Towards the end of 2019 the appearance of the very contagious novel virus SARS-CoV-2, spreading around the world like wildfire, has resulted in a medical condition called COVID-19, which was found to affect individuals differently.
In most infected individuals, the disease did not cause serious illness, but in a minority of patients it resulted in serious respiratory disease and even death. The severity of the weakening of the respiratory system ranged from mild to deadly, with some people carrying the virus but showing no symptoms at all. The respiratory symptoms are categorized from mild (no evidence of pneumonia), or moderate (pneumonia present), or severe (respiratory rate and oxygen saturation levels affected), or critical (with respiratory failure that requires mechanical ventilation and intensive care due to organ failure).
COVID-19 was initially thought to be a respiratory disease only, but was subsequently discovered to be a multi-organ, pro-inflammatory state that can affect not only the lungs, but also the heart, liver, kidneys, and other systems in the body. The disease has very low prevalence and almost no mortality in children, but the severity of the disease and the risk of mortality seems to increase with age, with people older than 70, as well as people with underlying health conditions, at high risk.
Researchers have identified seven groups of symptoms that persist in COVID-19 patients, even weeks after contracting the disease:
- Flu-like symptom, such as fever, cough, chills, and fatigue.
- Cold-like symptoms, such as nasal congestion, dry throat, and sneezing.
- Joint pain and muscle pain.
- Eye and mucosal inflammation. (The mucous membrane is the moist, inner lining of body cavities such as the nose, mouth, lungs, and stomach. Glands in the mucosa make mucus, a thick, slippery fluid.)
- Lung problems, such as shortness of breath and pneumonia.
- Gastrointestinal problems, such as diarrhea and nausea.
- Loss of sense of smell and taste.
Factors playing a role in individual responses to COVID-19:
Ongoing research has linked several factors to the differences in the severity of the disease between individuals, as discussed below.
Being predisposed to COVID-19.
International research findings from 4 continents (Asia, Europe, North America, and Africa) covering 65 000 patients, have linked similar characteristics and health conditions to severe cases of COVID-19. Older people, and people with pre-existing chronic health conditions, are at a much higher risk of developing severe to deadly COVID-19 symptoms. Researchers suggest that these individuals should be the priority to receive vaccination, to prevent high mortality rates from these high-risk individuals.
- Age – while age did not play a role in COVID-19 susceptibility, older people have a higher risk of developing severe forms of the disease and higher death rates. Several factors are deemed to play a role, such as heart muscle cells that change with age, as well as age related differences in the responses of the immune system. While most of the COVID-19 patients displayed lower levels of a type of white blood cell called T cells, which are crucial to fighting viral infections, older people had significantly less T cells.
- Obesity – obesity was twice as likely associated with an increased rate of hospitalization and critical illness from COVID-19, and even younger patients with obesity and diabetes are more likely to develop serious disease.
- Cardiovascular disease – The cardiovascular system supplies the body with blood and consists of the heart, arteries, veins, and capillaries. Cardiovascular disease is the most common cause of death in the world and the most common types are heart failure, heart attack, angina, coronary artery disease, rheumatic heart disease, atrial fibrillation, peripheral artery disease, aneurysm, atherosclerosis, and renal artery disease. Research has indicated that cardiovascular disease may double the risk of dying from COVID-19.
- Hypertension – patients with chronic high blood pressure are twice as likely to die from COVID-19.
- Stroke – although COVID-19 is a typical lung infection, in some severe cases COVID-19 may cause the development of small blood clots that can obstruct blood flow to the lungs, or travel to the brain, where it can result in severe stroke.
- Chronic kidney disease – patients with chronic kidney disease are three times more likely to die from COVID-19.
- Diabetes – patients with diabetes are 1,5 times more likely to die from COVID-19.
- Cancer – patients with cancer are also 1,5 times more likely to die from COVID-19.
Genetics.
To try and answer the question why individuals are affected differently by COVID-19, some research projects tried to find out whether genetics could play a role. Our genetic material is found in chromosomes in the nucleus of cells in the body. Chromosomes come in pairs, one of each inherited from each of our parents. There are 23 pairs of chromosomes in every cell in our bodies and they carry our DNA. While most of the DNA is the same between people, mutations (variants) do occur when the DNA is replicated in cells, making everyone’s DNA unique.
Research has determined that genetic variants in one region of chromosome 3 are linked to a higher risk, for carriers of this variant, to develop a severe form of COVID-19. This variant is found in some regions in the world and has been traced back to ancient Neanderthal man from southern Europe, dating back 60 000 years.
Other research has linked the risk of developing severe COVID-19 with weak spots in the immune system of a small percentage of patients, due to mutations in the genes involved in antiviral defense. In some patients, errors were found in the genes that produce antiviral interferons (a chemical given off by immune cells) – while in others with severe disease, “auto-antibodies” were created that attack the immune system instead of fighting the virus. These antibodies block interferon action.
In healthy people, the interferon molecules act as messenger substances that detect invading viruses and bacteria, which then summons the body’s immune system to fight the invaders in infected body cells.
The immune system.
The immune system is complex with a network of players, which interact with each other. The innate immune system gets triggered first to fight invading pathogens such as viruses and can immediately deal with many infections. The second layer of defense against invading pathogens is the adaptive immune system, which, as the name says, can adapt to protect the body against specific invaders over a longer period. The adaptive immune system is a more refined mechanism which can fine-tune and modify itself to combat a specific infection, while the innate immune system has a more generalized and instantaneous response.
When the COVID-19 virus enters the body, the virus binds to specific receptors on epithelial cells, which are the cells lining the surfaces of the body such as the skin, the lungs, the blood stream, and the gastrointestinal tract (the gut). Epithelial cells are the first cell type to encounter external stimuli, including viruses such as COVID-19. Replication of the virus in the cells can lead to cell damage and cell death, which alerts the immune system.
The body’s immune system activates various defense systems in the event of any infection, including viral infections. The danger of the COVID-19 virus is that it not only suppresses the interferon action, but also lets the human cells produce a pro viral protein called PLpro (papain-like protease). PLpro not only suppresses the development of interferons, but also plays a role in the release of new viral particles. These research results look promising for the development of PLpro inhibiting substances in the fight against COVID-19.
Research projects are also focusing on a better understanding of how COVID-19 attacks the body, to search for ways to stop its devastating effects. The spike-like proteins on the surface of the virus attaches to the cells targeted for infection. The way it attaches is to grab hold of a cell-surface chemical called heparan sulfate, which is a type of sugar molecule that binds with cells in the lungs and blood vessels, as well as in the smooth muscle of most organs. After binding with heparan sulfate, the virus enters human cells by attaching to a surface receptor protein called angiotensin-converting enzyme 2 (ACE2). The ACE2 host receptor is required for the host cell viral entry and further replication of the SARS-CoV-2 virus, not only in the lungs, but also in other systems in the body.
The interaction between the surface glycoproteins on the SARS-CoV-2 virus and ACE2 enzymes starts the inflammatory process:
- ACE2 on the pulmonary capillaries in the lungs can play a role in the development of COVID-19 related pneumonia and acute respiratory distress syndrome (ARDS) in COVID-19 patients.
- ACE2 on the epithelia cells in the gastrointestinal tract can play a role in the development of gastrointestinal symptoms of COVID-19, such as diarrhea, vomiting and abdominal pain.
- ACE2 in the brain has been linked to the virus crossing the blood-brain barrier, which can cause neurological symptoms such as headaches, nausea, and anosmia (the loss of smell and taste).
- ACE2 on the heart muscle cells can increase the possibility of COVID-19 related infection, which can lead to thrombosis and constriction of the vascular arteries in the heart muscle.
New research has shown that the virus also uses a receptor called neuropilin-1 to infect cells. Neuropilin-1 is found abundantly in many human tissues, including blood vessels, neurons, and the respiratory tract. Scientists compare ACE2 as a door lock to enter a cell, while neuropilin-1 could be a factor that directs the virus to the door. Research is ongoing.
While most COVID-19 related deaths are caused by acute respiratory distress syndrome (ARDA), some patient’s severe symptoms are caused by an overreaction of their immune system, with an extraordinarily strong inflammatory response. In fighting infections, the immune system secretes proteins called cytokines as a defense mechanism to help the body fight off the intruder. In a phenomenon called a “cytokine storm”, the immune system goes into an extreme overreaction in which the massive influx of cytokines leads to the dysregulation of the immune system and can also attack the body’s own tissues, rather than only the virus. A bit like a rabid dog attacking everyone in sight, instead of focusing on the intruder that woke him up.
In severe cases, the cytokine storm can damage the blood-brain barrier (a protective barrier for the blood vessels in the brain) and the virus can enter the brain and cause brain fog like symptoms such as dizziness, delirium, confusion, or difficulty concentrating. Other neurological effects are stroke, seizures, and swelling of the brain. Electroencephalogram (EEG) recordings of brain activity in patients can help to indicate signs of damage to brain function. Studies have found the most common abnormality in the brain scans of COVID-19 patients is an overall slowing of brain waves, which indicates general cerebral dysfunction. Older men are more easily affected. Scientists also warns that the abnormal EEG readings may not be due to the virus acting directly on the brain but may result from other side effects of the virus, such as reduced oxygen intake, or COVID-19 related heart problems.
T cells in the adaptive immune system play an important role in orchestrating the immune response. Apart from directly killing infected host cells, T cells help to raise the alarm when an intruder is detected by releasing cytokines. T-cells also have the ability to remember antigens and will know how to defeat them with a rapid and specialized response if they return, which can result in life-long immunity and this forms the basis of how vaccines work. Antigens are substances that previously caused the immune system to produce antibodies against them.
B cells play a central role in the immune system by making antibodies, but research has found that the cytokine storm in patients with severe COVID-19 kill off the antibodies made by the B cells. Antibodies are proteins made by B cells and used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. Antibodies can neutralize its target directly or tag it for attack by other parts of the immune system.
The gut.
The 8-meter-long gastrointestinal tract is a major component of the body’s immune surveillance system.
The microorganisms in the gut, collectively called the gut microbiota, includes bacteria, viruses, archaea (unicellular microorganisms) and fungi (yeast-like microorganisms such as Candida).
Research has indicated that the SARS-CoV-2 virus can infect the cells in the gut and multiply there. Differences in the composition of the gut microbiota of individuals may explain why up to one-third of COVID-19 patients present with gastrointestinal symptoms such as nausea and diarrhea. The lungs are affected by gut health, and vice versa. Unhealthy conditions (called dysbiosis) in one affects the other through a direct link called the gut-lung axis.
Dysbiosis in the gut microbiota results in permeability of the lining of the gut, leaving the way open for invading organisms and harmful substances to enter the blood stream. Scientists believe that disruption of the effectiveness of the gut barrier integrity (permeability) may lead to translocation of viruses such as COVID-19. After initially infecting the lungs, COVID-19 is suspected to migrate through damage in the lung tissue (bronchial-associated lymphoid tissue) to the intestine via the lymph circulation system and the blood stream. It is doubtful that oral transmission of COVID-19 would reach the large intestine, due to harsh biological barriers such as acid in the stomach and bile salts in the small intestine. (For further information please see the Health Insight blog “COVID-19 and the gut-lung axis”.)
Research into COVID-19 is ongoing, to fully understand the nature of the virus and its effects on the human body, in aid of finding a cure for the pandemic. These insights were relevant at the time of publication of this Health Insight Blog.
Sources.
What do we know about the relationship between our gut microbiota and COVID-19? Published 1 June 2020. Gut Microbiota for Health. A section of the European Society for Neurogastroenterology and Motility. (ESNM) (www.gutmicrobiotaforhealth.com)
Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Published September 2020 in Gastroenterology Volume 159, Issue 3. (www.sciencedirect.com)
What does COVID-19 do to your gut microbiome? Published 13 August 2020. Massive Science. (www.massivesci.com)
Gut reaction: how the gut microbiome may influence the severity of COVID-19. Published 21 June 2020. The Conversation. (An independent source of news and views form the academic and research community. (www.theconversation.com)
COVID-19: does age matter? Not with your likelihood of being infected – study. Published 15 October 2020. Health24. (www.health24.com)
Study sheds light on why COVID-19 hits elderly hardest. Published 6 October 2020. Health24. (www.health24.com)
Blood count may offer clues to treatment of COVID-19. Published 6 May 2020. Health24. (www.health24.com)
Risk of severe COVID-19 high for obese people, regardless of other factors. Published 19 October 2020. Health24. (www.health24.com)
Why does COVID-19 differ so much form patient to patient? T cells may hold the answer. Published 14 October 2020. Health24. (www.health24.com)
Some younger people get severe COVID-19 and scientists think they are close to finding out why. Published 20 October 2020. Health24. (www.health24.com)
More insight into the cytokine storm caused by COVID-19 could lead to a treatment. Published 29 May 2020. Health24. (www.health24.com)
Researchers discover a second ‘key’ that makes the new coronavirus infections. Published 26 October 2020. Health24. (www.health24.com)
Brain scans reveal a spectrum of abnormalities that cannot be fully explained. Published 5 November 2020. Health24. (www.health24.com)
COVID-19 and loss of smell: Harvard researchers uncover why it happens. Published 5 August 2020. Health24. (www.health24.com)
Seven different forms of disease identified in mild COVID-19 cases. Published 5 November 2020. Health24. (www.health24.com)
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HEALTH INSIGHT
November 2020