaccine or subsequent Covid-19 infection. SAGE Open Medical Case Reports. 2022;10. https://journals.sagepub.com/doi/full/10.1177/2050313X221124378