“What are the effects of COVID-19 on the lungs? - Medical News Today” plus 3 more

What are the effects of COVID-19 on the lungs? - Medical News Today
'Coronavirus has intelligence much stronger than other viruses' - Livemint
Over a third of coronavirus patients show neurological symptoms, study reports - TNW
Do Your Genes Predispose You to COVID-19? - Scientific American

What are the effects of COVID-19 on the lungs? - Medical News Today

Posted: 20 Apr 2020 12:00 AM PDT

How does the body respond when the SARS-CoV-2 virus infects it? Which physiological processes help or hinder us in getting rid of the virus, and which processes ensure that we have a mild form of COVID-19, the disease that the virus causes? In this Special Feature, we investigate.

close up of doctor looking at chest xray — In this Special Feature, we look at the effects of the SARS-CoV-2 infection on the lungs.

The more we learn about COVID-19, the more we have to question our assumptions about it.

Early on in the COVID-19 pandemic, our information about the disease came from clinical case reports of COVID-19 and what we knew about influenza pandemics and the severe acute respiratory syndrome (SARS) resulting from SARS-CoV.

SARS-CoV is a coronavirus that shares 82% of its genome with SARS-CoV-2. In 2003, it caused an international SARS epidemic.

It quickly became clear that COVID-19 was very different than seasonal influenza, with higher mortality and infectivity, but it took longer to realize that there were important differences and similarities with SARS.

For instance, COVID-19 is infectious even during the presymptomatic phase. Also, physiological processes that are harmful in one phase of the disease may become helpful later. For example, the angiotensin converting enzyme 2 (ACE2) receptor, which allows the virus to enter the body, may also be key to the protection of the lungs in the later phases of the disease.

This feature describes what we know so far about COVID-19. To explain the different processes that occur within the body, we have split the disease into four separate phases that roughly match the different levels of severity: mild, moderate, severe, and critical.

However, in reality, the physiological processes underlying these phases overlap. People with COVID-19 may or may not show features of earlier or later phases.

Both SARS-CoV-2 and SARS-CoV gain entry via a receptor called ACE2.

More commonly known for their role in controlling blood pressure and electrolytes, these receptors are also present in the lungs, back of the throat, gut, heart muscle, and kidneys.

In 2004, researchers from the University Medical Center Groningen in the Netherlands reported that ACE2 receptor cells were not present on the surface layer of cells in the nose and were, therefore, not an important site for SARS-CoV viral replication.

In SARS, there are hardly any upper respiratory tract symptoms, and viral units are rarely present outside the lungs. This fact initially took the focus away from continuing to look for ACE2 receptors in the nose.

Recently, an international team of researchers has found the ACE2 receptors on goblet (secretory) cells in and on ciliated (hairy) cells in the nose.

More recently, scientists have found ACE2 receptors in the mouth and tongue, potentially indicating a hand-to-mouth route of transmission.

Researchers also found a plentiful supply of a protease called TMPRSS2, which chemically splits off the top of the coronavirus spike to allow the SARS-CoV-2 RNA to enter into the nasal cells.

Once inside the cell, the virus's genetic material directs the cell to manufacture millions of new copies of itself.

According to a paper that has not yet undergone peer review, the protease TMPRSS2 can act more easily to remove the top section of the coronavirus spike because a genetic difference between SARS-CoV and SARS-CoV-2 means that there is now an easily broken section known as the furin-cleavage site.

As a result, SARS-CoV-2 can bind 10 times more tightly to insert its RNA into the cell, starting to explain why COVID-19 spreads so rapidly.

A small but very careful study of viral samples from nine people admitted to hospital following contact tracing — as part of a cluster of COVID-19 cases in Germany — has shown the importance of replication in the nose for the early spread of the virus.

On average, there were 676,000 copies of the virus per swab from the upper respiratory tract during the first 5 days of symptoms. The levels of the virus in six out of the nine participants were undetectable in the nose and throat by day 10. Samples were available from day 1 of symptoms.

In all but one of the nine individuals, the viral load in the upper respiratory tract swabs was dropping from day 1, suggesting that the peak preceded the onset of symptoms. This has clear implications for preventing the transmission of the virus.

In a preliminary report by Menni and colleagues, which has yet to go through peer review, loss of sense of smell occurred 6.6 times more commonly in people with other symptoms of COVID-19 who went on to have a positive COVID-19 PCR test (59%) than in those who had symptoms of COVID-19 but tested negative (18%).

The ACE2 receptors and the protease TMPRSS2 have also been found in the supporting structures for the sheet of nerve cells in the upper part of the nose, which transmit signals about smell to the brain.

This is the first research to provide a potential explanation for this important symptom of COVID-19. However, this study is also awaiting peer review.

According to Menni's study, loss of smell was the most commonly reported upper respiratory tract symptom in those testing positive for COVID-19, affecting 59% of people. It was more common than a persistent cough (58%) or a hoarse voice (32.3%).

Interestingly, data from the first description of 99 people who tested positive for COVID-19 in Wuhan, China, suggests that some symptoms you might expect to see from a respiratory virus are not that common in COVID-19. For instance, only 4% had a runny nose, and 5% had a sore throat.

The viral load study in Germany showed that active viral replication occurs in the upper respiratory tract. Seven out of nine participants listed a cough among their initial symptoms.

In contrast to the falling numbers of viral units in the upper respiratory tract, numbers in sputum rose for most of the participants.

In two individuals with some signs of lung infection, the virus in sputum peaked at day 10–11. It was present in the sputum up to day 28 in one person. Across all participants, there was an average of 7 million units in 1 milliliter (about 35 million units in a teaspoon). This amount is about 1,000 times more than that in people with SARS.

In the lung, the ACE2 receptor sits on top of lung cells called pneumocytes. These have an important role in producing surfactant — a compound that coats the air sacs (alveoli), thus helping maintain enough surface tension to keep the sacs open for the exchange of oxygen and carbon dioxide.

As soon as the body recognizes a foreign protein, it mounts the first response. One part of the body's immune response — the lymphocytes — begin to produce the first defense IgM-type antibodies and then the longer term specific neutralizing antibodies (the IgG type).

In the German viral study, 50% of the participants had IgM or IgG antibodies by day 7, and they all had these antibodies by day 14. The amount of antibodies did not predict the clinical course of the disease.

80% of people with COVID-19 will have mild or asymptomatic disease, with common symptoms including fever, cough, and loss of sense of smell. Most will only have phase 1 or 2 physiological responses to SARS-CoV-2 infection.

Approximately 13.8% of people with COVID-19 will have severe disease and will require hospitalization as they become short of breath. Of these individuals, 75% will have evidence of bilateral pneumonia.

Pneumonia in COVID-19 occurs when parts of the lung consolidate and collapse. Reduced surfactant in the alveoli from the viral destruction of pneumocytes makes it difficult for the lungs to keep the alveoli open.

As part of the immune response, white blood cells, such as neutrophils and macrophages, rush into the alveoli. Meanwhile, blood vessels around the air sacs become leaky in response to inflammatory chemicals that the white blood cells release.

This fluid puts pressure on the alveoli from outside and, in combination with the lack of surfactant, causes them to collapse.

As a result, breathing becomes difficult, and the surface area in the lung where oxygen transfer usually takes place becomes reduced, leading to breathlessness.

The body attempts to heal itself by promoting inflammatory and immune responses. The World Health Organization (WHO) advise against the use of glucocorticosteroids during this phase, as they could prevent the natural healing response. The evidence seems to refute this position, but this is a fast developing field, and findings are subject to change.

Most patients will recover at this stage with supportive intravenous fluids and oxygen via a mask or an external positive pressure mask.

The most common time for the onset of critical disease is 10 days, and it can come on suddenly in a small proportion of people with mild or moderate disease.

In severe acute respiratory distress syndrome (ARDS), the inflammation stage gives way to the fibrosis stage. Fibrin clots form in the alveoli, and fibrin-platelet microthrombi (small blood clots) pepper the small blood vessels in the lung that are responsible for gas exchange with the alveoli.

There is hope that drugs already licensed for anticlotting action in strokes could be helpful at this stage.

Cytokines are chemical mediators that white blood cells such as macrophages release, and they can engulf infected cells. These cytokines — which have names such as IL1, IL6, and TNFα — have actions that include dilating the vessel walls and making them more permeable. In extreme circumstances, this can lead to a collapse of the cardiovascular system.

Estrogen in mouse cells suppresses the release of cytokines from macrophages. Although animal studies often fail to translate into important findings in humans, this could be one explanation for worse outcomes from COVID-19 in males.

While smaller numbers of ACE2 receptors are protective in phase 1, as there are fewer landing sites for the virus, by the time we reach phase 4, these receptors may become protective.

ACE2 receptors in health play an important regulating role for the activities of angiotensin converting enzyme 1 (ACE1).

In response to infection, ACE1 creates excess angiotensin 2 from angiotensin 1.

Angiotensin 2 directly damages the lungs, causes blood vessel constriction, and makes the blood vessels leaky. Drugs that doctors typically use in the treatment of hypertension (ACE inhibitors and ARBs) may be helpful at this stage.

The role of ACE2 inhibitors in treating COVID-19 is a complex one. As some authors note, on the one hand, using them may lead to a higher risk of SARS-CoV-2 infection. On the other hand, ACE inhibitors may reduce the lung damage that this infection causes.

Furthermore, it is noteworthy that "the protective role of ACE2 in the respiratory system is supported by ample evidence, whereas the increased danger of infection is still a hypothesis."

This is why more research is necessary to understand the physiology of this challenging new disease.

For live updates on the latest developments regarding the novel coronavirus and COVID-19, click here.

'Coronavirus has intelligence much stronger than other viruses' - Livemint

Posted: 30 Apr 2020 05:30 AM PDT

NEW DELHI : The novel coronavirus (COVID-19) is behaving weirdly and it appears that it has an intelligence much stronger than other related viruses, according to an Indian researcher who recently created a molecule that has the potential to be developed into a drug that can cure Acute Respiratory Distress Syndrome (ARDS) in COVID-19 patients.

Speaking to IANS, Dr Subhabrata Sen, Professor, Department of Chemistry at Shiv Nadar University in Greater Noida, said that they hope their therapeutic approach will unravel solutions against maladies associated with acute respiratory distress syndrome.

His team found a set of New Chemical Entities (NCEs) with the ability to cure Acute Respiratory Distress Syndrome (ARDS) or Acute Lung Injury (ALI) induced by COVID-19 (SARS-CoV-2) or other Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), which are also caused by coronaviruses.

The two-fold strategy devised by the research team involved the application of the NCEs to inhibit attachment, entry and infection of the new SARS-CoV-2 through a known target on the virus and co-administration of a known drug (that modulates a set of hormonal receptors in human) and these NCEs to attenuate ARDS caused by a novel coronavirus.

"The new molecule that we have discovered is based on an indigenous ligand in the human body. In general, one of the disadvantages of small molecule therapeutics is that human body considers them as xenobiotic. Once they are administered in the system, the body tries to eliminate them quickly, through enzymatic reactions primarily in the liver," Dr Sen explained.

"The advantage of developing small molecules based on indigenous ligands is that the body accepts it more thinking as its own. Consequently, the molecule has lesser chances of getting excreted thereby gets more time to achieve its therapeutic purpose," he told IANS.

The research team has filed a provisional patent in India to protect the new chemical entities.

They believe their therapy would not only prevent COVID-19 from affecting a person's lungs but will also address lung injuries already inflicted by the virus, in cases the ventilators are not bringing much relief to COVID-19 patients suffering from ARDS.

Responding to the question on a human clinical trial, he said: "Our aim to start the animal trial by next month and then have the compounds ready for the human trial by the end of this year."

Speaking on the COVID-19 vaccine, Sen said that it is very difficult to say anything at this point of time.

"One of the ways to discover a vaccine involves administering a small fragment of the virus or a viral protein inside the human body to stimulate an immunological response. The trial by Professor Sara Gilbert's team in Oxford University started a week ago, so until a month goes by, nothing can be said with certainty," he informed.

According to Sen, the lockdown has helped India to curb the spread of COVID 19.

"Lockdown is a strategy to slow down the pandemic so that the government gets enough time to prepare for the worst-case scenario, which is yet to come," the professor added.

Over a third of coronavirus patients show neurological symptoms, study reports - TNW

Posted: 30 Apr 2020 12:58 AM PDT

As case numbers of COVID-19 continue to rise around the world, we are starting to see an increasing number of reports of neurological symptoms. Some studies report that over a third of patients show neurological symptoms.

In the vast majority of cases, COVID-19 is a respiratory infection that causes fever, aches, tiredness, sore throat, cough, and, in more severe cases, shortness of breath and respiratory distress. Yet we now understand that COVID-19 can also infect cells outside of the respiratory tract and cause a wide range of symptoms from the gastrointestinal disease (diarrhea and nausea) to heart damage and blood clotting disorders. It appears that we have to add neurological symptoms to this list, too.

Several recent studies have identified the presence of neurological symptoms in COVID-19 cases. Some of these studies are case reports where symptoms are observed in individuals. Several reports have described COVID-19 patients suffering from Guillain–Barré syndrome. Guillain–Barré syndrome is a neurological disorder where the immune system responds to an infection and ends up mistakenly attacking nerve cells, resulting in muscle weakness and eventually paralysis.

Read: [A brief history of coronaviruses — and why COVID-19 is different]

Other case studies have described severe COVID-19 encephalitis (brain inflammation and swelling) and stroke in healthy young people with otherwise mild COVID-19 symptoms.

Larger studies from China and France have also investigated the prevalence of neurological disorders in COVID-19 patients. These studies have shown that 36% of patients have neurological symptoms. Many of these symptoms were mild and include things like headaches or dizziness that could be caused by a robust immune response. Other more specific and severe symptoms were also seen and include loss of smell or taste, muscle weakness, stroke, seizure, and hallucinations.

Some people lose their sense of smell. Elipetit/Shutterstock

These symptoms are seen more often in severe cases, with estimates ranging from 46% to 84% of severe cases showing neurological symptoms. Changes in consciousness, such as disorientation, inattention, and movement disorders, were also seen in severe cases and found to persist after recovery.

Crossing the blood-brain barrier

SARS-CoV-2, the coronavirus that causes COVID-19, may cause neurological disorders by directly infecting the brain or as a result of the strong activation of the immune system.

Recent studies have found the novel coronavirus in the brains of fatal cases of COVID-19. It has also been suggested that infection of olfactory neurons in the nose may enable the virus to spread from the respiratory tract to the brain.

Cells in the human brain express the ACE2 protein on their surface. ACE2 is a protein involved in blood pressure regulation and is the receptor the virus uses to enter and infect cells. ACE2 is also found on endothelial cells that line blood vessels. Infection of endothelial cells may allow the virus to pass from the respiratory tract to the blood and then across the blood-brain barrier into the brain. Once in the brain, replication of the virus may cause neurological disorders.

SARS-CoV-2 infection also results in a very strong response by the immune system. This immune response may directly cause neurological disorders in the form of Guillain–Barré syndrome. But brain inflammation might also indirectly cause neurological damage, such as through brain swelling. And it's associated with – though doesn't necessarily cause – neurodegenerative diseases such as Alzheimer's and Parkinson's.

Not unique, but still worrying

SARS-CoV-2 is not unique in being a respiratory virus that can also infect the brain. Influenza, measles, and respiratory syncytial viruses can all infect the brain or central nervous system and cause neurological disease.

Other coronaviruses have also been found to infect the brain and cause neurological disorders. The related seasonal coronavirus, HCoV-OC43, typically causes very mild respiratory symptoms but can also cause encephalitis in humans. Similarly, the coronavirus that causes Mers and the 2003 Sars virus can cause severe neurological disorders.

Respiratory viruses getting into the brain is thankfully a rare occurrence. But with millions of COVID-19 infections worldwide, there is the risk of significant neurological disease, especially in severe cases.

It is important to be aware of the possibility of neurological manifestations of COVID-19, both during acute illness as well as the possibility of long-term effects. This also highlights the continued importance of preventing viral transmission and identifying those who are and have been, infected.

This article is republished from The Conversation by Jeremy Rossman, Honorary Senior Lecturer in Virology and President of Research-Aid Networks, University of Kent under a Creative Commons license. Read the original article.

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Do Your Genes Predispose You to COVID-19? - Scientific American

Posted: 30 Apr 2020 08:09 AM PDT

Since the start of the COVID-19 pandemic several months ago, scientists have been puzzling over the different ways the disease manifests itself. They range from cases with no symptoms at all to severe ones that involve acute respiratory distress syndrome, which can be fatal. What accounts for this variability? Might the answer lie in our genes?

Coronaviruses have raised such questions for more than 15 years. In researching the 2003 outbreak of severe acute respiratory syndrome (SARS), Ralph Baric and his colleagues at the University of North Carolina at Chapel Hill identified a gene that, when silenced by a mutation, makes mice highly susceptible to SARS-CoV, the coronavirus that causes the disease. Called TICAM2, the gene codes for a protein that helps activate a family of receptors, called toll-like receptors (TLRs), that are involved in innate immunity, the first line of defense against pathogens.

Attention has now shifted to SARS-CoV-2, the new coronavirus that causes COVID-19. And TLRs have once again drawn researchers' interest—this time to help explain the excess number of men who suffer from severe infections.

Men made up 73 percent of severe cases of COVID-19 in intensive care in France, according to a national survey published April 23. Behavioral and hormonal differences may be partially responsible. But genes may also factor into the mix. Unlike men, women have two X chromosomes and so carry double the copies of the gene TLR7, a key detector of viral activity that helps boost immunity.

The genetics of blood groups may offer some insight into whether you are liable to be infected with the virus. In late March Peng George Wang of the Southern University of Science and Technology in China and his colleagues released the results of a preprint study—not yet peer-reviewed—that compared the distribution of blood types among 2,173 COVID-19 patients in three hospitals in the Chinese cities of Wuhan and Shenzhen with that of uninfected people in the same areas. Blood type A appears to be associated with a higher risk of contracting the virus, whereas type O offers the most protection for reasons that have yet to be determined.

The earlier SARS outbreak also offers lessons. Blood types bear two different kinds of saccharide (sugar) molecules on the surface of red blood cells. One corresponds to type A, the other type B. Each kind of molecule is produced by an enzyme whose gene exists in two forms (one for type A and the other for type B). A third gene variant encodes an inactive enzyme: type O (from the German ohne, meaning "without"). A person possessing variants A and B of the enzyme has type AB blood.

Each sugar, A or B, may act as an antigen. It can trigger the production of antibodies that target the antigens it lacks, which is why care must be taken with blood transfusions. In the ABO blood group system, type O blood is the richest in antibodies—possessing both anti-A and anti-B—whereas type AB blood does not have either of them.

In 2008 Jacques Le Pendu of the University of Nantes in France and his colleagues investigated an in vitro model of SARS-CoV. The researchers showed that the binding of the virus's protein S to a cell's ACE2 (angiotensin-converting enzyme 2) receptor, which is necessary for infection to take place, is inhibited by the anti-A antibody, though data on the anti-B antibody are still lacking.

A close relative of ACE2 in blood pressure control is angiotensin-converting enzyme 1 (ACE1). The ACE1 D gene, one of several genetic variants of the enzyme, is associated with low levels of expression of the ACE2 gene. As a result, cells contain fewer of the receptors that allow infection by SARS-CoV. The frequency of ACE1 D differs from one country to another, particularly in Europe, which raises the question of whether the geographical distribution of this variant correlates with COVID-19 prevalence. Might it reflect the epidemiology of the disease on a global scale? Marc De Buyzere and his colleagues at Ghent University in Belgium found that to be the case.

Using data from 25 countries (spanning a region from Portugal to Estonia and from Turkey to Finland), the researchers showed that 38 percent of the variability in disease prevalence is explained by the frequency of the ACE1 D gene. A similar correlation turned up for mortality statistics. The researchers also noted that the ACE1 D gene is less frequent in two Asian countries severely hit by SARS-CoV-2.

A further genetic component of susceptibility to the new coronavirus may lie in the genes that encode human leukocyte antigens (HLAs), a set of proteins that keep the human immune system from attacking the body itself. These proteins make up the major histocompatibility complex (MHC), which marks "self" and distinguishes it from "nonself." Reid Thompson and his colleagues at the Oregon Health & Science University discovered a link between specific HLA genes and the severity of COVID-19.

Carriers of a variant called HLA-B*46:01 appear to be particularly susceptible to SARS-CoV-2, as was previously shown to be the case with SARS-CoV. In contrast, the HLA-B*15:03 variant may provide some protection. According to the researchers, identification of a person's HLA genes, which can be done quickly and inexpensively, may help to better predict the severity of disease—and even to identify those who would benefit most from vaccination.

Several projects are underway to investigate the genetic variants that influence SARS-CoV-2 infection in greater depth. Andrea Ganna of the University of Helsinki has launched the COVID-19 Host Genetics Initiative, which aims to mobilize the international community of geneticists working on this topic. Jean-Laurent Casanova of the Necker Hospital for Sick Children in Paris and the Rockefeller University is coordinating a similar effort to identify genetic variants that promote the development of particularly severe forms of COVID-19 in people under 50 years of age.

We may not all be equal when it comes to SARS-CoV-2. But identifying why these inequalities exist could help reduce them.

This article originally appeared in Pour la Science and was reproduced with permission.

Read more about the coronavirus outbreak here.

Severe Acute Respiratory Syndrome