Covid-19 is confusing and complicated, but aren’t all systemic diseases like that?
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Why People Don’t Always Get Sick
About 40–45% of Covid-19 cases are asymptomatic (or symptomless), as estimated by a review of published research and unpublished preprints. But the range varies a lot from 6.3% to 96%. Asymptomatic cases contribute to silent transmission, which is arguably the most critical factor in the success of Covid-19.
Some people do not exhibit symptoms, and some do. Why?
Numerous explanations have been put forward — viral load, ACE2 receptor levels, genetic predispositions, sex chromosomes, tuberculosis co-infection, smoking, stiff lung fibroblast, gut microbiota dysbiosis, fitness level, vitamin D status, ethnicity, social inequalities, age, or medical comorbidities (e.g., heart diseases, diabetes, chronic obstructive pulmonary disease, obesity, etc.).
There are probably more, but these risk factors can have additive or multiplier effects to give a score. If this score reaches a threshold, Covid-19 happens. (Note: Scientists called this score with statistical terms such as relative risk, odds ratio, or hazard ratio)
And these risk factors also determine how Covid-19 turns out. A score far exceeding the threshold (where Covid-19 develops) means severe Covid-19. Likewise, a score just slightly over the threshold means mild Covid-19. And a score moderately over the threshold means moderate Covid-19.
So, countless risk factors interact to determine how Covid-19 unfolds — whether one gets sick or how sick one gets.
It also appears that asymptomatic individuals may not be 100% safe after all. Markham Heid covered this topic in Elemental in June. He cited studies showing that about half of asymptomatic cases show lung abnormalities in chest scans, although scientists are unsure of its health consequences. This indicates that obvious external symptoms (e.g., fever, coughing, etc.) do not always reflect internal organ damage that may be subtle or overlooked. “How big a deal is this? No one’s sure,” Heid wrote.
Why People Show Different Symptoms
When Covid-19 happens, it mainly hits the lungs. But it can sometimes attack the brain, peripheral nerves, smell, taste, hearing, thyroid, liver, heart, gastrointestinal tract, pancreas, kidneys, spleen, blood vessels, toes, skin, etc.
How could one disease cause such a diverse set of symptoms?
Arguably the most convincing answer is that Covid-19 infects the small blood vessels surrounding the air sacs, which connect to larger blood vessels that transverse all organs. While SARS-CoV-2 uses ACE2 to dock onto cells, it also needs the furin protein to catalyze the release of its genetic material into the cell. And ACE2 and furin are widely distributed in the body.
Depending on where the virus ends up, each person would show varying symptoms. If the virus localizes more in the gastrointestinal tract, the person might get diarrhea or abdominal pain. If the virus concentrates more on the pancreas, the person might develop poor control of blood glucose.
As SARS-CoV-2 infects the blood vessels that transverse all organs, it can end up anywhere in the body, especially in organs already in a high injury state.
Another explanation in line with this is the body’s pro-oxidative and pro-inflammatory states. We can call it the organ’s injury state that must be kept at a minimum. This injury state is determined by the relative balance between free radicals and pro-inflammatory cytokines with antioxidants and anti-inflammatory cytokines, respectively. And this balance is arguably affected most by lifestyle factors.
If an organ’s injury state is high, it ceases some of its functions and focuses on repairing itself. As follows, if a person’s brain is already in a high injury state, Covid-19 is more likely to push the brain into dysfunction. Put it another way; a weaker organ is more vulnerable to Covid-19 damage.
Therefore, Covid-19 is a systemic disease that strikes many organs. In fact, many diseases work systematically. Diabetes, obesity, periodontal diseases, tuberculosis, HIV, or autoimmunity all have adverse effects on various organs. So, Covid-19 is not unique in this regard. The human body is a system of interconnected organs; after all, the defect of one inevitably affects the other.
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Why People Heal Differently
One in ten Covid-19 patients experiences prolonged symptoms of fatigue, cough, headache, chest pain, smell loss, sore throats, and delirium for weeks to months. Others reported shortness of breath, racing heartbeats, weight loss, brain fog, or concentration and memory difficulties that also last up to months. These symptoms can also come in waves — as in the symptoms can come and go.
In hospitalized cases, 87% of 143 discharged patients in Italy still had at least one lingering Covid-19 symptom at a 60-day follow-up, such as fatigue (53%), dyspnoea (43%), joint pain (27%), and chest pain (22%). And 44% of patients reported poor quality of life.
This is evidence that Covid-19 can cause CFS/MS (chronic fatigue syndrome or myalgic encephalomyelitis), a disease of multi-organ impairment that weakens the whole body for six months or more. “There is a long history of infections as a trigger but other factors contributing to a longer-term disability,” said Professor Simon Wessely, the former president of the Royal College of Psychiatrists. “If the virus is found to enter the brain, this might increase the risk.”Data on prior post-infection fatigue syndrome showed that full recovery might take up to a year. Patients can only rely on adequate rest, hydration, and nutrition.
CFS/MS occurred in 10–50% of those who suffered severe diseases from SARS, MERS, Ross River virus, Epstein-Barr virus, or Q fever (Coxiella burnetii). And they took up a year to fully recover, although some cases were quicker. So, again, Covid-19 is not unique in this respect. There are no available drugs, and exercise might worsen CFS/MS. Thus, patients best opt for proper hydration, rest, stress management, and nutrition.
Why do some people experience post-viral fatigue or recover very slowly?
Reason 1: The damage done to the brain and lungs is too great.
Delirium is impaired consciousness that may come with psychotic features such as hallucinations, paranoia, irrational thoughts, or grotesque dreams. It affects 20–30% of Covid-19 patients; in severe cases in need of ICU care, the number is 60–70%. A 2010 study found that 71% of ICU delirium survivors had cognitive impairment. And, in another study, 66% of survivors had impaired memory recall at a 2-year follow-up. The majority of delirium survivors suffer long-term brain damage.
As per the conclusion of a meta-analysis of 65 peer-reviewed and seven preprint studies in The Lancet Psychiatry: “SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term.”
A study by researchers at University College London detailed 49 cases of dangerous Covid-19 brain diseases. Adrain Owen, a prominent neuroscientist who was appointed as an Officer of the Most Excellent Order of the British Empire (OBE) for his contributions to science, told Reuters in response to the study: “My worry is that we have millions of people with Covid-19 now. And if in a year’s time we have 10 million recovered people, and those people have cognitive deficits . . . then that’s going to affect their ability to work and their ability to go about activities of daily living.”
As for the lungs, acute respiratory distress syndrome (ARDS) is a frequent indication of severe Covid-19. Chest scans showed that ARDS could leave permanent lung scarring called pulmonary fibrosis. People with scarred lungs suffer life-long breathlessness. Improving aerobic capacity can compensate for the lower lung function to some extent. In a study of 149 Covid-19 patients, over 40% of them still had lung scarring at the 3-week chest scan follow-up, and only 53% manage to recover from their damaged lungs fully.
Delirium is common in Covid-19, and most of its survivors will not have the same brain function as before. Likewise is ARDS that scars the lungs of its victims.
Reason 2: The lingering immune response from autoimmunity or viral persistence.
Another reason is that the immune system is still on alert — either in the absence or presence of virus particles. The former is related to some kinds of autoimmunity and the latter to viral persistence.
In post-viral autoimmunity, several mechanisms are responsible — molecular mimicry, epitope spreading, bystander activation, or immortalization of infected B cells. While each of these follows distinct molecular pathways, they all make the immune cells attack their host. Viruses known to induce autoimmunity include Coxsackie B virus, rotavirus, influenza A viruses, herpesvirus, measles, mumps, and rubella.
Both post-viral autoimmunity and viral persistence are not at all unique to Covid-19.
For viral persistence, I have previously described it in the article below. In brief, at least 15 other viruses can establish a persistent infection. Common reasons for viral persistence include co-existence with the immune system, low antibody production, immune evasion, or viral reactivation. These lead to the ineffective clearance of viral elements — be it dead fragments or whole virions — that can still trigger immune reactions.
Demystifying How the Body Reacts to Covid-19
This article explains the three phases of Covid-19, in which variations can occur in how a person responds.
- In the first stage, Covid-19 either happens or not, based on several risk factors. But even in those who are symptomless, Covid-19 may still cause internal damage with unknown health implications.
- In the second stage, Covid-19 can cause a myriad of different symptoms involving various organs. Covid-19 is a systemic disease that can end up anywhere in the body. And the body organ’s injury state also plays a role in which organ is more susceptible to Covid-19.
- In the third stage, Covid-19 can persist for weeks to months — causing the post-viral syndrome of prolonged fatigue or neuropsychiatric symptoms. Reasons for this could be the massive damage inflicted on the brain or lungs. Or it could be that the immune system is still on alert due to post-viral autoimmunity or viral persistence.
People react differently to each stage, which makes Covid-19 confusing and hard to predict. But are not all systemic diseases complicated?
A disease of insulin (insulin resistance), for example, can lead to diabetes, pre-diabetes, metabolic syndrome, or the person could still be somewhat healthy. A person with diabetes, in turn, has a malfunctioning pancreas, but poorly controlled blood glucose could also hurt the brain, blood vessels, nerves, heart, or immune cells. And, diabetes affects people differently in the long run, too: The disease may get worse, turn into something else, or be reversed with diet and exercise.
Every disease is multifaceted, especially systematic ones like obesity, periodontal diseases, tuberculosis, HIV, or autoimmunity. Perhaps it is that there are so many cases that we see more facets of Covid-19. And, with that, more attention as well, which is warranted considering the enormous disease burden Covid-19 has inflicted on the world in such a short timespan.
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