The Perplexing Long-COVID Syndrome: Its Biological Causes

Shin

And what now?

A syndrome is a collection of symptoms of unclear causes, which is different from a disease with a defined set of symptoms and a cause. For example, coronavirus disease 2019 (Covid-19) is a disease of the lower respiratory tract that’s caused by a virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, long-Covid is a syndrome involving multiple organ systems and biological causes.

Despite being a syndrome, long-Covid is very real. Survivors of Covid-19, regardless of initial disease severity, do indeed face more long-term health issues than non-survivors.

How common is it?

The latest data (as of 1st August 2021) from the U.K. Office for National Statistics (ONS) reported that 3% of people who had tested positive for SARS-CoV-2 experienced at least one continuous symptom at 12–16 weeks after infection. If only symptomatic cases are counted, this percentage is 6.7%. And this percentage is only 0.5% in the control group who had never been tested positive for SARS-CoV-2.

The 12 symptoms the ONS investigated were fever, headache, muscle ache, weakness or tiredness, nausea or vomiting, abdominal pain, diarrhea, sore throat, cough, shortness of breath, loss of taste, and loss of smell. However, brain fog or cognitive symptoms were not examined — probably because we didn’t expect them to be part of long-Covid in the beginning — so the ONS’s prevalence estimates may actually be an underestimate.

Long-Covid is more common among survivors of more severe Covid-19. In a 6-month follow-up study of 183 previously hospitalized persons for Covid-19, 56% developed long-COVID. Of this 56%, 31% had no difficulties doing their usual daily activities, 15% faced some limitations, 7% could not do some activities, and 3% became dependent on caregivers. Before Covid-19, 85% of the survivors were healthy; after Covid-19, it’s down to 44% at 6-month.

One meta-analysis of 15 studies and one systematic review of 45 studies estimated that 70-80% of Covid-19 survivors developed persistent symptoms representing long-Covid for weeks or months after the initial infection. But most of the reviewed studies did not have control groups to subtract the background rates of common long-Covid symptoms like fatigue. Even before the pandemic, 7–45% of the general population already has fatigue.

So, the true prevalence of long-Covid is probably 5–10% in survivors of mild Covid-19, which should be lesser in survivors of asymptomatic Covid-19 and higher in survivors of severe Covid-19.

Children can get long-Covid, too, although the rate at which this occurs is still debated. Vaccinated people (with either Pfizer’s mRNA, Moderna’s mRNA, or AstraZeneca’s DNA vaccines; two doses) can also develop long-Covid, but this risk is 49% lower than unvaccinated people.

Probable biological causes

1. Long-term organ dysfunction

Covid-19 is known to harm multiple organ systems, especially in its severe stage, due to excessive systemic inflammation and blood clots that have systemic-wide effects. As organs need time to heal — if it even heals — the resulting organ injury could produce persistent symptoms.

For instance, it’s common to see abnormal imaging scan results of the lungs weeks or months after Covid-19, especially after severe Covid-19. Some of the imaging scans represent pulmonary fibrosis, a condition of lung scarring. People with pulmonary fibrosis have sub-optimal lung function that cannot exchange gases (oxygen and carbon dioxide) properly, which could cause symptoms of breathlessness, fatigue, and exercise intolerance.

Long-term imaging scan abnormalities of the brain, heart, kidney, pancreas, and spleen — have also been detected in survivors of Covid-19. An imaging scan is deemed ‘abnormal’ when the imaged organ doesn’t look right, but it doesn’t tell us what the specific problem is. So, abnormal imaging scans might or might not indicate organ injury or malfunction.

While it makes sense that more severe Covid-19 would lead to more severe long-term organ abnormalities, even mild Covid-19 can cause similar problems. For instance, one imaging study detected persistent brain structural changes in Covid-19 survivors compared to non-Covid controls at 3-month follow-up, and 80% of those survivors had only mild Covid-19.

2. Virus persistence

Prolonged shedding of SARS-CoV-2 has been detected in the respiratory and intestinal tracts, as well as nasopharyngeal and fecal swabs, of infected persons for months. Viral shedding follows after viral replication, indicating that SARS-CoV-2 may remain active in the body for months in some individuals, which might trigger chronic immune responses.

In one study, for example, 5.3% of 203 survivors of symptomatic Covid-19 were still PCR-positive for SARS-CoV-2 after 90 days. This 5.3% of survivors also showed increased cytotoxic T-cell responses specific for SARS-CoV-2. Thus, SARS-CoV-2 persistence in the body can trigger persistent immune responses that could be responsible for some of the long-Covid symptoms.

SARS-CoV-2 could persist in some of the immune-privileged body sites, such as the brain, where the adaptive immune system tends to stay away from. Alternatively, SARS-CoV-2 could also integrate genetic pieces of itself into the cell’s genome to establish a persistent infection.

In fact, previous studies on other RNA viruses besides SARS-CoV-2 already found that RNA viruses like corona-, entero-, hepatitis C, Zika, Ebola, and measle viruses could establish persistence in the body, which might contribute to the development of chronic diseases. This isn’t surprising given that evolution would favor viruses with a strong will to survive.

3. Reactivation of dormant herpesviruses

Herpesviruses are notorious for their latent life cycle that can establish dormancy in the body (e.g., brain, thyroid, heart, breast, lung, liver, kidney, etc.) permanently. So, herpesviruses stay for life. And more than 90% of humans harbor at least one type of herpesvirus in the body.

In the latent or dormant state, no active viral replication occurs, so no immune responses occur as well. But under conditions of cellular stress — such as psychological stress, fever, chemotherapy, and immunosuppression— latent herpesviruses can reactivate and alarm the immune system. Frequent viral reactivations have been tied to various chronic diseases.

For example, herpes simplex virus type 1 (HSV-1) reactivations can cause neuroinflammation, which has been implicated in the development of mild cognitive impairment and Alzheimer’s disease. Epstein-Barr virus (EBV) reactivation can activate genes involved in chronic diseases, namely multiple sclerosis, rheumatoid arthritis, type 1 diabetes, celiac disease, and lupus.

One study has found that 55% of 67 Covid-19 patients produced antibodies against EBV and that EBV/SARS-CoV-2 co-infection produced higher levels of inflammatory biomarkers, necessitating more corticosteroid use. There have been other case reports of herpesvirus reactivations in Covid-19 patients.

As a result, latent herpesviruses “that [re]activate under conditions of SARS-CoV-2-driven immunosuppression or immune dysregulation might also infect new body sites and cell types, allowing them to drive new symptoms,” Dr. Proal and Dr. VanElzakker wrote in their review paper.

4. Altered activities of other bacteria, fungi, or parasites

“Like viruses, many bacterial, fungal, and parasitic pathogens also change their activity and/or infect new tissue and the CNS [central nervous system] under conditions of immune dysregulation or stress,” the review authors continued.

One example is Bartonella henselae, a tick-borne bacterium that can infect and damage blood vessel cells, causing vascular and immune problems. Another example is Toxoplasma gondii — a common latent parasite residing in nerve cells in about one-third of the population — that has been tied to irregularities in brain functions, including lipid metabolism, immune cell migration, and olfaction in the brain. And immunosuppression, be it from drugs or diseases, is a risk factor for Toxoplasma reactivation.

So, Covid-19 altering the immune system may also, in turn, alter the pre-existing states of other latent or dormant pathogens in the body. But no reports of bacterial, fungal, or parasitic reactivations have been documented in long-Covid, so this biological explanation remains speculative for now.

5. Functional redundancy

Functional redundancy means that the activity of one pathogen can enhance the virulence of another pathogen if they both share a similar mechanism of action.

One relevant example is interferon, a key anti-viral defense of the immune system that interferes with viral activities. But SARS-CoV-2 is notorious for encoding proteins that dysregulate interferons as a method to evade the immune system. Other viruses such as herpes simplex virus (HSV), hepatitis C virus (HCV), and influenza virus can inhibit interferons too.

Thus, multiple viruses attacking the same aspect of the immune system — the interferons — could produce an additive or synergistic effect in hindering virus control. Put it another way, patients already infected with interferon-suppressing viruses at the time of SARS-CoV-2 infection “may have more trouble mounting an immune response that fully clears SARS-CoV-2 from all body sites,” the review authors explained.

Functional redundancy also applies to the hypoxia-inducible factor (HIF-1) that plays an essential role in cell survival during hypoxia, a condition of low oxygen levels. SARS-CoV-2 and other pathogens (e.g., Bartonella henselae and herpesviruses) can stimulate HIF-1 to drive a state of hypoxia, impairing basic cell functions such as mitochondrial energy production and immune responses. And hypoxia is another form of cellular stress that can reactivate latent herpesviruses and contribute to chronic diseases.

6. Genetic factors

Some genetic variations present in the population may also influence the risk of long-Covid, especially gene variants of the immune system.

For instance, mannose-binding lectin 2 and toll-like receptors are crucial elements of the innate immune system that initiates early responses against and eradicate viruses like SARS-CoV-2. But suppose SARS-CoV-2-infected individuals have a weaker or defective variant of such genes. In that case, they may not mount proper immune responses against SARS-CoV-2, possibly leading to long-Covid as a result of unsuccessful virus clearance.

Another genetic factor could be human endogenous retroviruses (HERV) DNA sequences that comprise about 8% of the human genome. HERVs are ancient relics of retrovirus infections that our ancestors faced. Despite its ancientness, HERV DNA still interacts with the innate immune system to maintain a basal immune alert against infections. In fact, the bronchoalveolar lavage fluids from the lungs of Covid-19 patients have been found to exhibit signs of HERV DNA dysregulation. Whether this outcome is long-lasting remains unclear at present, however.

7. Microbiome dysregulation

Modern science has accepted that we are as much microbial as humans. Microbes live in our oral cavity, lungs, urinary tract, and especially the gut, which we collectively call the microbiome that can help or harm us.

Certain gut bacteria like Lactobacillus and Bifidobacterium species can manufacture brain neurochemicals, such as dopamine and serotonin, that can influence the vagus nerve linking the gut and brain. Some gut bacteria synthesize butyrate that’s anti-inflammatory and preserves the gut lining.

When these beneficial microbes get outgrown by harmful ones like Clostridium and Escherichia species, gut dysbiosis occurs. This can happen when the host undergoes stress, be it psychological or physical (injuries or diseases). Gut dysbiosis has systemic consequences because it causes leaky gut lining, leaking out what should have stayed in the gut. So, gut dysbiosis is present in numerous chronic diseases, such as major depression, irritable bowel syndrome, obesity, and chronic fatigue syndrome.

And Covid-19 patients have been found to develop a shift in microbiome patterns to an undesirable state, representing gut dysbiosis, which persisted even after hospital discharge. Plus, long-Covid suffers often experience gastrointestinal symptoms: diarrhea, abdominal pain, nausea/vomiting, appetite loss, and other abdominal discomforts.

8. Autoantibody production

Autoantibodies are self-reactive antibodies that react to one’s own cells. Oftentimes, the immune system makes auto-antibodies when the intended target (like a specific protein of a virus) is structurally similar to one of our cell types. We call this molecular mimicry.

Higher amounts of autoantibodies against proteins of the immune system have been found in antibodies of SARS-CoV-2-infected (including mild and asymptomatic cases) compared to uninfected individuals. Another study found that a small subset of antibodies generated against SARS-CoV-2 could cross-react with proteins of the gut, kidney, lung, heart, and brain.

Anti-nuclear autoantibodies have also been detected in 30–50% of Covid-19 patients. While its unclear if such auto-antibodies are long-lasting in Covid-19 survivors, anti-nuclear antibodies are actually biomarkers of chronic autoimmune disorders, such as lupus and rheumatoid arthritis. And these two autoimmune disorders also bear symptomatic similarities to long-Covid, such as fatigue, joint pain, concentration problems, and headache.

9. Brainstem dysfunction

The brainstem is the stalk of the brain that connects to the spinal cord and vagus nerve that, in turn, connects to nearly all organs in the body. The brainstem also harbors numerous distinct sub-regions that regulate basic respiratory, cardiovascular, gastrointestinal, and neurological processes.

For example, the Bötzinger and pre-Bötzinger complexes in the brainstem control rhythmic breathing during expiration and inspiration, respectively. The brainstem also contains the caudal ventrolateral medulla (CVLM) that stores neurons that regulate heart rhythm. Some of the brainstem regions also regulate the autonomic nervous system and sickness behavior.

In the human brain, the brainstem has the highest expression of ACE2, the receptor that SARS-CoV-2 uses to infect cells. This explains how certain autopsy reports have found SARS-CoV-2 genes and proteins, as well as inflamed cells and tissue damage, in the brainstem.

As neurons rarely regenerate, the brainstem damage during SARS-CoV-2 infection could be long-lasting and initiate long-Covid. In fact, brainstem functions and long-Covid symptoms overlap to a great extent:

More convincingly, an imaging study has found hypometabolic abnormalities in several brain regions, including the brainstem, of long-Covid sufferers that were absent in healthy participants. (Hypo means underperforming, so hypometabolism means slow metabolism.)

Brainstem dysfunction has also been found in other chronic disorders, such as chronic pain, chronic migraine, and chronic fatigue syndrome. So, it’s not surprising that long-Covid involves the brainstem as well.

What now?

These nine putative biological explanations of long-Covid are not mutually exclusive, however. They can overlap in any fashion to contribute to long-Covid, explaining why it’s such a diverse syndrome that baffles many.

No single biological cause also means no single treatment. This is a common predicament of treating a syndrome, a collection of symptoms of unclear causes or multiple factors with no single cause. Other examples of syndromes with no single established treatment include chronic fatigue syndrome and metabolic syndrome.

A disease, by contrast, usually has a causative factor. For instance, diabetes is an insulin problem, so insulin treatment can work. Covid-19 is a virus problem and, later in severe stages, an immune system problem as well, so antivirals, vaccines, and immunomodulators can work.

So, the path to addressing the long-Covid, the post-Covid-19 syndrome, is dark. We still don’t know how to treat it successfully. We only know how to treat its symptoms: painkillers for muscle and joint pain; ibuprofen or paracetamol for headaches; beta-blockers for reducing heart rate; breathing exercises for breathlessness; psychological therapies or counseling for mental health problems; and physiotherapy for general weakness.

Thankfully, huge research and medical investments have been put into long-Covid. The U.K.National Institute for Health Research (NIHR) has allocated £20 million to support research on biomarkers and treatments of long-Covid, alongside £10 million to support the recovery of long-Covid sufferers. The U.S. National Institute of Health (NIH) is also investing US$1.15 billion into the research on the epidemiology, pathophysiology, long-term effects, treatments, and prevention of long-Covid.

In the end, long-Covid tells us that post-viral syndrome is not to be underestimated. Even though the Covid-19 pandemic would end, its repercussions in initiating a global increase in chronic syndrome will endure indefinitely. We don’t know how long long-Covid would last: it could be several months or even years.

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