Super Moon and Blue Moon on 31 January 2018. Same event in the next 150 years time.

Ice patterns in the Gunpowder River as seen from the Paper Mill bridge in Phoenix, MD after the snowstorm.

At certain brain wave frequencies, a sense of "ego boundary" vanishes. In the "theta" state, we are resting deeply and still conscious, at the threshold of drifting away from or back into conscious awareness.There is also a prana breathing tube that runs through the body. It connects the apexes of this Star Tetrahedral field. Learning how to breathe through this tube, combined with rotating the fields, produces the merkaba, a vehicle of ascension. As the brain enters deeper states, our consciousness is less concerned with the physical state, our 'third eye' is active, and separation becomes natural. You can be aware of your truth in every moment of every day by drawing on the deepest blue strand you can find. That strand won’t let you listen to third-dimensional words that are designed to deceive you. You will walk away from words that are not in the highest truth. With your truth strand out front, you won’t be deceived. You’ll know and hear truth, and if you hear an untruth, it will not work for you.Your blueprints have always been available to you, and when they’re interwoven, you can use this exercise to travel through the etheric fabric to find what you’re looking for. When you present your request properly to your higher self, you’ll be surprised by just how much you do know about where you want to go. Much of what you know is unsaid, hidden in your feelings, but accessible..Prana breathing tube that runs through the body. It connects the apexes of this Star Tetrahedral field. Learning how to breathe through this tube, combined with rotating the fields, produces the merkaba, a vehicle of ascension.he photon energy belt that the Earth will move through during the Shift is so huge that I cannot provide you with a precise description of its immensity. Second, prana is a vital life-giving breath, involving deep inhalation, which allows the photon energy to enter into the body through the crown chakra. Finally, your pineal gland is the receptacle of the photon energy in the body..These are three identical fields superimposed over each other, the only difference among them being that the physical body alone is locked, it does not rotate. The merkaba is created by counter-rotating fields of energy. The mental Star Tetrahedral field is electrical in nature, male, and rotates to the left. Since the higher energies work with your feelings, your focus must be on your emotional body. If you learn to think emotionally, you will be aware that your emotions guide everything within your realm. Your emotional body is between your mental and physical bodies, so when you feel something, the latter two bodies go along for the ride..The emotional Star Tetrahedral field is magnetic in nature, female, and rotates to the right. It is the linking together of the mind, heart, and physical body in a specific geometrical ratio and at a critical speed that produces the merkaba.The MerKaBa (sometimes spelled merkavah and, or merkabah) is a vehicle of Ascension. It was believed in ancient times, and even written about by the Hebrews, that the merkavah could be turned on by certain principles in meditation. This involves breathing changes & mind, heart, and body changes that alter the way a person perceives reality..The word “Mer” denotes counter-rotating fields of light, “Ka” Spirit, and “Ba” body, or reality. So the Mer-Ka-Ba then, is a counter-rotating Living field of light that encompasses both Spirit and body and it’s a dimensional vehicle. It’s far more than just that, in fact there isn’t anything that it isn’t. It is the image through which all things were created, and that image is around your body in a geometrical set of patterns.The field extends out a full fifty to sixty feet in diameter (18 to 20 meters), depending on your height. It looks like a flying saucer (Fig. 1). That field is an immense science that is being studied everywhere throughout the cosmos. How well someone understands the MerKaBa, is usually in direct relationship to their consciousness level..

If, when speaking to your higher self, you say, “I want to get from here to there and I want you to guide me,” your higher self will do whatever it wants, and it might be years before you see any results, because your higher self has no concept of time. If you want the unseen energies to guide you, you must learn to communicate with them effectively, and that means you must work with your feelings. The unseen energies do not understand language or words as you know them. They can feel you, and if they can feel you, they will know what you want. When these energies respond to your feelings, you will feel the responding communication from them. So, when you ask your higher self to guide you from here to there in the shortest manner possible, it means nothing, unless you focus on getting the feeling of where you want to go, and how and when you want to get there. If you give those feelings to your higher self, after you’ve woven them through the two brains, you will accomplish your goal. The key here is weaving the local and omni brains together. Practice this by contacting the Elven world, where the language is closest to yours here on the Earth plane. Photon, or love, energy is at the root of the current Shift in Consciousness. Pineal gland is the true master gland. It is situated between the eyes. It is the organ of clairvoyance, Third eye, the eye of Ra or Heru (God). Biblical Jacob saw God face to face on the island of Pe-ni-el. Its secretes melatonin which is anti ageing in effect and anti oxidant in nature. This also secretes melanin which colours our skin. The pineal gland, the most enigmatic of endocrine organs, has long been of interest to anatomists. Several millennia ago it was thought to be a valve that controlled the flow of memories into consciousness. René Descartes, the 17th-century French philosopher-mathematician, concluded that the pineal was the seat of the soul. A corollary notion was that calcification of the pineal caused psychiatric disease, a concept that provided support for those who considered psychotic behavior to be rampant; modern examination techniques have revealed that all pineal glands become more or less calcified..The pineal organ is small, weighing little more than 0.1 gram. It lies deep within the brain between the two cerebral hemispheres and above the third ventricle of the spinal column. It has a rich supply of adrenergic nerve fibers that greatly influence its secretions. Microscopically, the gland is composed of pinealocytes (rather typical endocrine cells except for extensions that mingle with those of adjacent cells). Supporting cells that are similar to astrocytes of the brain are interspersed.. The pineal gland contains a number of peptides, including GnRH, TRH, and vasotocin, along with a number of important neurotransmitters such as somatostatin, norepinephrine, serotonin, and histamine. The major pineal hormone, however, is melatonin, a derivative of the amino acid tryptophan. Melatonin was first discovered because it lightens amphibian skin, an effect opposite to that of melanocyte-stimulating hormone of the anterior pituitary. Secretion of melatonin is enhanced whenever the sympathetic nervous system is stimulated. Of greater interest, however, is the fact that secretion increases soon after an animal is placed in the dark; the opposite effect takes place immediately upon exposure to light. Its major action, well documented in animals, is to block the secretion of GnRH by the hypothalamus and of gonadotropins by the pituitary. While it was long thought that a decrease in melatonin secretion heralded the onset of puberty, this hypothesis cannot be supported by studies in humans. It is possible that the pineal contains an as yet unidentified hormone that serves that function. Melotonin is the only hormone secreted by the pineal gland. (The pineal gland is a tiny endocrine gland situated at the centre of the brain.) Melatonin was discovered in 1958 by Aaron B. Lerner and other researchers working at Yale University. Melatonin is produced in humans, other mammals, birds, reptiles, and amphibians. It is present in very small amounts in the human body. Melatonin was previously known to cause the skins of amphibians to blanch, but its functions in mammals remained uncertain until research discoveries in the 1970s and '80s suggested that it regulates both sleeping cycles and the hormonal changes that usher in sexual maturity during adolescence. The pineal gland's production of melatonin varies both with the time of day and with age; production of melatonin is dramatically increased during the nighttime hours and falls off during the day, and melatonin levels are much higher in children under age seven than in adolescents and are lower still in adults. Melatonin apparently acts to keep a child's body from undergoing sexual maturation, since sex hormones such as luteotropin, which play a role in the development of sexual organs, emerge only after melatonin levels have declined. This hypothesis is supported by the fact that children with tumors of the pineal gland often reach sexual maturity unusually early in life, presumably because the pineal's production of melatonin has been hampered. Melatonin also seems to play an important role in regulating sleeping cycles; test subjects injected with the hormone become sleepy, suggesting that the increased production of melatonin coincident with nightfall acts as a fundamental mechanism for making people sleepy. With dawn the pineal gland stops producing melatonin, and wakefulness and alertness ensue. The high level of melatonin production in young children may explain their tendency to sleep longer than adults. In mammals other than humans melatonin possibly acts as a breeding and mating cue, since it is produced in greater amounts in response to the longer nights of winter and less so during summer. Animals who time their mating or breeding to coincide with favorable seasons (such as spring) may depend on melatonin production as a kind of biological clock that regulates their reproductive cycles on the basis of the length of the solar day.When activated, the pineal gland becomes the line of communication, with the higher planes. The crown chakra, reaches down, until its vortex touches the pineal gland. Prana, or pure energy, is received through this energy center in the head. With Practice, the vibration level of the astral body is raised, allowing it, to separate from the physical. To activate the 'third eye' and perceive higher dimensions, the pineal gland and the pituitary body, must vibrate in unison, which is achieved through meditation and / or relaxation. When a correct relationship is established, between personality, operating through the pituitary body, and the soul, operating through the pineal gland, a magnetic field is created. The negative and positive forces, interact and become strong enough, to create the 'light in the head. ' With this 'light in the head' activated, astral projectors can withdraw themselves, from the body, carrying the light with them. Astral Travel, and other occult abilities, are closely associated with the development of the 'light in the head'. After physical relaxation, concentration upon the pineal gland, is achieved, by staring at a point in the middle of the forehead. Without straining the muscles of the eye, this will activate the pineal gland and the 'third eye'. Beginning with the withdrawal of the senses and the physical consciousness, the consciousness is centered in the region of the pineal gland. The perceptive faculty and the point of realization, are centralized in the area between the middle of the forehead and the pineal gland. The trick is to visualize, very intently, the subtle body... escaping through the trap door of the brain. A "popping sound" may occur at the time separation of the astral body, in the area of the pineal gland. Visualization exercises, are the first step, in directing the energies in our inner systems, to activate the 'third eye'. The magnetic field is created around the pineal gland, by focusing the mind on the midway point, between the pineal gland and the pituitary body. The creative imagination visualizes something, and the thought energy of the mind gives life and direction to this form. 'Third eye' development, imagination, and visualization are important ingredients, in many methods to separate from the physical form. Intuition is also achieved, through 'third eye' development. Knowledge and memory of the astral plane, are not registered in full waking consciousness, until the intuition becomes strong enough. Flashes of intuition come, with increasing consistency, as the 'third eye' is activated to a greater degree, through practice. Universal Knowledge... can also be acquired...The pineal gland, corresponds with divine thought, after being touched by the vibrating light of Kundalini. Kundalini starts its ascent, towards the head center, after responding to the vibrations from the 'light in the head.' The light is located at the top of the sutratma, or 'soul thread', which passes down from the highest plane of our being... into the physical vehicle. The 'third eye,' or 'Eye of Siva,' the organ of spiritual vision, is intimately related to karma, as we become more spiritual in the natural course of evolution. As human beings continue to evolve, further out of matter, on the journey from spirit to matter... back to spirit, the pineal gland will continue to rise from its state of age - long dormancy, bringing back to humanity... astral capacities and spiritual abilities...Your body produces its own photon energy, but you can bring more of this golden energy into your body by prana breathing it in through your crown and down through your pineal. That simple activity will awaken your God cell, also known as your Signature Cell, which is in your pineal gland. Prana breathing will flow the golden particles from the pineal through the whole of your physical body, affecting the emotional, mental and spiritual bodies in the process.Next, your thought process must be pure. If you want to get from Manhattan to a specific place in Queens and you’ve never been to Queens, you must have pure thoughts about the journey, concentrating only on the specific place you want to reach, feeling every aspect of it. Then you must go into the etheric pattern until you find and get through that little “gray space” that lets you know you’ve left the third-dimensional reality. You will find yourself in Queens, looking at the specific place you wanted to reach. You will then have to back away from it until the neighborhood where it actually is comes into focus. You will recognize the surrounding neighborhood. You may not have seen how you got there, but you will have enough information, such as an address, to Google it or to ask someone how to get there. You can go from where you are to any place in the world that way during these pre-Shift times. As a four-bodied energy, you have spiritual, mental, emotional, and physical bodies, and you have four strands of DNA that correspond to each of those bodies. The first strand of DNA is the physical, the second, the emotional, the third, the mental, and the fourth, the spiritual...The four strands of DNA are powerful, but one strand is more powerful than the rest and that is the golden strand. Each set of four strands of DNA has one golden strand, which is found in the spiritual, or etheric, body. The golden strand is pure photon energy. The photon energy you bring into your body through prana breathing gets woven with everything else via the pineal gland. During the Shift, you will let go of your third-dimensional reality with the help of that magical golden fourth strand of DNA, which is equipped to transfer you into the fourth dimension.The foundation of our spiritual practice has to be very clear to us, otherwise it is very easy to enter into mistaken techniques and practices. In the Gnostic tradition, we always seek to re-evaluate our spiritual approach; our teacher Samael Aun Weor was very rigorous in his analysis of himself, his spiritual practice, and his technique. He constantly re-evaluated his method, and corrected himself in order to ensure he was on the right path. This is because he relied on practical experience, and was constantly examining the nature of suffering in himself, and was not satisfied with concept or theory. Samael Aun Weor suffered a lot, and that suffering is what gave him the impulse, the motivation, to constantly revise his spiritual practice in order to conquer suffering, and also to help others to do the same. Really, this viewpoint about suffering is the foundation of every genuine path, so understanding suffering is the foundational aspect of all teachings. In essence, spiritual practice is about harnessing energy. In the first levels, in the foundational and Mahayana levels, the two classifications of teaching, we are really learning how to discipline our mind stream and attune it with the mind stream of Christ. This is why Bodhichitta can also be translated as Christ mind (bodhi = wisdom = Chokmah; chitta = mind).

Bodhichitta is a kind of energy that vibrates with the ray of creation, with the Ain Soph Aur, a type of light that emerges out of the Absolute, a light that comes from Adhi-Buddha, the primordial Buddha. This light, which is the supreme clear light, is the type of light that is absolutely perfect, and is the first and primordial expression of the divine. It is a light of unbelievable, indescribable radiance, whose chief characteristic is a brilliant, shining love. If you meditate on that, simply that, you will comprehend why most of the teachings of Tantra you find in the world are black. They are completely contradictory to that light. That light is not interested in pleasure. That light is not interested in the satisfaction of desire. Those are the interests of demons.

When that light emerges out of the Absolute abstract space, it emerges as a form of an archetype, related to the world of Atziluth in Kabbalah. An archetype is a blue print, a primordial form that has not yet become. For that becoming to happen, there has to be a long process of development, and that is the path of initiation, the path through which the soul is born, the soul is created. We are only the embryo of soul, a seed. We are not a soul yet. This is why Jesus said, “With patience you will possess your soul.”

The development and creation of the soul depends upon it being nourished by the light of Christ, this Christic force, which is also called Avalokiteshvara, Quetzalcoatl, Vishnu, and Osiris. They are all the same force. Christ is not a person, but an energy, an intelligence, a light.

That energy creates what we see here as the Tree of Life. That energy descends and condenses and unravels and reveals everything that exists. It is also called the great breath, and is symbolized in Kabbalah and other religions as the breath of God that emerges out of the nothingness. That great breath, that exhalation, is how everything comes to exist, macrocosmically and microcosmically. That Great Breath in Sanskrit is called Prana. The relationship between the Pineal Gland and the Sun shows how much influence the Sun has on us. It is our body clock. The Pineal Gland also reads the Sun and informs animals when it is time to hibernate..Many primitive cultures related to the Sun as the closest physical structure to God due to it’s influence on daily life. Without the Sun life would be over, but the Sun shows up everyday and on-time. The Sun not only influences human bodies internally, but provides the energy for the food humans need to survive to grow. Thus the Sun is the source of life on this planet.

Left: This is your brain. Right: This is your brain after intermittent binge drinking.

 

DURHAM, N.C. -- Studies have demonstrated how just a few sessions of binge drinking during adolescence can knock out neurons (shown in blue arch) in the hippocampus, the brain’s memory core.

 

But researchers at Duke Medicine have found that binge drinking can also send hippocampal cells called astrocytes (shown in green) awry later in adulthood, potentially impairing the brain’s ability to form new synapses and heal itself from injury.

 

The study, published November 5 in Alcoholism: Clinical & Experimental Research, used a rodent model as a surrogate for the adolescent human brain. The researchers exposed the animals to alcohol doses that would result in a blood-alcohol concentration of about .15 in humans.

 

Researchers didn’t see immediate effects on astrocytes, but once the animals reached adulthood, the cells appeared to go into overdrive.

 

Image credit: Mary-Louise Risher/Duke Medicine

 

This image is not owned by the NIH. It is shared with the public under license. If you have a question about using or reproducing this image, please contact the creator listed in the credits. All rights to the work remain with the original creator.

 

NIH funding from:

The National Institute on Alcohol Abuse and Alcoholism (NIAAA),

The National Institute on Drug Abuse (NIDA)

  

The image depicts the interaction between a brain cell known as astrocyte (shown in blue) and a synthetic material (shown in green) that mimics the extracellular environment. The material made of peptides and DNA forms fibrous bundles (highlighted in yellow) that are similar to the ones present in the spinal cord when an injury occurs. The architecture of the synthetic matrix triggers the cell to become reactive as evident by its morphology.

Nature Communications, July 2017, www.nature.com/articles/ncomms15982

 

Courtesy of Dr. Mark McClendon , Northwestern University

 

Image Details

Instrument used: Quanta SEM

Magnification: 5,200X

Horizontal Field Width: 30um

Vacuum: 1 e-3Pa

Voltage: 3kV

Spot: 3

Working Distance: 10

Detector: SE

 

Astrocytes (green), seen here in a mouse brain, are star-shaped glial cells in the brain and spinal cord. They outnumber neurons by more than five-fold. Research suggests that, among other functions, astrocytes regulate blood flow, store and distribute energy, and play a role in the transmission of electrical signals. Credit: NICHD

  

Researchers investigate star-shaped brain cells: NIH-funded researchers used 3-D collections of brain tissue grown from human cells to study the brain’s star-shaped astrocytes.

 

More information: www.nih.gov/news-events/news-releases/scientists-give-sta...

 

Credit: Pasca Lab, Stanford University

 

NIH support from: NINDS, NIMH, NIGMS, NCATS

Human neural progenitor cells were isolated under selective culture conditions from the developing human brain and directed through lineage differentiation to GFAP + (glial fibrillary acid protein) astrocytes. Following 3 weeks in astrocyte selective medium, cells were fixed and stained with antibodies to intermediate filament proteins that characterize the cells as either astrocytes (GFAP in orange) or neural progenitor cells (nestin in green). Nuclei are stained with DAPI in blue. Microscopic examination over the course of differentiation showed loss of progenitor cells (nestin down regulation) as cell population increasingly became astrocytes (GFAP up regulation).

 

Photomicrograph was taken on Axiovert 200M Zeiss inverted microscope at 200 x magnification.

 

Credit: Carol Ibe, Eugene Major, National Institute of Neurological Disorders and Stroke, National Institutes of Health

An NIH study in rats shows that star-shaped brain cells, called astrocytes (red) may play an active role in breathing.

 

More information: www.nih.gov/news-events/news-releases/star-cells-may-help...

 

Credit: Jeffrey C. Smith Lab, National Institute of Neurological Disorders and Stroke, NIH

"This image represents human neural stem cells from fetal cortex. Cells are stained for nuclear (Hoechst, blue), neuronal (TUJ-1, green), and astrocyte (GFAP, red) markers. Images are acquired using the InCell Analyzer 1000™. The images taken from this assay are analyzed using the Developer Toolbox™ software.

This image is one of many taken from BCI’s growing platform of human neural stem cell differentiation assays. BCI uses this assay along with several others in its neurogenesis platform to identify clinical-stage compounds, novel targets and compounds optimal for CNS indications.

"

 

Retinal ganglion cells are neurons that send information about light from the eye to the brain via a structure called the optic nerve. Here new neurons (green) and their supporting cells, called astrocytes (red), were created in a petri dish from stem cells. Making retinal ganglion cells and astrocytes from stem cells may one day help doctors rewire optic nerves damaged by glaucoma.

 

Credit: National Eye Institute, NIH

 

(Courtesy of Thomas V. Johnson, Naoki Nakaya, and Stanislav Tomarev of the NEI Laboratory of Retinal Cell and Molecular Biology, Molecular Mechanisms of Glaucoma Section)

 

Cultured adult rat neural stem cells. Red indicates stem cells differentiating into astrocytes, green shows oligodendrocytes, and blue indicates the cell nuclei.

 

This photo was taken in the lab of David Schaffer at the University of California, Berkeley.

 

Learn more about CIRM-funded stem cell research: www.cirm.ca.gov

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic.

 

Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. Of those people who develop noticeable symptoms, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging), and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). Older people are more likely to have severe symptoms. At least a third of the people who are infected with the virus remain asymptomatic and do not develop noticeable symptoms at any point in time, but they still can spread the disease.[ Around 20% of those people will remain asymptomatic throughout infection, and the rest will develop symptoms later on, becoming pre-symptomatic rather than asymptomatic and therefore having a higher risk of transmitting the virus to others. Some people continue to experience a range of effects—known as long COVID—for months after recovery, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

The virus that causes COVID-19 spreads mainly when an infected person is in close contact[a] with another person. Small droplets and aerosols containing the virus can spread from an infected person's nose and mouth as they breathe, cough, sneeze, sing, or speak. Other people are infected if the virus gets into their mouth, nose or eyes. The virus may also spread via contaminated surfaces, although this is not thought to be the main route of transmission. The exact route of transmission is rarely proven conclusively, but infection mainly happens when people are near each other for long enough. People who are infected can transmit the virus to another person up to two days before they themselves show symptoms, as can people who do not experience symptoms. People remain infectious for up to ten days after the onset of symptoms in moderate cases and up to 20 days in severe cases. Several testing methods have been developed to diagnose the disease. The standard diagnostic method is by detection of the virus' nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

 

Preventive measures include physical or social distancing, quarantining, ventilation of indoor spaces, covering coughs and sneezes, hand washing, and keeping unwashed hands away from the face. The use of face masks or coverings has been recommended in public settings to minimise the risk of transmissions. Several vaccines have been developed and several countries have initiated mass vaccination campaigns.

 

Although work is underway to develop drugs that inhibit the virus, the primary treatment is currently symptomatic. Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.

 

SIGNS AND SYSTOMS

Symptoms of COVID-19 are variable, ranging from mild symptoms to severe illness. Common symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, and breathing difficulties. People with the same infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, and throat disorders, loss of taste combined with loss of smell is associated with COVID-19.

 

Most people (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) and 5% of patients suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can spread the disease. Other infected people will develop symptoms later, called "pre-symptomatic", or have very mild symptoms and can also spread the virus.

 

As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.

Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects for months after recovery—named long COVID—and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

CAUSE

TRANSMISSION

Coronavirus disease 2019 (COVID-19) spreads from person to person mainly through the respiratory route after an infected person coughs, sneezes, sings, talks or breathes. A new infection occurs when virus-containing particles exhaled by an infected person, either respiratory droplets or aerosols, get into the mouth, nose, or eyes of other people who are in close contact with the infected person. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection.

 

The closer people interact, and the longer they interact, the more likely they are to transmit COVID-19. Closer distances can involve larger droplets (which fall to the ground) and aerosols, whereas longer distances only involve aerosols. Larger droplets can also turn into aerosols (known as droplet nuclei) through evaporation. The relative importance of the larger droplets and the aerosols is not clear as of November 2020; however, the virus is not known to spread between rooms over long distances such as through air ducts. Airborne transmission is able to particularly occur indoors, in high risk locations such as restaurants, choirs, gyms, nightclubs, offices, and religious venues, often when they are crowded or less ventilated. It also occurs in healthcare settings, often when aerosol-generating medical procedures are performed on COVID-19 patients.

 

Although it is considered possible there is no direct evidence of the virus being transmitted by skin to skin contact. A person could get COVID-19 indirectly by touching a contaminated surface or object before touching their own mouth, nose, or eyes, though this is not thought to be the main way the virus spreads. The virus is not known to spread through feces, urine, breast milk, food, wastewater, drinking water, or via animal disease vectors (although some animals can contract the virus from humans). It very rarely transmits from mother to baby during pregnancy.

 

Social distancing and the wearing of cloth face masks, surgical masks, respirators, or other face coverings are controls for droplet transmission. Transmission may be decreased indoors with well maintained heating and ventilation systems to maintain good air circulation and increase the use of outdoor air.

 

The number of people generally infected by one infected person varies. Coronavirus disease 2019 is more infectious than influenza, but less so than measles. It often spreads in clusters, where infections can be traced back to an index case or geographical location. There is a major role of "super-spreading events", where many people are infected by one person.

 

A person who is infected can transmit the virus to others up to two days before they themselves show symptoms, and even if symptoms never appear. People remain infectious in moderate cases for 7–12 days, and up to two weeks in severe cases. In October 2020, medical scientists reported evidence of reinfection in one person.

 

VIROLOGY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature.

 

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.

 

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have an animal (zoonotic) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The structure of the M protein resembles the sugar transporter SemiSWEET.

 

The many thousands of SARS-CoV-2 variants are grouped into clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR).

 

Several notable variants of SARS-CoV-2 emerged in late 2020. Cluster 5 emerged among minks and mink farmers in Denmark. After strict quarantines and a mink euthanasia campaign, it is believed to have been eradicated. The Variant of Concern 202012/01 (VOC 202012/01) is believed to have emerged in the United Kingdom in September. The 501Y.V2 Variant, which has the same N501Y mutation, arose independently in South Africa.

 

SARS-CoV-2 VARIANTS

Three known variants of SARS-CoV-2 are currently spreading among global populations as of January 2021 including the UK Variant (referred to as B.1.1.7) first found in London and Kent, a variant discovered in South Africa (referred to as 1.351), and a variant discovered in Brazil (referred to as P.1).

 

Using Whole Genome Sequencing, epidemiology and modelling suggest the new UK variant ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020) transmits more easily than other strains.

 

PATHOPHYSIOLOGY

COVID-19 can affect the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective. As the alveolar disease progresses, respiratory failure might develop and death may follow.

 

Whether SARS-CoV-2 is able to invade the nervous system remains unknown. The virus is not detected in the CNS of the majority of COVID-19 people with neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID-19, but these results need to be confirmed. SARS-CoV-2 could cause respiratory failure through affecting the brain stem as other coronaviruses have been found to invade the CNS. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood-brain barrier to gain access to the CNS, possibly within an infected white blood cell.

 

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

 

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism have been found people transferred to Intensive care unit (ICU) with COVID-19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in people infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia. Furthermore, microvascular blood vessel damage has been reported in a small number of tissue samples of the brains – without detected SARS-CoV-2 – and the olfactory bulbs from those who have died from COVID-19.

 

Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of hospitalized patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

 

Autopsies of people who died of COVID-19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.

 

IMMUNOPATHOLOGY

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID-19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.

 

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

 

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID-19 . Lymphocytic infiltrates have also been reported at autopsy.

 

VIRAL AND HOST FACTORS

VIRUS PROTEINS

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus host range and cellular tropism via the receptor binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID-19 vaccines.

 

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response.

 

HOST FACTORS

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-COV2 virus targets causing COVID-19. Theoretically the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID-19, though animal data suggest some potential protective effect of ARB. However no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.

 

The virus' effect on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome.

 

HOST CYTOKINE RESPONSE

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm. Levels of interleukin 1B, interferon-gamma, interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID-19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID-19 disease.

 

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID-19, it is related to worse prognosis and increased fatality. The storm causes the acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis, acute kidney injury, and vasculitis. The production of IL-1, IL-2, IL-6, TNF-alpha, and interferon-gamma, all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system, the microglia, neurons, and astrocytes, are also be involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.

 

DIAGNOSIS

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.

 

VIRAL TESTING

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests, which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited." The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease.

 

A number of laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK.

 

The University of Oxford's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" On 7 September, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results."

 

IMAGING

Chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.

 

Many groups have created COVID-19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID-19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive.

Coding

In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.

 

PATHOLOGY

The main pathological findings at autopsy are:

 

Macroscopy: pericarditis, lung consolidation and pulmonary oedema

Lung findings:

minor serous exudation, minor fibrin exudation

pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation

diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

plasmocytosis in BAL

Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

Liver: microvesicular steatosis

 

PREVENTION

Preventive measures to reduce the chances of infection include staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.

 

Those diagnosed with COVID-19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.

 

The first COVID-19 vaccine was granted regulatory approval on 2 December by the UK medicines regulator MHRA. It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID-19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID-19 is trying to decrease and delay the epidemic peak, known as "flattening the curve". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.

 

VACCINE

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus causing coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which enabled accelerated development of various vaccine technologies during early 2020. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19.

 

In Phase III trials, several COVID‑19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of March 2021, 12 vaccines were authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, and CoviVac), four viral vector vaccines (Sputnik V, the Oxford–AstraZeneca vaccine, Convidicea, and the Johnson & Johnson vaccine), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer). In total, as of March 2021, 308 vaccine candidates were in various stages of development, with 73 in clinical research, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development.

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. As of 17 March 2021, 400.22 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses, and Sputnik V, Sinopharm, Sinovac, and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. By December 2020, more than 10 billion vaccine doses had been preordered by countries, with about half of the doses purchased by high-income countries comprising 14% of the world's population.

 

SOCIAL DISTANCING

Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. Many governments are now mandating or recommending social distancing in regions affected by the outbreak.

 

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.

 

SELF-ISOLATION

Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.

Face masks and respiratory hygiene

 

The WHO and the US CDC recommend individuals wear non-medical face coverings in public settings where there is an increased risk of transmission and where social distancing measures are difficult to maintain. This recommendation is meant to reduce the spread of the disease by asymptomatic and pre-symptomatic individuals and is complementary to established preventive measures such as social distancing. Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing. A face covering without vents or holes will also filter out particles containing the virus from inhaled and exhaled air, reducing the chances of infection. But, if the mask include an exhalation valve, a wearer that is infected (maybe without having noticed that, and asymptomatic) would transmit the virus outwards through it, despite any certification they can have. So the masks with exhalation valve are not for the infected wearers, and are not reliable to stop the pandemic in a large scale. Many countries and local jurisdictions encourage or mandate the use of face masks or cloth face coverings by members of the public to limit the spread of the virus.

 

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease. When not wearing a mask, the CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. Healthcare professionals interacting directly with people who have COVID-19 are advised to use respirators at least as protective as NIOSH-certified N95 or equivalent, in addition to other personal protective equipment.

 

HAND-WASHING AND HYGIENE

Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. The CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

 

SURFACE CLEANING

After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body cause infection. Current evidence indicates that contact with infected surfaces is not the main driver of Covid-19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticized as hygiene theater, giving a false sense of security against something primarily spread through the air.

 

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight. Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%).

 

On many surfaces, including as glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. As a general rule of thumb, the virus dies faster on porous surfaces than on non-porous surfaces.

However, this rule is not absolute, and of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces.

 

Surfaces may be decontaminated with 62–71 percent ethanol, 50–100 percent isopropanol, 0.1 percent sodium hypochlorite, 0.5 percent hydrogen peroxide, and 0.2–7.5 percent povidone-iodine. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used. The CDC recommends that if a COVID-19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons should be disinfected. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inocuylum volumes) can be seen in the supplementary material of.

 

VENTILATION AND AIR FILTRATION

The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.

 

HEALTHY DIET AND LIFESTYLE

The Harvard T.H. Chan School of Public Health recommends a healthy diet, being physically active, managing psychological stress, and getting enough sleep.

 

While there is no evidence that vitamin D is an effective treatment for COVID-19, there is limited evidence that vitamin D deficiency increases the risk of severe COVID-19 symptoms. This has led to recommendations for individuals with vitamin D deficiency to take vitamin D supplements as a way of mitigating the risk of COVID-19 and other health issues associated with a possible increase in deficiency due to social distancing.

 

TREATMENT

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. Thus, the cornerstone of management of COVID-19 is supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

 

Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.

 

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.

Several experimental treatments are being actively studied in clinical trials. Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful. Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment. Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy.

 

PROGNOSIS

The severity of COVID-19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalization. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID-19 and with a transfer to ICU.

 

Some early studies suggest 10% to 20% of people with COVID-19 will experience symptoms lasting longer than a month.[191][192] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020 WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID-19 symptoms that fluctuate over time as "really concerning." They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros has concluded that therefore herd immunity is "morally unconscionable and unfeasible".

 

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within 2 months of discharge. The average to readmit was 8 days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease.

 

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers, air pollution is similarly associated with risk factors, and pre-existing heart and lung diseases and also obesity contributes to an increased health risk of COVID-19.

 

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research that looked into the COVID-19 infections in hospitalized kidney transplant recipients found a mortality rate of 11%.

See also: Impact of the COVID-19 pandemic on children

 

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years. They are likely to have milder symptoms and a lower chance of severe disease than adults. A European multinational study of hospitalized children published in The Lancet on 25 June 2020 found that about 8% of children admitted to a hospital needed intensive care. Four of those 582 children (0.7%) died, but the actual mortality rate could be "substantially lower" since milder cases that did not seek medical help were not included in the study.

 

Genetics also plays an important role in the ability to fight off the disease. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID-19. Genetic screening is able to detect interferon effector genes.

 

Pregnant women may be at higher risk of severe COVID-19 infection based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.

 

COMPLICATIONS

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death. Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots. Approximately 20–30% of people who present with COVID-19 have elevated liver enzymes, reflecting liver injury.

 

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions). Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID-19 and have an altered mental status.

 

LONGER-TERM EFFECTS

Some early studies suggest that that 10 to 20% of people with COVID-19 will experience symptoms lasting longer than a month. A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath. About 5-10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.

 

By a variety of mechanisms, the lungs are the organs most affected in COVID-19.[228] The majority of CT scans performed show lung abnormalities in people tested after 28 days of illness.

 

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long lasting effects, including pulmonary fibrosis. Overall, approximately one third of those investigated after 4 weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in people who are asymptomatic, but with the suggestion of continuing improvement with the passing of more time.

 

IMMUNITY

The immune response by humans to CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralizing antibodies in blood strongly correlates with protection from infection, but the level of neutralizing antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralizing antibody two months after infection. In another study, the level of neutralizing antibody fell 4-fold 1 to 4 months after the onset of symptoms. However, the lack of antibody in the blood does not mean antibody will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least 6 months after appearance of symptoms. Nevertheless, 15 cases of reinfection with SARS-CoV-2 have been reported using stringent CDC criteria requiring identification of a different variant from the second infection. There are likely to be many more people who have been reinfected with the virus. Herd immunity will not eliminate the virus if reinfection is common. Some other coronaviruses circulating in people are capable of reinfection after roughly a year. Nonetheless, on 3 March 2021, scientists reported that a much more contagious Covid-19 variant, Lineage P.1, first detected in Japan, and subsequently found in Brazil, as well as in several places in the United States, may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.

 

MORTALITY

Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly.

 

The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 2.2% (2,685,770/121,585,388) as of 18 March 2021. The number varies by region. The CFR may not reflect the true severity of the disease, because some infected individuals remain asymptomatic or experience only mild symptoms, and hence such infections may not be included in official case reports. Moreover, the CFR may vary markedly over time and across locations due to the availability of live virus tests.

 

INFECTION FATALITY RATE

A key metric in gauging the severity of COVID-19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk. This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR, the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases.

 

CURRENT ESTIMATES

A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO.

 

EARLIER ESTIMATES OF IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.[ On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID-19 (0.3% of the population).Antibody testing in New York City suggested an IFR of ~0.9%,[258] and ~1.4%. In Bergamo province, 0.6% of the population has died. In September 2020 the U.S. Center for Disease Control & Prevention reported preliminary estimates of age-specific IFRs for public health planning purposes.

 

SEX DIFFERENCES

Early reviews of epidemiologic data showed gendered impact of the pandemic and a higher mortality rate in men in China and Italy. The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected people were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.

 

ETHNIC DIFFERENCES

In the US, a greater proportion of deaths due to COVID-19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the U.K., a greater proportion of deaths due to COVID-19 have occurred in those of a Black, Asian, and other ethnic minority background. More severe impacts upon victims including the relative incidence of the necessity of hospitalization requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet. This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe.

 

COMORBIDITIES

Most of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease. According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), Ischemic Heart Disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths).

 

Most critical respiratory comorbidities according to the CDC, are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis. Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms. COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.

 

In August 2020 the CDC issued a caution that tuberculosis infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID-19 couldn't rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB related deaths by 2025.

 

NAME

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu, Middle East Respiratory Syndrome, and Zika virus. In January 2020, the WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species, or groups of people in disease and virus names in part to prevent social stigma. The official names COVID-19 and SARS-CoV-2 were issued by the WHO on 11 February 2020. Tedros Adhanom explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.

 

HISTORY

The virus is thought to be natural and of an animal origin, through spillover infection. There are several theories about where the first case (the so-called patient zero) originated. Phylogenetics estimates that SARS-CoV-2 arose in October or November 2019. Evidence suggests that it descends from a coronavirus that infects wild bats, and spread to humans through an intermediary wildlife host.

 

The first known human infections were in Wuhan, Hubei, China. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as 1 December 2019.Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals. In May 2020 George Gao, the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event, but that it was not the site of the initial outbreak.[ Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.

 

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of coronavirus cases in Hubei gradually increased, reaching 60 by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS, causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.

 

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases—enough to trigger an investigation.

 

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen. Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared the coronavirus a Public Health Emergency of International Concern. By this time, the outbreak spread by a factor of 100 to 200 times.

 

Italy had its first confirmed cases on 31 January 2020, two tourists from China. As of 13 March 2020 the WHO considered Europe the active centre of the pandemic. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020.

 

After 55 days without a locally transmitted case, Beijing reported a new COVID-19 case on 11 June 2020 which was followed by two more cases on 12 June. By 15 June there were 79 cases officially confirmed, most of them were people that went to Xinfadi Wholesale Market.

 

RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID-19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December.

 

MISINFORMATION

After the initial outbreak of COVID-19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online.

 

In September 2020, the U.S. CDC published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.

 

OTHER ANIMALS

Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis.

 

Some pets, especially cats and ferrets, can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviors which increase the risk of transmission include kissing, licking, and petting the animal.

 

The virus does not appear to be able to infect pigs, ducks, or chickens at all.[ Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.

 

Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID-19 virus.

 

Minks, which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms. Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations. A vaccine for mink and other animals is being researched.

 

RESEARCH

International research on vaccines and medicines in COVID-19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.

 

As of December 2020, hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica. As of November 2020, more than 200 possible treatments had been studied in humans so far.

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on epidemiological models, estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID-19 including computational fluid dynamics models to study the flow physics of COVID-19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID-19 on organizations worldwide.

 

TREATMENT-RELATED RESEARCH

Repurposed antiviral drugs make up most of the research into COVID-19 treatments. Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.

 

In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs, lopinavir/ritonavir; and interferon-beta. More than 300 active clinical trials were underway as of April 2020.

 

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020, France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID-19 treatment.

 

In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID-19 who do not require supplemental oxygen.

 

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID-19 patients.

 

WIKIPEDIA

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic.

 

Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. Of those people who develop noticeable symptoms, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging), and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). Older people are more likely to have severe symptoms. At least a third of the people who are infected with the virus remain asymptomatic and do not develop noticeable symptoms at any point in time, but they still can spread the disease.[ Around 20% of those people will remain asymptomatic throughout infection, and the rest will develop symptoms later on, becoming pre-symptomatic rather than asymptomatic and therefore having a higher risk of transmitting the virus to others. Some people continue to experience a range of effects—known as long COVID—for months after recovery, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

The virus that causes COVID-19 spreads mainly when an infected person is in close contact[a] with another person. Small droplets and aerosols containing the virus can spread from an infected person's nose and mouth as they breathe, cough, sneeze, sing, or speak. Other people are infected if the virus gets into their mouth, nose or eyes. The virus may also spread via contaminated surfaces, although this is not thought to be the main route of transmission. The exact route of transmission is rarely proven conclusively, but infection mainly happens when people are near each other for long enough. People who are infected can transmit the virus to another person up to two days before they themselves show symptoms, as can people who do not experience symptoms. People remain infectious for up to ten days after the onset of symptoms in moderate cases and up to 20 days in severe cases. Several testing methods have been developed to diagnose the disease. The standard diagnostic method is by detection of the virus' nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

 

Preventive measures include physical or social distancing, quarantining, ventilation of indoor spaces, covering coughs and sneezes, hand washing, and keeping unwashed hands away from the face. The use of face masks or coverings has been recommended in public settings to minimise the risk of transmissions. Several vaccines have been developed and several countries have initiated mass vaccination campaigns.

 

Although work is underway to develop drugs that inhibit the virus, the primary treatment is currently symptomatic. Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.

 

SIGNS AND SYSTOMS

Symptoms of COVID-19 are variable, ranging from mild symptoms to severe illness. Common symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, and breathing difficulties. People with the same infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, and throat disorders, loss of taste combined with loss of smell is associated with COVID-19.

 

Most people (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) and 5% of patients suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can spread the disease. Other infected people will develop symptoms later, called "pre-symptomatic", or have very mild symptoms and can also spread the virus.

 

As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.

Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects for months after recovery—named long COVID—and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

CAUSE

TRANSMISSION

Coronavirus disease 2019 (COVID-19) spreads from person to person mainly through the respiratory route after an infected person coughs, sneezes, sings, talks or breathes. A new infection occurs when virus-containing particles exhaled by an infected person, either respiratory droplets or aerosols, get into the mouth, nose, or eyes of other people who are in close contact with the infected person. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection.

 

The closer people interact, and the longer they interact, the more likely they are to transmit COVID-19. Closer distances can involve larger droplets (which fall to the ground) and aerosols, whereas longer distances only involve aerosols. Larger droplets can also turn into aerosols (known as droplet nuclei) through evaporation. The relative importance of the larger droplets and the aerosols is not clear as of November 2020; however, the virus is not known to spread between rooms over long distances such as through air ducts. Airborne transmission is able to particularly occur indoors, in high risk locations such as restaurants, choirs, gyms, nightclubs, offices, and religious venues, often when they are crowded or less ventilated. It also occurs in healthcare settings, often when aerosol-generating medical procedures are performed on COVID-19 patients.

 

Although it is considered possible there is no direct evidence of the virus being transmitted by skin to skin contact. A person could get COVID-19 indirectly by touching a contaminated surface or object before touching their own mouth, nose, or eyes, though this is not thought to be the main way the virus spreads. The virus is not known to spread through feces, urine, breast milk, food, wastewater, drinking water, or via animal disease vectors (although some animals can contract the virus from humans). It very rarely transmits from mother to baby during pregnancy.

 

Social distancing and the wearing of cloth face masks, surgical masks, respirators, or other face coverings are controls for droplet transmission. Transmission may be decreased indoors with well maintained heating and ventilation systems to maintain good air circulation and increase the use of outdoor air.

 

The number of people generally infected by one infected person varies. Coronavirus disease 2019 is more infectious than influenza, but less so than measles. It often spreads in clusters, where infections can be traced back to an index case or geographical location. There is a major role of "super-spreading events", where many people are infected by one person.

 

A person who is infected can transmit the virus to others up to two days before they themselves show symptoms, and even if symptoms never appear. People remain infectious in moderate cases for 7–12 days, and up to two weeks in severe cases. In October 2020, medical scientists reported evidence of reinfection in one person.

 

VIROLOGY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature.

 

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.

 

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have an animal (zoonotic) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The structure of the M protein resembles the sugar transporter SemiSWEET.

 

The many thousands of SARS-CoV-2 variants are grouped into clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR).

 

Several notable variants of SARS-CoV-2 emerged in late 2020. Cluster 5 emerged among minks and mink farmers in Denmark. After strict quarantines and a mink euthanasia campaign, it is believed to have been eradicated. The Variant of Concern 202012/01 (VOC 202012/01) is believed to have emerged in the United Kingdom in September. The 501Y.V2 Variant, which has the same N501Y mutation, arose independently in South Africa.

 

SARS-CoV-2 VARIANTS

Three known variants of SARS-CoV-2 are currently spreading among global populations as of January 2021 including the UK Variant (referred to as B.1.1.7) first found in London and Kent, a variant discovered in South Africa (referred to as 1.351), and a variant discovered in Brazil (referred to as P.1).

 

Using Whole Genome Sequencing, epidemiology and modelling suggest the new UK variant ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020) transmits more easily than other strains.

 

PATHOPHYSIOLOGY

COVID-19 can affect the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective. As the alveolar disease progresses, respiratory failure might develop and death may follow.

 

Whether SARS-CoV-2 is able to invade the nervous system remains unknown. The virus is not detected in the CNS of the majority of COVID-19 people with neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID-19, but these results need to be confirmed. SARS-CoV-2 could cause respiratory failure through affecting the brain stem as other coronaviruses have been found to invade the CNS. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood-brain barrier to gain access to the CNS, possibly within an infected white blood cell.

 

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

 

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism have been found people transferred to Intensive care unit (ICU) with COVID-19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in people infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia. Furthermore, microvascular blood vessel damage has been reported in a small number of tissue samples of the brains – without detected SARS-CoV-2 – and the olfactory bulbs from those who have died from COVID-19.

 

Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of hospitalized patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

 

Autopsies of people who died of COVID-19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.

 

IMMUNOPATHOLOGY

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID-19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.

 

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

 

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID-19 . Lymphocytic infiltrates have also been reported at autopsy.

 

VIRAL AND HOST FACTORS

VIRUS PROTEINS

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus host range and cellular tropism via the receptor binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID-19 vaccines.

 

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response.

 

HOST FACTORS

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-COV2 virus targets causing COVID-19. Theoretically the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID-19, though animal data suggest some potential protective effect of ARB. However no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.

 

The virus' effect on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome.

 

HOST CYTOKINE RESPONSE

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm. Levels of interleukin 1B, interferon-gamma, interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID-19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID-19 disease.

 

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID-19, it is related to worse prognosis and increased fatality. The storm causes the acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis, acute kidney injury, and vasculitis. The production of IL-1, IL-2, IL-6, TNF-alpha, and interferon-gamma, all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system, the microglia, neurons, and astrocytes, are also be involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.

 

DIAGNOSIS

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.

 

VIRAL TESTING

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests, which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited." The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease.

 

A number of laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK.

 

The University of Oxford's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" On 7 September, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results."

 

IMAGING

Chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.

 

Many groups have created COVID-19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID-19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive.

Coding

In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.

 

PATHOLOGY

The main pathological findings at autopsy are:

 

Macroscopy: pericarditis, lung consolidation and pulmonary oedema

Lung findings:

minor serous exudation, minor fibrin exudation

pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation

diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

plasmocytosis in BAL

Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

Liver: microvesicular steatosis

 

PREVENTION

Preventive measures to reduce the chances of infection include staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.

 

Those diagnosed with COVID-19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.

 

The first COVID-19 vaccine was granted regulatory approval on 2 December by the UK medicines regulator MHRA. It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID-19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID-19 is trying to decrease and delay the epidemic peak, known as "flattening the curve". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.

 

VACCINE

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus causing coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which enabled accelerated development of various vaccine technologies during early 2020. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19.

 

In Phase III trials, several COVID‑19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of March 2021, 12 vaccines were authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, and CoviVac), four viral vector vaccines (Sputnik V, the Oxford–AstraZeneca vaccine, Convidicea, and the Johnson & Johnson vaccine), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer). In total, as of March 2021, 308 vaccine candidates were in various stages of development, with 73 in clinical research, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development.

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. As of 17 March 2021, 400.22 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses, and Sputnik V, Sinopharm, Sinovac, and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. By December 2020, more than 10 billion vaccine doses had been preordered by countries, with about half of the doses purchased by high-income countries comprising 14% of the world's population.

 

SOCIAL DISTANCING

Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. Many governments are now mandating or recommending social distancing in regions affected by the outbreak.

 

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.

 

SELF-ISOLATION

Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.

Face masks and respiratory hygiene

 

The WHO and the US CDC recommend individuals wear non-medical face coverings in public settings where there is an increased risk of transmission and where social distancing measures are difficult to maintain. This recommendation is meant to reduce the spread of the disease by asymptomatic and pre-symptomatic individuals and is complementary to established preventive measures such as social distancing. Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing. A face covering without vents or holes will also filter out particles containing the virus from inhaled and exhaled air, reducing the chances of infection. But, if the mask include an exhalation valve, a wearer that is infected (maybe without having noticed that, and asymptomatic) would transmit the virus outwards through it, despite any certification they can have. So the masks with exhalation valve are not for the infected wearers, and are not reliable to stop the pandemic in a large scale. Many countries and local jurisdictions encourage or mandate the use of face masks or cloth face coverings by members of the public to limit the spread of the virus.

 

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease. When not wearing a mask, the CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. Healthcare professionals interacting directly with people who have COVID-19 are advised to use respirators at least as protective as NIOSH-certified N95 or equivalent, in addition to other personal protective equipment.

 

HAND-WASHING AND HYGIENE

Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. The CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

 

SURFACE CLEANING

After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body cause infection. Current evidence indicates that contact with infected surfaces is not the main driver of Covid-19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticized as hygiene theater, giving a false sense of security against something primarily spread through the air.

 

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight. Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%).

 

On many surfaces, including as glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. As a general rule of thumb, the virus dies faster on porous surfaces than on non-porous surfaces.

However, this rule is not absolute, and of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces.

 

Surfaces may be decontaminated with 62–71 percent ethanol, 50–100 percent isopropanol, 0.1 percent sodium hypochlorite, 0.5 percent hydrogen peroxide, and 0.2–7.5 percent povidone-iodine. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used. The CDC recommends that if a COVID-19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons should be disinfected. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inocuylum volumes) can be seen in the supplementary material of.

 

VENTILATION AND AIR FILTRATION

The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.

 

HEALTHY DIET AND LIFESTYLE

The Harvard T.H. Chan School of Public Health recommends a healthy diet, being physically active, managing psychological stress, and getting enough sleep.

 

While there is no evidence that vitamin D is an effective treatment for COVID-19, there is limited evidence that vitamin D deficiency increases the risk of severe COVID-19 symptoms. This has led to recommendations for individuals with vitamin D deficiency to take vitamin D supplements as a way of mitigating the risk of COVID-19 and other health issues associated with a possible increase in deficiency due to social distancing.

 

TREATMENT

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. Thus, the cornerstone of management of COVID-19 is supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

 

Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.

 

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.

Several experimental treatments are being actively studied in clinical trials. Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful. Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment. Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy.

 

PROGNOSIS

The severity of COVID-19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalization. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID-19 and with a transfer to ICU.

 

Some early studies suggest 10% to 20% of people with COVID-19 will experience symptoms lasting longer than a month.[191][192] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020 WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID-19 symptoms that fluctuate over time as "really concerning." They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros has concluded that therefore herd immunity is "morally unconscionable and unfeasible".

 

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within 2 months of discharge. The average to readmit was 8 days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease.

 

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers, air pollution is similarly associated with risk factors, and pre-existing heart and lung diseases and also obesity contributes to an increased health risk of COVID-19.

 

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research that looked into the COVID-19 infections in hospitalized kidney transplant recipients found a mortality rate of 11%.

See also: Impact of the COVID-19 pandemic on children

 

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years. They are likely to have milder symptoms and a lower chance of severe disease than adults. A European multinational study of hospitalized children published in The Lancet on 25 June 2020 found that about 8% of children admitted to a hospital needed intensive care. Four of those 582 children (0.7%) died, but the actual mortality rate could be "substantially lower" since milder cases that did not seek medical help were not included in the study.

 

Genetics also plays an important role in the ability to fight off the disease. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID-19. Genetic screening is able to detect interferon effector genes.

 

Pregnant women may be at higher risk of severe COVID-19 infection based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.

 

COMPLICATIONS

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death. Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots. Approximately 20–30% of people who present with COVID-19 have elevated liver enzymes, reflecting liver injury.

 

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions). Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID-19 and have an altered mental status.

 

LONGER-TERM EFFECTS

Some early studies suggest that that 10 to 20% of people with COVID-19 will experience symptoms lasting longer than a month. A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath. About 5-10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.

 

By a variety of mechanisms, the lungs are the organs most affected in COVID-19.[228] The majority of CT scans performed show lung abnormalities in people tested after 28 days of illness.

 

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long lasting effects, including pulmonary fibrosis. Overall, approximately one third of those investigated after 4 weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in people who are asymptomatic, but with the suggestion of continuing improvement with the passing of more time.

 

IMMUNITY

The immune response by humans to CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralizing antibodies in blood strongly correlates with protection from infection, but the level of neutralizing antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralizing antibody two months after infection. In another study, the level of neutralizing antibody fell 4-fold 1 to 4 months after the onset of symptoms. However, the lack of antibody in the blood does not mean antibody will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least 6 months after appearance of symptoms. Nevertheless, 15 cases of reinfection with SARS-CoV-2 have been reported using stringent CDC criteria requiring identification of a different variant from the second infection. There are likely to be many more people who have been reinfected with the virus. Herd immunity will not eliminate the virus if reinfection is common. Some other coronaviruses circulating in people are capable of reinfection after roughly a year. Nonetheless, on 3 March 2021, scientists reported that a much more contagious Covid-19 variant, Lineage P.1, first detected in Japan, and subsequently found in Brazil, as well as in several places in the United States, may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.

 

MORTALITY

Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly.

 

The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 2.2% (2,685,770/121,585,388) as of 18 March 2021. The number varies by region. The CFR may not reflect the true severity of the disease, because some infected individuals remain asymptomatic or experience only mild symptoms, and hence such infections may not be included in official case reports. Moreover, the CFR may vary markedly over time and across locations due to the availability of live virus tests.

 

INFECTION FATALITY RATE

A key metric in gauging the severity of COVID-19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk. This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR, the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases.

 

CURRENT ESTIMATES

A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO.

 

EARLIER ESTIMATES OF IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.[ On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID-19 (0.3% of the population).Antibody testing in New York City suggested an IFR of ~0.9%,[258] and ~1.4%. In Bergamo province, 0.6% of the population has died. In September 2020 the U.S. Center for Disease Control & Prevention reported preliminary estimates of age-specific IFRs for public health planning purposes.

 

SEX DIFFERENCES

Early reviews of epidemiologic data showed gendered impact of the pandemic and a higher mortality rate in men in China and Italy. The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected people were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.

 

ETHNIC DIFFERENCES

In the US, a greater proportion of deaths due to COVID-19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the U.K., a greater proportion of deaths due to COVID-19 have occurred in those of a Black, Asian, and other ethnic minority background. More severe impacts upon victims including the relative incidence of the necessity of hospitalization requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet. This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe.

 

COMORBIDITIES

Most of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease. According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), Ischemic Heart Disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths).

 

Most critical respiratory comorbidities according to the CDC, are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis. Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms. COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.

 

In August 2020 the CDC issued a caution that tuberculosis infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID-19 couldn't rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB related deaths by 2025.

 

NAME

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu, Middle East Respiratory Syndrome, and Zika virus. In January 2020, the WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species, or groups of people in disease and virus names in part to prevent social stigma. The official names COVID-19 and SARS-CoV-2 were issued by the WHO on 11 February 2020. Tedros Adhanom explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.

 

HISTORY

The virus is thought to be natural and of an animal origin, through spillover infection. There are several theories about where the first case (the so-called patient zero) originated. Phylogenetics estimates that SARS-CoV-2 arose in October or November 2019. Evidence suggests that it descends from a coronavirus that infects wild bats, and spread to humans through an intermediary wildlife host.

 

The first known human infections were in Wuhan, Hubei, China. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as 1 December 2019.Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals. In May 2020 George Gao, the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event, but that it was not the site of the initial outbreak.[ Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.

 

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of coronavirus cases in Hubei gradually increased, reaching 60 by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS, causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.

 

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases—enough to trigger an investigation.

 

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen. Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared the coronavirus a Public Health Emergency of International Concern. By this time, the outbreak spread by a factor of 100 to 200 times.

 

Italy had its first confirmed cases on 31 January 2020, two tourists from China. As of 13 March 2020 the WHO considered Europe the active centre of the pandemic. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020.

 

After 55 days without a locally transmitted case, Beijing reported a new COVID-19 case on 11 June 2020 which was followed by two more cases on 12 June. By 15 June there were 79 cases officially confirmed, most of them were people that went to Xinfadi Wholesale Market.

 

RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID-19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December.

 

MISINFORMATION

After the initial outbreak of COVID-19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online.

 

In September 2020, the U.S. CDC published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.

 

OTHER ANIMALS

Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis.

 

Some pets, especially cats and ferrets, can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviors which increase the risk of transmission include kissing, licking, and petting the animal.

 

The virus does not appear to be able to infect pigs, ducks, or chickens at all.[ Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.

 

Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID-19 virus.

 

Minks, which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms. Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations. A vaccine for mink and other animals is being researched.

 

RESEARCH

International research on vaccines and medicines in COVID-19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.

 

As of December 2020, hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica. As of November 2020, more than 200 possible treatments had been studied in humans so far.

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on epidemiological models, estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID-19 including computational fluid dynamics models to study the flow physics of COVID-19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID-19 on organizations worldwide.

 

TREATMENT-RELATED RESEARCH

Repurposed antiviral drugs make up most of the research into COVID-19 treatments. Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.

 

In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs, lopinavir/ritonavir; and interferon-beta. More than 300 active clinical trials were underway as of April 2020.

 

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020, France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID-19 treatment.

 

In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID-19 who do not require supplemental oxygen.

 

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID-19 patients.

 

WIKIPEDIA

Rat brain slice showing neural stem cells (blue) that divide throughout life to produce astrocytes (red) and mature neurons (green).

 

This photo was taken in the lab of David Schaffer at the University of California, Berkeley.

 

Learn more about CIRM-funded stem cell research: www.cirm.ca.gov

Co-culture of primary rat hippocampal neurons and astrocytes stained for βIII-tubulin (green), GFAP (red) and DNA (blue).

Neurotoxicity

 

A group of cultured adult neural stem cells. Blue indicates the nucleus and green represents a protein only found in immature neural cells.

 

This photo was taken in the lab of David Schaffer at the University of California, Berkeley.

 

Learn more about CIRM-funded stem cell research: www.cirm.ca.gov

Cultured adult rat neural stem cells differentiating into mature nerve cells.

 

This photo was taken in the lab of David Schaffer at the University of California, Berkeley.

 

Learn more about CIRM-funded stem cell research: www.cirm.ca.gov

neurons are most striking when they seem astronomical.

 

for grins, and to test a new technique, dye-coated tungsten particles were shot into a plate of primary neural culture with a gene-gun. the more diffuse, amorphous cells are glia (astrocytes), the smaller more varicose ones are neurons (probably only visable if the picture is viewed at a large size).

Rendering of three-dimensional image stack showing HIV virions (red) localized on filopodial bridges between an infected T cell (gold) and uninfected fetal astrocyte (blue) in vitro. Data from focused ion beam scanning electron microscopy (FIB-SEM).

 

See also www.electron.nci.nih.gov

 

Credit: Thao Do, Sriram Subramaniam, National Cancer Institute, National Institutes of Health

In a mouse model of stuttering (lower panel), there are fewer astrocytes, shown in green, compared to controls (upper panel) in the corpus callosum, the area of the brain that enables the left and right hemispheres to communicate.

Researchers believe that stuttering — a potentially lifelong and debilitating speech disorder — stems from problems with the circuits in the brain that control speech, but precisely how and where these problems occur is unknown. Using a mouse model of stuttering, scientists report that a loss of cells in the brain called astrocytes are associated with stuttering. The mice had been engineered with a human gene mutation previously linked to stuttering. The study, which appeared online in the Proceedings of the National Academy of Sciences, offers insights into the neurological deficits associated with stuttering.

 

Read more:

www.nih.gov/news-events/news-releases/nih-study-mice-iden...

 

Credit: Tae-Un Han, Ph.D., National Institute on Deafness and Communication Disorders, NIH

cross section: human pineal gland

magnification: 200x

hematoxylin eosin stain

 

Technical Questions:bioimagesoer@gmail.com

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic.

 

Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. Of those people who develop noticeable symptoms, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging), and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). Older people are more likely to have severe symptoms. At least a third of the people who are infected with the virus remain asymptomatic and do not develop noticeable symptoms at any point in time, but they still can spread the disease.[ Around 20% of those people will remain asymptomatic throughout infection, and the rest will develop symptoms later on, becoming pre-symptomatic rather than asymptomatic and therefore having a higher risk of transmitting the virus to others. Some people continue to experience a range of effects—known as long COVID—for months after recovery, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

The virus that causes COVID-19 spreads mainly when an infected person is in close contact[a] with another person. Small droplets and aerosols containing the virus can spread from an infected person's nose and mouth as they breathe, cough, sneeze, sing, or speak. Other people are infected if the virus gets into their mouth, nose or eyes. The virus may also spread via contaminated surfaces, although this is not thought to be the main route of transmission. The exact route of transmission is rarely proven conclusively, but infection mainly happens when people are near each other for long enough. People who are infected can transmit the virus to another person up to two days before they themselves show symptoms, as can people who do not experience symptoms. People remain infectious for up to ten days after the onset of symptoms in moderate cases and up to 20 days in severe cases. Several testing methods have been developed to diagnose the disease. The standard diagnostic method is by detection of the virus' nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

 

Preventive measures include physical or social distancing, quarantining, ventilation of indoor spaces, covering coughs and sneezes, hand washing, and keeping unwashed hands away from the face. The use of face masks or coverings has been recommended in public settings to minimise the risk of transmissions. Several vaccines have been developed and several countries have initiated mass vaccination campaigns.

 

Although work is underway to develop drugs that inhibit the virus, the primary treatment is currently symptomatic. Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.

 

SIGNS AND SYSTOMS

Symptoms of COVID-19 are variable, ranging from mild symptoms to severe illness. Common symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, and breathing difficulties. People with the same infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, and throat disorders, loss of taste combined with loss of smell is associated with COVID-19.

 

Most people (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) and 5% of patients suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can spread the disease. Other infected people will develop symptoms later, called "pre-symptomatic", or have very mild symptoms and can also spread the virus.

 

As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.

Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects for months after recovery—named long COVID—and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

CAUSE

TRANSMISSION

Coronavirus disease 2019 (COVID-19) spreads from person to person mainly through the respiratory route after an infected person coughs, sneezes, sings, talks or breathes. A new infection occurs when virus-containing particles exhaled by an infected person, either respiratory droplets or aerosols, get into the mouth, nose, or eyes of other people who are in close contact with the infected person. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection.

 

The closer people interact, and the longer they interact, the more likely they are to transmit COVID-19. Closer distances can involve larger droplets (which fall to the ground) and aerosols, whereas longer distances only involve aerosols. Larger droplets can also turn into aerosols (known as droplet nuclei) through evaporation. The relative importance of the larger droplets and the aerosols is not clear as of November 2020; however, the virus is not known to spread between rooms over long distances such as through air ducts. Airborne transmission is able to particularly occur indoors, in high risk locations such as restaurants, choirs, gyms, nightclubs, offices, and religious venues, often when they are crowded or less ventilated. It also occurs in healthcare settings, often when aerosol-generating medical procedures are performed on COVID-19 patients.

 

Although it is considered possible there is no direct evidence of the virus being transmitted by skin to skin contact. A person could get COVID-19 indirectly by touching a contaminated surface or object before touching their own mouth, nose, or eyes, though this is not thought to be the main way the virus spreads. The virus is not known to spread through feces, urine, breast milk, food, wastewater, drinking water, or via animal disease vectors (although some animals can contract the virus from humans). It very rarely transmits from mother to baby during pregnancy.

 

Social distancing and the wearing of cloth face masks, surgical masks, respirators, or other face coverings are controls for droplet transmission. Transmission may be decreased indoors with well maintained heating and ventilation systems to maintain good air circulation and increase the use of outdoor air.

 

The number of people generally infected by one infected person varies. Coronavirus disease 2019 is more infectious than influenza, but less so than measles. It often spreads in clusters, where infections can be traced back to an index case or geographical location. There is a major role of "super-spreading events", where many people are infected by one person.

 

A person who is infected can transmit the virus to others up to two days before they themselves show symptoms, and even if symptoms never appear. People remain infectious in moderate cases for 7–12 days, and up to two weeks in severe cases. In October 2020, medical scientists reported evidence of reinfection in one person.

 

VIROLOGY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature.

 

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.

 

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have an animal (zoonotic) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The structure of the M protein resembles the sugar transporter SemiSWEET.

 

The many thousands of SARS-CoV-2 variants are grouped into clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR).

 

Several notable variants of SARS-CoV-2 emerged in late 2020. Cluster 5 emerged among minks and mink farmers in Denmark. After strict quarantines and a mink euthanasia campaign, it is believed to have been eradicated. The Variant of Concern 202012/01 (VOC 202012/01) is believed to have emerged in the United Kingdom in September. The 501Y.V2 Variant, which has the same N501Y mutation, arose independently in South Africa.

 

SARS-CoV-2 VARIANTS

Three known variants of SARS-CoV-2 are currently spreading among global populations as of January 2021 including the UK Variant (referred to as B.1.1.7) first found in London and Kent, a variant discovered in South Africa (referred to as 1.351), and a variant discovered in Brazil (referred to as P.1).

 

Using Whole Genome Sequencing, epidemiology and modelling suggest the new UK variant ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020) transmits more easily than other strains.

 

PATHOPHYSIOLOGY

COVID-19 can affect the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective. As the alveolar disease progresses, respiratory failure might develop and death may follow.

 

Whether SARS-CoV-2 is able to invade the nervous system remains unknown. The virus is not detected in the CNS of the majority of COVID-19 people with neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID-19, but these results need to be confirmed. SARS-CoV-2 could cause respiratory failure through affecting the brain stem as other coronaviruses have been found to invade the CNS. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood-brain barrier to gain access to the CNS, possibly within an infected white blood cell.

 

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

 

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism have been found people transferred to Intensive care unit (ICU) with COVID-19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in people infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia. Furthermore, microvascular blood vessel damage has been reported in a small number of tissue samples of the brains – without detected SARS-CoV-2 – and the olfactory bulbs from those who have died from COVID-19.

 

Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of hospitalized patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

 

Autopsies of people who died of COVID-19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.

 

IMMUNOPATHOLOGY

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID-19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.

 

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

 

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID-19 . Lymphocytic infiltrates have also been reported at autopsy.

 

VIRAL AND HOST FACTORS

VIRUS PROTEINS

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus host range and cellular tropism via the receptor binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID-19 vaccines.

 

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response.

 

HOST FACTORS

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-COV2 virus targets causing COVID-19. Theoretically the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID-19, though animal data suggest some potential protective effect of ARB. However no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.

 

The virus' effect on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome.

 

HOST CYTOKINE RESPONSE

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm. Levels of interleukin 1B, interferon-gamma, interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID-19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID-19 disease.

 

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID-19, it is related to worse prognosis and increased fatality. The storm causes the acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis, acute kidney injury, and vasculitis. The production of IL-1, IL-2, IL-6, TNF-alpha, and interferon-gamma, all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system, the microglia, neurons, and astrocytes, are also be involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.

 

DIAGNOSIS

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.

 

VIRAL TESTING

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests, which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited." The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease.

 

A number of laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK.

 

The University of Oxford's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" On 7 September, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results."

 

IMAGING

Chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.

 

Many groups have created COVID-19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID-19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive.

Coding

In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.

 

PATHOLOGY

The main pathological findings at autopsy are:

 

Macroscopy: pericarditis, lung consolidation and pulmonary oedema

Lung findings:

minor serous exudation, minor fibrin exudation

pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation

diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

plasmocytosis in BAL

Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

Liver: microvesicular steatosis

 

PREVENTION

Preventive measures to reduce the chances of infection include staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.

 

Those diagnosed with COVID-19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.

 

The first COVID-19 vaccine was granted regulatory approval on 2 December by the UK medicines regulator MHRA. It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID-19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID-19 is trying to decrease and delay the epidemic peak, known as "flattening the curve". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.

 

VACCINE

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus causing coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which enabled accelerated development of various vaccine technologies during early 2020. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19.

 

In Phase III trials, several COVID‑19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of March 2021, 12 vaccines were authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, and CoviVac), four viral vector vaccines (Sputnik V, the Oxford–AstraZeneca vaccine, Convidicea, and the Johnson & Johnson vaccine), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer). In total, as of March 2021, 308 vaccine candidates were in various stages of development, with 73 in clinical research, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development.

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. As of 17 March 2021, 400.22 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses, and Sputnik V, Sinopharm, Sinovac, and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. By December 2020, more than 10 billion vaccine doses had been preordered by countries, with about half of the doses purchased by high-income countries comprising 14% of the world's population.

 

SOCIAL DISTANCING

Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. Many governments are now mandating or recommending social distancing in regions affected by the outbreak.

 

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.

 

SELF-ISOLATION

Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.

Face masks and respiratory hygiene

 

The WHO and the US CDC recommend individuals wear non-medical face coverings in public settings where there is an increased risk of transmission and where social distancing measures are difficult to maintain. This recommendation is meant to reduce the spread of the disease by asymptomatic and pre-symptomatic individuals and is complementary to established preventive measures such as social distancing. Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing. A face covering without vents or holes will also filter out particles containing the virus from inhaled and exhaled air, reducing the chances of infection. But, if the mask include an exhalation valve, a wearer that is infected (maybe without having noticed that, and asymptomatic) would transmit the virus outwards through it, despite any certification they can have. So the masks with exhalation valve are not for the infected wearers, and are not reliable to stop the pandemic in a large scale. Many countries and local jurisdictions encourage or mandate the use of face masks or cloth face coverings by members of the public to limit the spread of the virus.

 

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease. When not wearing a mask, the CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. Healthcare professionals interacting directly with people who have COVID-19 are advised to use respirators at least as protective as NIOSH-certified N95 or equivalent, in addition to other personal protective equipment.

 

HAND-WASHING AND HYGIENE

Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. The CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

 

SURFACE CLEANING

After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body cause infection. Current evidence indicates that contact with infected surfaces is not the main driver of Covid-19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticized as hygiene theater, giving a false sense of security against something primarily spread through the air.

 

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight. Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%).

 

On many surfaces, including as glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. As a general rule of thumb, the virus dies faster on porous surfaces than on non-porous surfaces.

However, this rule is not absolute, and of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces.

 

Surfaces may be decontaminated with 62–71 percent ethanol, 50–100 percent isopropanol, 0.1 percent sodium hypochlorite, 0.5 percent hydrogen peroxide, and 0.2–7.5 percent povidone-iodine. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used. The CDC recommends that if a COVID-19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons should be disinfected. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inocuylum volumes) can be seen in the supplementary material of.

 

VENTILATION AND AIR FILTRATION

The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.

 

HEALTHY DIET AND LIFESTYLE

The Harvard T.H. Chan School of Public Health recommends a healthy diet, being physically active, managing psychological stress, and getting enough sleep.

 

While there is no evidence that vitamin D is an effective treatment for COVID-19, there is limited evidence that vitamin D deficiency increases the risk of severe COVID-19 symptoms. This has led to recommendations for individuals with vitamin D deficiency to take vitamin D supplements as a way of mitigating the risk of COVID-19 and other health issues associated with a possible increase in deficiency due to social distancing.

 

TREATMENT

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. Thus, the cornerstone of management of COVID-19 is supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

 

Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.

 

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.

Several experimental treatments are being actively studied in clinical trials. Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful. Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment. Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy.

 

PROGNOSIS

The severity of COVID-19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalization. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID-19 and with a transfer to ICU.

 

Some early studies suggest 10% to 20% of people with COVID-19 will experience symptoms lasting longer than a month.[191][192] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020 WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID-19 symptoms that fluctuate over time as "really concerning." They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros has concluded that therefore herd immunity is "morally unconscionable and unfeasible".

 

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within 2 months of discharge. The average to readmit was 8 days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease.

 

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers, air pollution is similarly associated with risk factors, and pre-existing heart and lung diseases and also obesity contributes to an increased health risk of COVID-19.

 

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research that looked into the COVID-19 infections in hospitalized kidney transplant recipients found a mortality rate of 11%.

See also: Impact of the COVID-19 pandemic on children

 

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years. They are likely to have milder symptoms and a lower chance of severe disease than adults. A European multinational study of hospitalized children published in The Lancet on 25 June 2020 found that about 8% of children admitted to a hospital needed intensive care. Four of those 582 children (0.7%) died, but the actual mortality rate could be "substantially lower" since milder cases that did not seek medical help were not included in the study.

 

Genetics also plays an important role in the ability to fight off the disease. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID-19. Genetic screening is able to detect interferon effector genes.

 

Pregnant women may be at higher risk of severe COVID-19 infection based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.

 

COMPLICATIONS

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death. Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots. Approximately 20–30% of people who present with COVID-19 have elevated liver enzymes, reflecting liver injury.

 

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions). Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID-19 and have an altered mental status.

 

LONGER-TERM EFFECTS

Some early studies suggest that that 10 to 20% of people with COVID-19 will experience symptoms lasting longer than a month. A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath. About 5-10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.

 

By a variety of mechanisms, the lungs are the organs most affected in COVID-19.[228] The majority of CT scans performed show lung abnormalities in people tested after 28 days of illness.

 

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long lasting effects, including pulmonary fibrosis. Overall, approximately one third of those investigated after 4 weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in people who are asymptomatic, but with the suggestion of continuing improvement with the passing of more time.

 

IMMUNITY

The immune response by humans to CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralizing antibodies in blood strongly correlates with protection from infection, but the level of neutralizing antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralizing antibody two months after infection. In another study, the level of neutralizing antibody fell 4-fold 1 to 4 months after the onset of symptoms. However, the lack of antibody in the blood does not mean antibody will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least 6 months after appearance of symptoms. Nevertheless, 15 cases of reinfection with SARS-CoV-2 have been reported using stringent CDC criteria requiring identification of a different variant from the second infection. There are likely to be many more people who have been reinfected with the virus. Herd immunity will not eliminate the virus if reinfection is common. Some other coronaviruses circulating in people are capable of reinfection after roughly a year. Nonetheless, on 3 March 2021, scientists reported that a much more contagious Covid-19 variant, Lineage P.1, first detected in Japan, and subsequently found in Brazil, as well as in several places in the United States, may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.

 

MORTALITY

Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly.

 

The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 2.2% (2,685,770/121,585,388) as of 18 March 2021. The number varies by region. The CFR may not reflect the true severity of the disease, because some infected individuals remain asymptomatic or experience only mild symptoms, and hence such infections may not be included in official case reports. Moreover, the CFR may vary markedly over time and across locations due to the availability of live virus tests.

 

INFECTION FATALITY RATE

A key metric in gauging the severity of COVID-19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk. This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR, the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases.

 

CURRENT ESTIMATES

A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO.

 

EARLIER ESTIMATES OF IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.[ On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID-19 (0.3% of the population).Antibody testing in New York City suggested an IFR of ~0.9%,[258] and ~1.4%. In Bergamo province, 0.6% of the population has died. In September 2020 the U.S. Center for Disease Control & Prevention reported preliminary estimates of age-specific IFRs for public health planning purposes.

 

SEX DIFFERENCES

Early reviews of epidemiologic data showed gendered impact of the pandemic and a higher mortality rate in men in China and Italy. The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected people were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.

 

ETHNIC DIFFERENCES

In the US, a greater proportion of deaths due to COVID-19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the U.K., a greater proportion of deaths due to COVID-19 have occurred in those of a Black, Asian, and other ethnic minority background. More severe impacts upon victims including the relative incidence of the necessity of hospitalization requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet. This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe.

 

COMORBIDITIES

Most of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease. According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), Ischemic Heart Disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths).

 

Most critical respiratory comorbidities according to the CDC, are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis. Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms. COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.

 

In August 2020 the CDC issued a caution that tuberculosis infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID-19 couldn't rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB related deaths by 2025.

 

NAME

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu, Middle East Respiratory Syndrome, and Zika virus. In January 2020, the WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species, or groups of people in disease and virus names in part to prevent social stigma. The official names COVID-19 and SARS-CoV-2 were issued by the WHO on 11 February 2020. Tedros Adhanom explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.

 

HISTORY

The virus is thought to be natural and of an animal origin, through spillover infection. There are several theories about where the first case (the so-called patient zero) originated. Phylogenetics estimates that SARS-CoV-2 arose in October or November 2019. Evidence suggests that it descends from a coronavirus that infects wild bats, and spread to humans through an intermediary wildlife host.

 

The first known human infections were in Wuhan, Hubei, China. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as 1 December 2019.Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals. In May 2020 George Gao, the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event, but that it was not the site of the initial outbreak.[ Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.

 

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of coronavirus cases in Hubei gradually increased, reaching 60 by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS, causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.

 

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases—enough to trigger an investigation.

 

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen. Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared the coronavirus a Public Health Emergency of International Concern. By this time, the outbreak spread by a factor of 100 to 200 times.

 

Italy had its first confirmed cases on 31 January 2020, two tourists from China. As of 13 March 2020 the WHO considered Europe the active centre of the pandemic. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020.

 

After 55 days without a locally transmitted case, Beijing reported a new COVID-19 case on 11 June 2020 which was followed by two more cases on 12 June. By 15 June there were 79 cases officially confirmed, most of them were people that went to Xinfadi Wholesale Market.

 

RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID-19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December.

 

MISINFORMATION

After the initial outbreak of COVID-19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online.

 

In September 2020, the U.S. CDC published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.

 

OTHER ANIMALS

Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis.

 

Some pets, especially cats and ferrets, can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviors which increase the risk of transmission include kissing, licking, and petting the animal.

 

The virus does not appear to be able to infect pigs, ducks, or chickens at all.[ Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.

 

Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID-19 virus.

 

Minks, which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms. Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations. A vaccine for mink and other animals is being researched.

 

RESEARCH

International research on vaccines and medicines in COVID-19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.

 

As of December 2020, hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica. As of November 2020, more than 200 possible treatments had been studied in humans so far.

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on epidemiological models, estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID-19 including computational fluid dynamics models to study the flow physics of COVID-19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID-19 on organizations worldwide.

 

TREATMENT-RELATED RESEARCH

Repurposed antiviral drugs make up most of the research into COVID-19 treatments. Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.

 

In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs, lopinavir/ritonavir; and interferon-beta. More than 300 active clinical trials were underway as of April 2020.

 

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020, France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID-19 treatment.

 

In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID-19 who do not require supplemental oxygen.

 

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID-19 patients.

 

WIKIPEDIA

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic.

 

Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. Of those people who develop noticeable symptoms, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging), and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). Older people are more likely to have severe symptoms. At least a third of the people who are infected with the virus remain asymptomatic and do not develop noticeable symptoms at any point in time, but they still can spread the disease.[ Around 20% of those people will remain asymptomatic throughout infection, and the rest will develop symptoms later on, becoming pre-symptomatic rather than asymptomatic and therefore having a higher risk of transmitting the virus to others. Some people continue to experience a range of effects—known as long COVID—for months after recovery, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

The virus that causes COVID-19 spreads mainly when an infected person is in close contact[a] with another person. Small droplets and aerosols containing the virus can spread from an infected person's nose and mouth as they breathe, cough, sneeze, sing, or speak. Other people are infected if the virus gets into their mouth, nose or eyes. The virus may also spread via contaminated surfaces, although this is not thought to be the main route of transmission. The exact route of transmission is rarely proven conclusively, but infection mainly happens when people are near each other for long enough. People who are infected can transmit the virus to another person up to two days before they themselves show symptoms, as can people who do not experience symptoms. People remain infectious for up to ten days after the onset of symptoms in moderate cases and up to 20 days in severe cases. Several testing methods have been developed to diagnose the disease. The standard diagnostic method is by detection of the virus' nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

 

Preventive measures include physical or social distancing, quarantining, ventilation of indoor spaces, covering coughs and sneezes, hand washing, and keeping unwashed hands away from the face. The use of face masks or coverings has been recommended in public settings to minimise the risk of transmissions. Several vaccines have been developed and several countries have initiated mass vaccination campaigns.

 

Although work is underway to develop drugs that inhibit the virus, the primary treatment is currently symptomatic. Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.

 

SIGNS AND SYSTOMS

Symptoms of COVID-19 are variable, ranging from mild symptoms to severe illness. Common symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, and breathing difficulties. People with the same infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, and throat disorders, loss of taste combined with loss of smell is associated with COVID-19.

 

Most people (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) and 5% of patients suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can spread the disease. Other infected people will develop symptoms later, called "pre-symptomatic", or have very mild symptoms and can also spread the virus.

 

As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.

Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects for months after recovery—named long COVID—and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

CAUSE

TRANSMISSION

Coronavirus disease 2019 (COVID-19) spreads from person to person mainly through the respiratory route after an infected person coughs, sneezes, sings, talks or breathes. A new infection occurs when virus-containing particles exhaled by an infected person, either respiratory droplets or aerosols, get into the mouth, nose, or eyes of other people who are in close contact with the infected person. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection.

 

The closer people interact, and the longer they interact, the more likely they are to transmit COVID-19. Closer distances can involve larger droplets (which fall to the ground) and aerosols, whereas longer distances only involve aerosols. Larger droplets can also turn into aerosols (known as droplet nuclei) through evaporation. The relative importance of the larger droplets and the aerosols is not clear as of November 2020; however, the virus is not known to spread between rooms over long distances such as through air ducts. Airborne transmission is able to particularly occur indoors, in high risk locations such as restaurants, choirs, gyms, nightclubs, offices, and religious venues, often when they are crowded or less ventilated. It also occurs in healthcare settings, often when aerosol-generating medical procedures are performed on COVID-19 patients.

 

Although it is considered possible there is no direct evidence of the virus being transmitted by skin to skin contact. A person could get COVID-19 indirectly by touching a contaminated surface or object before touching their own mouth, nose, or eyes, though this is not thought to be the main way the virus spreads. The virus is not known to spread through feces, urine, breast milk, food, wastewater, drinking water, or via animal disease vectors (although some animals can contract the virus from humans). It very rarely transmits from mother to baby during pregnancy.

 

Social distancing and the wearing of cloth face masks, surgical masks, respirators, or other face coverings are controls for droplet transmission. Transmission may be decreased indoors with well maintained heating and ventilation systems to maintain good air circulation and increase the use of outdoor air.

 

The number of people generally infected by one infected person varies. Coronavirus disease 2019 is more infectious than influenza, but less so than measles. It often spreads in clusters, where infections can be traced back to an index case or geographical location. There is a major role of "super-spreading events", where many people are infected by one person.

 

A person who is infected can transmit the virus to others up to two days before they themselves show symptoms, and even if symptoms never appear. People remain infectious in moderate cases for 7–12 days, and up to two weeks in severe cases. In October 2020, medical scientists reported evidence of reinfection in one person.

 

VIROLOGY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature.

 

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.

 

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have an animal (zoonotic) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The structure of the M protein resembles the sugar transporter SemiSWEET.

 

The many thousands of SARS-CoV-2 variants are grouped into clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR).

 

Several notable variants of SARS-CoV-2 emerged in late 2020. Cluster 5 emerged among minks and mink farmers in Denmark. After strict quarantines and a mink euthanasia campaign, it is believed to have been eradicated. The Variant of Concern 202012/01 (VOC 202012/01) is believed to have emerged in the United Kingdom in September. The 501Y.V2 Variant, which has the same N501Y mutation, arose independently in South Africa.

 

SARS-CoV-2 VARIANTS

Three known variants of SARS-CoV-2 are currently spreading among global populations as of January 2021 including the UK Variant (referred to as B.1.1.7) first found in London and Kent, a variant discovered in South Africa (referred to as 1.351), and a variant discovered in Brazil (referred to as P.1).

 

Using Whole Genome Sequencing, epidemiology and modelling suggest the new UK variant ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020) transmits more easily than other strains.

 

PATHOPHYSIOLOGY

COVID-19 can affect the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective. As the alveolar disease progresses, respiratory failure might develop and death may follow.

 

Whether SARS-CoV-2 is able to invade the nervous system remains unknown. The virus is not detected in the CNS of the majority of COVID-19 people with neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID-19, but these results need to be confirmed. SARS-CoV-2 could cause respiratory failure through affecting the brain stem as other coronaviruses have been found to invade the CNS. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood-brain barrier to gain access to the CNS, possibly within an infected white blood cell.

 

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

 

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism have been found people transferred to Intensive care unit (ICU) with COVID-19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in people infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia. Furthermore, microvascular blood vessel damage has been reported in a small number of tissue samples of the brains – without detected SARS-CoV-2 – and the olfactory bulbs from those who have died from COVID-19.

 

Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of hospitalized patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

 

Autopsies of people who died of COVID-19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.

 

IMMUNOPATHOLOGY

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID-19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.

 

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

 

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID-19 . Lymphocytic infiltrates have also been reported at autopsy.

 

VIRAL AND HOST FACTORS

VIRUS PROTEINS

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus host range and cellular tropism via the receptor binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID-19 vaccines.

 

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response.

 

HOST FACTORS

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-COV2 virus targets causing COVID-19. Theoretically the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID-19, though animal data suggest some potential protective effect of ARB. However no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.

 

The virus' effect on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome.

 

HOST CYTOKINE RESPONSE

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm. Levels of interleukin 1B, interferon-gamma, interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID-19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID-19 disease.

 

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID-19, it is related to worse prognosis and increased fatality. The storm causes the acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis, acute kidney injury, and vasculitis. The production of IL-1, IL-2, IL-6, TNF-alpha, and interferon-gamma, all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system, the microglia, neurons, and astrocytes, are also be involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.

 

DIAGNOSIS

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.

 

VIRAL TESTING

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests, which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited." The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease.

 

A number of laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK.

 

The University of Oxford's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" On 7 September, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results."

 

IMAGING

Chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.

 

Many groups have created COVID-19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID-19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive.

Coding

In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.

 

PATHOLOGY

The main pathological findings at autopsy are:

 

Macroscopy: pericarditis, lung consolidation and pulmonary oedema

Lung findings:

minor serous exudation, minor fibrin exudation

pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation

diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

plasmocytosis in BAL

Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

Liver: microvesicular steatosis

 

PREVENTION

Preventive measures to reduce the chances of infection include staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.

 

Those diagnosed with COVID-19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.

 

The first COVID-19 vaccine was granted regulatory approval on 2 December by the UK medicines regulator MHRA. It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID-19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID-19 is trying to decrease and delay the epidemic peak, known as "flattening the curve". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.

 

VACCINE

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus causing coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which enabled accelerated development of various vaccine technologies during early 2020. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19.

 

In Phase III trials, several COVID‑19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of March 2021, 12 vaccines were authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, and CoviVac), four viral vector vaccines (Sputnik V, the Oxford–AstraZeneca vaccine, Convidicea, and the Johnson & Johnson vaccine), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer). In total, as of March 2021, 308 vaccine candidates were in various stages of development, with 73 in clinical research, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development.

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. As of 17 March 2021, 400.22 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses, and Sputnik V, Sinopharm, Sinovac, and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. By December 2020, more than 10 billion vaccine doses had been preordered by countries, with about half of the doses purchased by high-income countries comprising 14% of the world's population.

 

SOCIAL DISTANCING

Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. Many governments are now mandating or recommending social distancing in regions affected by the outbreak.

 

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.

 

SELF-ISOLATION

Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.

Face masks and respiratory hygiene

 

The WHO and the US CDC recommend individuals wear non-medical face coverings in public settings where there is an increased risk of transmission and where social distancing measures are difficult to maintain. This recommendation is meant to reduce the spread of the disease by asymptomatic and pre-symptomatic individuals and is complementary to established preventive measures such as social distancing. Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing. A face covering without vents or holes will also filter out particles containing the virus from inhaled and exhaled air, reducing the chances of infection. But, if the mask include an exhalation valve, a wearer that is infected (maybe without having noticed that, and asymptomatic) would transmit the virus outwards through it, despite any certification they can have. So the masks with exhalation valve are not for the infected wearers, and are not reliable to stop the pandemic in a large scale. Many countries and local jurisdictions encourage or mandate the use of face masks or cloth face coverings by members of the public to limit the spread of the virus.

 

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease. When not wearing a mask, the CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. Healthcare professionals interacting directly with people who have COVID-19 are advised to use respirators at least as protective as NIOSH-certified N95 or equivalent, in addition to other personal protective equipment.

 

HAND-WASHING AND HYGIENE

Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. The CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

 

SURFACE CLEANING

After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body cause infection. Current evidence indicates that contact with infected surfaces is not the main driver of Covid-19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticized as hygiene theater, giving a false sense of security against something primarily spread through the air.

 

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight. Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%).

 

On many surfaces, including as glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. As a general rule of thumb, the virus dies faster on porous surfaces than on non-porous surfaces.

However, this rule is not absolute, and of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces.

 

Surfaces may be decontaminated with 62–71 percent ethanol, 50–100 percent isopropanol, 0.1 percent sodium hypochlorite, 0.5 percent hydrogen peroxide, and 0.2–7.5 percent povidone-iodine. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used. The CDC recommends that if a COVID-19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons should be disinfected. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inocuylum volumes) can be seen in the supplementary material of.

 

VENTILATION AND AIR FILTRATION

The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.

 

HEALTHY DIET AND LIFESTYLE

The Harvard T.H. Chan School of Public Health recommends a healthy diet, being physically active, managing psychological stress, and getting enough sleep.

 

While there is no evidence that vitamin D is an effective treatment for COVID-19, there is limited evidence that vitamin D deficiency increases the risk of severe COVID-19 symptoms. This has led to recommendations for individuals with vitamin D deficiency to take vitamin D supplements as a way of mitigating the risk of COVID-19 and other health issues associated with a possible increase in deficiency due to social distancing.

 

TREATMENT

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. Thus, the cornerstone of management of COVID-19 is supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

 

Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.

 

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.

Several experimental treatments are being actively studied in clinical trials. Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful. Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment. Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy.

 

PROGNOSIS

The severity of COVID-19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalization. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID-19 and with a transfer to ICU.

 

Some early studies suggest 10% to 20% of people with COVID-19 will experience symptoms lasting longer than a month.[191][192] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020 WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID-19 symptoms that fluctuate over time as "really concerning." They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros has concluded that therefore herd immunity is "morally unconscionable and unfeasible".

 

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within 2 months of discharge. The average to readmit was 8 days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease.

 

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers, air pollution is similarly associated with risk factors, and pre-existing heart and lung diseases and also obesity contributes to an increased health risk of COVID-19.

 

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research that looked into the COVID-19 infections in hospitalized kidney transplant recipients found a mortality rate of 11%.

See also: Impact of the COVID-19 pandemic on children

 

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years. They are likely to have milder symptoms and a lower chance of severe disease than adults. A European multinational study of hospitalized children published in The Lancet on 25 June 2020 found that about 8% of children admitted to a hospital needed intensive care. Four of those 582 children (0.7%) died, but the actual mortality rate could be "substantially lower" since milder cases that did not seek medical help were not included in the study.

 

Genetics also plays an important role in the ability to fight off the disease. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID-19. Genetic screening is able to detect interferon effector genes.

 

Pregnant women may be at higher risk of severe COVID-19 infection based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.

 

COMPLICATIONS

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death. Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots. Approximately 20–30% of people who present with COVID-19 have elevated liver enzymes, reflecting liver injury.

 

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions). Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID-19 and have an altered mental status.

 

LONGER-TERM EFFECTS

Some early studies suggest that that 10 to 20% of people with COVID-19 will experience symptoms lasting longer than a month. A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath. About 5-10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.

 

By a variety of mechanisms, the lungs are the organs most affected in COVID-19.[228] The majority of CT scans performed show lung abnormalities in people tested after 28 days of illness.

 

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long lasting effects, including pulmonary fibrosis. Overall, approximately one third of those investigated after 4 weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in people who are asymptomatic, but with the suggestion of continuing improvement with the passing of more time.

 

IMMUNITY

The immune response by humans to CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralizing antibodies in blood strongly correlates with protection from infection, but the level of neutralizing antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralizing antibody two months after infection. In another study, the level of neutralizing antibody fell 4-fold 1 to 4 months after the onset of symptoms. However, the lack of antibody in the blood does not mean antibody will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least 6 months after appearance of symptoms. Nevertheless, 15 cases of reinfection with SARS-CoV-2 have been reported using stringent CDC criteria requiring identification of a different variant from the second infection. There are likely to be many more people who have been reinfected with the virus. Herd immunity will not eliminate the virus if reinfection is common. Some other coronaviruses circulating in people are capable of reinfection after roughly a year. Nonetheless, on 3 March 2021, scientists reported that a much more contagious Covid-19 variant, Lineage P.1, first detected in Japan, and subsequently found in Brazil, as well as in several places in the United States, may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.

 

MORTALITY

Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly.

 

The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 2.2% (2,685,770/121,585,388) as of 18 March 2021. The number varies by region. The CFR may not reflect the true severity of the disease, because some infected individuals remain asymptomatic or experience only mild symptoms, and hence such infections may not be included in official case reports. Moreover, the CFR may vary markedly over time and across locations due to the availability of live virus tests.

 

INFECTION FATALITY RATE

A key metric in gauging the severity of COVID-19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk. This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR, the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases.

 

CURRENT ESTIMATES

A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO.

 

EARLIER ESTIMATES OF IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.[ On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID-19 (0.3% of the population).Antibody testing in New York City suggested an IFR of ~0.9%,[258] and ~1.4%. In Bergamo province, 0.6% of the population has died. In September 2020 the U.S. Center for Disease Control & Prevention reported preliminary estimates of age-specific IFRs for public health planning purposes.

 

SEX DIFFERENCES

Early reviews of epidemiologic data showed gendered impact of the pandemic and a higher mortality rate in men in China and Italy. The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected people were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.

 

ETHNIC DIFFERENCES

In the US, a greater proportion of deaths due to COVID-19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the U.K., a greater proportion of deaths due to COVID-19 have occurred in those of a Black, Asian, and other ethnic minority background. More severe impacts upon victims including the relative incidence of the necessity of hospitalization requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet. This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe.

 

COMORBIDITIES

Most of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease. According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), Ischemic Heart Disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths).

 

Most critical respiratory comorbidities according to the CDC, are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis. Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms. COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.

 

In August 2020 the CDC issued a caution that tuberculosis infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID-19 couldn't rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB related deaths by 2025.

 

NAME

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu, Middle East Respiratory Syndrome, and Zika virus. In January 2020, the WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species, or groups of people in disease and virus names in part to prevent social stigma. The official names COVID-19 and SARS-CoV-2 were issued by the WHO on 11 February 2020. Tedros Adhanom explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.

 

HISTORY

The virus is thought to be natural and of an animal origin, through spillover infection. There are several theories about where the first case (the so-called patient zero) originated. Phylogenetics estimates that SARS-CoV-2 arose in October or November 2019. Evidence suggests that it descends from a coronavirus that infects wild bats, and spread to humans through an intermediary wildlife host.

 

The first known human infections were in Wuhan, Hubei, China. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as 1 December 2019.Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals. In May 2020 George Gao, the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event, but that it was not the site of the initial outbreak.[ Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.

 

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of coronavirus cases in Hubei gradually increased, reaching 60 by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS, causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.

 

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases—enough to trigger an investigation.

 

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen. Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared the coronavirus a Public Health Emergency of International Concern. By this time, the outbreak spread by a factor of 100 to 200 times.

 

Italy had its first confirmed cases on 31 January 2020, two tourists from China. As of 13 March 2020 the WHO considered Europe the active centre of the pandemic. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020.

 

After 55 days without a locally transmitted case, Beijing reported a new COVID-19 case on 11 June 2020 which was followed by two more cases on 12 June. By 15 June there were 79 cases officially confirmed, most of them were people that went to Xinfadi Wholesale Market.

 

RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID-19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December.

 

MISINFORMATION

After the initial outbreak of COVID-19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online.

 

In September 2020, the U.S. CDC published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.

 

OTHER ANIMALS

Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis.

 

Some pets, especially cats and ferrets, can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviors which increase the risk of transmission include kissing, licking, and petting the animal.

 

The virus does not appear to be able to infect pigs, ducks, or chickens at all.[ Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.

 

Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID-19 virus.

 

Minks, which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms. Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations. A vaccine for mink and other animals is being researched.

 

RESEARCH

International research on vaccines and medicines in COVID-19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.

 

As of December 2020, hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica. As of November 2020, more than 200 possible treatments had been studied in humans so far.

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on epidemiological models, estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID-19 including computational fluid dynamics models to study the flow physics of COVID-19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID-19 on organizations worldwide.

 

TREATMENT-RELATED RESEARCH

Repurposed antiviral drugs make up most of the research into COVID-19 treatments. Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.

 

In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs, lopinavir/ritonavir; and interferon-beta. More than 300 active clinical trials were underway as of April 2020.

 

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020, France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID-19 treatment.

 

In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID-19 who do not require supplemental oxygen.

 

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID-19 patients.

 

WIKIPEDIA

cross section: human pineal gland

magnification: 100x phase contrast

hematoxylin eosin stain

 

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More brain cells. The ring of cells are astrocytes and blue are neurones.

NIH-funded mouse study suggests scar formation may help, not hinder, nerve regrowth.

This image illustrates how previously injured axons (in red) can grow through a dense astrocyte scar (in green) in the presence of molecules that stimulate growth (in blue).

 

Credit: Dr. Michael V. Sofroniew, UCLA

 

This image is not owned by the NIH. It is shared with the public under license. If you have a question about using or reproducing this image, please contact the creator listed in the credits. All rights to the work remain with the original creator.

 

More information: www.nih.gov/news-events/new-role-identified-scars-site-in...

 

NIH funding from: National Institute of Neurological Disorders and Stroke (NINDS)

The pineal gland is about 8 mm in diameter, encased in a tightly adherent pia mater, divided into a number of connective tissues wrapped lobes. Small blood vessels may be visible in the septate spaces between the lobes.

The pineal gland is largely composed of two cell types, better distinguished at higher magnifications.

Roughly 95% of the pineal gland consists of pinealocytes, the cells that produce the hormone melatonin which works with the hypothalamus to regulate sleep wake cycles. Pinealocytes are arranged in small clusters or rosettes. They can be identified by their large, round, pale staining nuclei, surrounded by wide rims of light staining cytoplasm. In some preparations it may be possible to see long cytoplasmic processes extending from the pinealocytes into the septae.

 

Closely associated with the pinealocytes are supportive astrocytes with smaller darker nuclei and long cytoplasmic projections.

In some parts of the brain and notably the pineal gland, there are large irregularly shaped dark purple staining calcifications termed corpora arenacea or brain sand. These salts of calcium, magnesium and ammonium increase in size and number in the brain with aging but have no know function.

 

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Astrocytes cells from the brain ensure that neurons remain healthy. can become cancerous and result in gliomas. These cells are stained to show their filamentous “cytoskeleton” which determines their shape as well as impacting their ability to move. In cancer cells, the more they move, the more aggressive the disease. Photo Credit –John Bechberger, M.Sc.; Christian Naus, Ph.D.

cross section: human pineal gland

magnification: 100x

hematoxylin eosin stain

 

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cross section: human pineal gland

magnification: 200x

hematoxylin eosin stain

 

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cross section: human pineal gland

magnification: 100x

hematoxylin eosin stain

 

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cross section: human pineal gland

magnification: 40x

hematoxylin eosin stain

 

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cross section: human pineal gland

magnification: 100x phase contrast

hematoxylin eosin stain

 

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cross section: human pineal gland

magnification: 200x

hematoxylin eosin stain

 

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A brain tumor is a mass or lump that forms inside the skull. Brain tumors can be cancerous or non-cancerous. It can cause a variety of symptoms, depending on their size and location. Treatment for brain tumors depends on the type and severity of the tumor.

 

Types of Brain Tumors

There are different types of brain tumors. The most common type is called a glioma. Gliomas start in the glial cells, which are the cells that surround and support nerve cells. Other types of brain tumors include:

 

Astrocytoma: Astrocytomas are tumors that develop from star-shaped cells called astrocytes. These tumors can occur in any part of the brain or spinal cord, but most often occur in the brain. Astrocytomas can be benign (not cancerous) or malignant (cancerous). They can grow slowly or rapidly, and can cause a variety of symptoms, depending on where they are located in the brain. Treatment for astrocytomas depends on the type and size of the tumor, as well as on the patient's age and health.

 

Oligodendroglioma: An oligodendroglioma is a tumor that starts in the cells that cover and protect nerve fibers in the brain. These tumors are usually slow growing and may not cause any problems for many years. However, if they grow large enough, they can cause problems such as seizures, headaches, or problems with balance and coordination. Oligodendrogliomas are classified as either low grade or high grade. Low grade tumors are less likely to spread than high grade tumors.

 

Ependymoma: Ependymomas are tumors that form in the cells that line the fluid-filled cavities of the brain and spinal cord. They can occur in any age group, but are most common in children and young adults. Symptoms vary depending on the location and size of the tumor, but may include headache, nausea, vomiting, seizures, and problems with balance and walking. Ependymomas are classified as either low-grade or high-grade, depending on how quickly they grow and how aggressive they are. Treatment typically includes surgery, radiation therapy, and chemotherapy.

 

Medulloblastoma: Medulloblastoma is a type of brain tumor that begins in the cerebellum, the part of the brain that controls balance and coordination. The tumor is most often found in children, but can occur in adults as well. Symptoms may include headache, nausea, vomiting, and difficulty walking. Treatment typically includes surgery, radiation therapy, and chemotherapy.

Autism spectrum disorder[a] (ASD), or simply autism, is a neurodevelopmental disorder "characterized by persistent deficits in social communication and social interaction across multiple contexts" and "restricted, repetitive patterns of behavior, interests, or activities".[11] Sensory abnormalities are also included in the diagnostic manuals. Common associated traits such as motor coordination impairment are typical of the condition but not required for diagnosis. A formal diagnosis requires that symptoms cause significant impairment in multiple functional domains, in addition to being atypical or excessive for the person's age and sociocultural context.[12][13]

 

Autism is a spectrum disorder, meaning it manifests in various ways, with its severity and support needs varying widely across different autistic people.[12][13][14] For example, some autistic people are nonverbal, while others have proficient spoken language. Furthermore, the spectrum is multi-dimensional and not all dimensions have been identified as of 2024.[15][16]

 

Public health authorities and guideline developers classify autism as a neurodevelopmental disorder,[12][17][13][18][19] but the autism rights movement (and some researchers) disagree with the classification. From the latter point of view, autistic people may be diagnosed with a disability, but that disability may be rooted in the structures of a society rather than the person.[20][21][22] On the contrary, other scientists argue that autism impairs functioning in many ways that are inherent to the disorder itself and unrelated to society.[23][24] The neurodiversity perspective has led to significant controversy among those who are autistic and advocates, practitioners, and charities.[25][26]

 

The precise causes of autism are unknown in most individual cases. Research shows that the disorder is highly heritable and polygenic, and neurobiological risks from the environment are also relevant.[27][28][29] Boys are also significantly far more frequently diagnosed than girls.[30]

 

Autism frequently co-occurs with attention deficit hyperactivity disorder (ADHD), epilepsy, and intellectual disability.[31][32][33] Disagreements persist about what should be part of the diagnosis, whether there are meaningful subtypes or stages of autism,[34] and the significance of autism-associated traits in the wider population.[35][36]

 

The combination of broader criteria, increased awareness, and the potential increase of actual prevalence has led to considerably increased estimates of autism prevalence since the 1990s.[37][38] The WHO estimates about 1 in 100 children had autism between 2012 and 2021, as that was the average estimate in studies during that period, with a trend of increasing prevalence over time.[b][9][10] This increasing prevalence has contributed to the myth perpetuated by anti-vaccine activists that autism is caused by vaccines.[39]

 

There is no known cure for autism, and some advocates dispute the need to find one.[40][41] Interventions such as applied behavior analysis (ABA), speech therapy, and occupational therapy can help these children gain self-care, social, and language skills.[42][43] Guidelines from the Centres for Disease Control (CDC), and European Society for Child & Adolescent Psychiatry endorse the use of ABA on the grounds that it reduces symptoms impairing daily functioning and quality of life,[42][44] but the National Institute for Health and Care Excellence cites a lack of high-quality evidence to support its use.[45] Additionally, some in the autism rights movement oppose its application due to a perception that it emphasises normalisation.[46][47][48] No medication has been shown to reduce ASD's core symptoms,[44] but some can alleviate comorbid issues.[49][50][51]

 

Classification

Spectrum model

Before the DSM-5 (2013) and ICD-11 (2022) diagnostic manuals were adopted, ASD was found under the diagnostic category pervasive developmental disorder. The previous system relied on a set of closely related and overlapping diagnoses such as Asperger syndrome and the syndrome formerly known as Kanner syndrome. This created unclear boundaries between the terms, so for the DSM-5 and ICD-11, a spectrum approach was taken. The new system is also more restrictive, meaning fewer people qualify for diagnosis.[52]

 

The DSM-5 and ICD-11 use different categorization tools to define this spectrum. DSM-5 uses a "level" system, which ranks how in need of support the patient is, level 1 being the mildest and level 3 the severest,[53] while the ICD-11 system has two axes, intellectual impairment and language impairment,[54] as these are seen as the most crucial factors.

 

Autism is currently defined as a highly variable neurodevelopmental disorder[55] that is generally thought to cover a broad and deep spectrum, manifesting very differently from one person to another. Some have high support needs, may be nonspeaking, and experience developmental delays; this is more likely with other co-existing diagnoses. Others have relatively low support needs; they may have more typical speech-language and intellectual skills but atypical social/conversation skills, narrowly focused interests, and wordy, pedantic communication.[56] They may still require significant support in some areas of their lives. The spectrum model should not be understood as a continuum running from mild to severe, but instead means that autism can present very differently in each person.[57] How it presents in a person can depend on context, and may vary over time.[58]

 

While the DSM and ICD greatly influence each other, there are also differences. For example, Rett syndrome was included in ASD in the DSM-5, but in the ICD-11 it was excluded and placed in the chapter on Developmental Anomalies. The ICD and the DSM change over time, and there has been collaborative work toward a convergence of the two since 1980 (when DSM-III was published and ICD-9 was current), including more rigorous biological assessment—in place of historical experience—and a simplification of the classification system.[59][60][61][62]

 

As of 2023, empirical and theoretical research is leading to a growing consensus among researchers that the established ASD criteria are ineffective descriptors of autism as a whole, and that alternative research approaches must be encouraged, such as going back to autism prototypes, exploring new causal models of autism, or developing transdiagnostic endophenotypes.[63] Proposed alternatives to the current disorder-focused spectrum model deconstruct autism into at least two separate phenomena: (1) a non-pathological spectrum of behavioral traits in the population,[64][65] and (2) the neuropathological burden of rare genetic mutations and environmental risk factors potentially leading to neurodevelopmental and psychological disorders,[64][65] (3) governed by an individual's cognitive ability to compensate.[64]

 

ICD

The World Health Organization's International Classification of Diseases (11th revision), ICD-11, was released in June 2018 and came into full effect as of January 2022.[66][59] It describes ASD as follows:[67]

 

Autism spectrum disorder is characterised by persistent deficits in the ability to initiate and to sustain reciprocal social interaction and social communication, and by a range of restricted, repetitive, and inflexible patterns of behaviour, interests or activities that are clearly atypical or excessive for the individual's age and sociocultural context. The onset of the disorder occurs during the developmental period, typically in early childhood, but symptoms may not become fully manifest until later, when social demands exceed limited capacities. Deficits are sufficiently severe to cause impairment in personal, family, social, educational, occupational or other important areas of functioning and are usually a pervasive feature of the individual's functioning observable in all settings, although they may vary according to social, educational, or other context. Individuals along the spectrum exhibit a full range of intellectual functioning and language abilities.

 

— ICD-11, chapter 6, section A02

ICD-11 was produced by professionals from 55 countries out of the 90 involved and is the most widely used reference worldwide.

 

DSM

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), released in 2022, is the current version of the DSM. It is the predominant mental health diagnostic system used in the United States and Canada, and is often used in Anglophone countries.

 

Its fifth edition, DSM-5, released in May 2013, was the first to define ASD as a single diagnosis,[68] which is still the case in the DSM-5-TR.[69] ASD encompasses previous diagnoses, including the four traditional diagnoses of autism—classic autism, Asperger syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS)—and the range of diagnoses that included the word "autism".[70] Rather than distinguishing among these diagnoses, the DSM-5 and DSM-5-TR adopt a dimensional approach with one diagnostic category for disorders that fall under the autism spectrum umbrella. Within that category, the DSM-5 and the DSM include a framework that differentiates each person by dimensions of symptom severity, as well as by associated features (i.e., the presence of other disorders or factors that likely contribute to the symptoms, other neurodevelopmental or mental disorders, intellectual disability, or language impairment).[69] The symptom domains are (a) social communication and (b) restricted, repetitive behaviors, and there is the option of specifying a separate severity—the negative effect of the symptoms on the person—for each domain, rather than just overall severity.[71] Before the DSM-5, the DSM separated social deficits and communication deficits into two domains.[72] Further, the DSM-5 changed to an onset age in the early developmental period, with a note that symptoms may manifest later when social demands exceed capabilities, rather than the previous, more restricted three years of age.[73] These changes remain in the DSM-5-TR.[69]

 

Signs and symptoms

See also: Outline of autism

Pre-diagnosis

For many autistic people, characteristics first appear during infancy or childhood and follow a steady course without remission (different developmental timelines are described in more detail below).[74] Autistic people may be severely impaired in some respects but average, or even superior, in others.[75][76][77]

 

Clinicians consider assessment for ASD when a patient shows:

 

Regular difficulties in social interaction or communication

Restricted or repetitive behaviors (often called "stimming")

Resistance to changes or restricted interests

These features are typically assessed with the following, when appropriate:

 

Problems in obtaining or sustaining employment or education

Difficulties in initiating or sustaining social relationships

Connections with mental health or learning disability services

A history of neurodevelopmental conditions (including learning disabilities and ADHD) or mental health conditions[78][79]

There are many signs associated with autism; the presentation varies widely. Common signs and symptoms include:[80][81]

 

Abnormalities in eye contact

Little or no babbling as an infant

Not showing interest in indicated objects

Delayed language skills (e.g., having a smaller vocabulary than peers or difficulty expressing themselves in words)

Reduced interest in other children or caretakers, possibly with more interest in objects

Difficulty playing reciprocal games (e.g., peek-a-boo)

Hyper- or hypo-sensitivity to or unusual response to the smell, texture, sound, taste, or appearance of things

Resistance to changes in routine

Repetitive, limited, or otherwise unusual usage of toys (e.g., lining up toys)

Repetition of words or phrases, including echolalia

Repetitive motions or movements, including stimming

Broader autism phenotype

The broader autism phenotype describes people who may not have ASD but do have autistic traits, such as abnormalities in eye contact and stimming.[82]

  

In 1996, American academic Temple Grandin published Emergence: Labeled Autistic, describing her life experiences as an autistic person.

Social and communication skills

According to the medical model, autistic people experience social communications impairments. Until 2013, deficits in social function and communication were considered two separate symptom domains.[83] The current social communication domain criteria for autism diagnosis require people to have deficits across three social skills: social-emotional reciprocity, nonverbal communication, and developing and sustaining relationships.[69]

 

A deficit-based view predicts that autistic–autistic interaction would be less effective than autistic–non-autistic interactions or even non-functional.[84] But recent research has found that autistic–autistic interactions are as effective in information transfer as interactions between non-autistics are, and that communication breaks down only between autistics and non-autistics.[84][85] Also contrary to social cognitive deficit interpretations, recent (2019) research recorded similar social cognitive performances in autistic and non-autistic adults, with both of them rating autistic individuals less favorably than non-autistic individuals; however, autistic individuals showed more interest in engaging with autistic people than non-autistic people did, and learning of a person's ASD diagnosis did not influence their interest level.[86]

 

Thus, there has been a recent shift to acknowledge that autistic people may simply respond and behave differently than people without ASD.[87] So far, research has identified two unconventional features by which autistic people create shared understanding (intersubjectivity): "a generous assumption of common ground that, when understood, led to rapid rapport, and, when not understood, resulted in potentially disruptive utterances; and a low demand for coordination that ameliorated many challenges associated with disruptive turns."[85] Autistic interests, and thus conversational topics, seem to be largely driven by an intense interest in specific topics (monotropism).[88][89]

 

Historically, autistic children were said to be delayed in developing a theory of mind, and the empathizing–systemizing theory has argued that while autistic people have compassion (affective empathy) for others with similar presentation of symptoms, they have limited, though not necessarily absent, cognitive empathy.[90] This may present as social naïvety,[91] lower than average intuitive perception of the utility or meaning of body language, social reciprocity,[92] or social expectations, including the habitus, social cues, and some aspects of sarcasm,[93] which to some degree may also be due to comorbid alexithymia.[94] But recent research has increasingly questioned these findings, as the "double empathy problem" theory (2012) argues that there is a lack of mutual understanding and empathy between both non-autistic persons and autistic individuals.[95][96][97][98][99]

 

As communication is bidirectional,[100] research on communication difficulties has since also begun to study non-autistic behavior, with researcher Catherine Crompton writing in 2020 that non-autistic people "struggle to identify autistic mental states, identify autistic facial expressions, overestimate autistic egocentricity, and are less willing to socially interact with autistic people. Thus, although non-autistic people are generally characterised as socially skilled, these skills may not be functional or effectively applied when interacting with autistic people."[84] Any previously observed communication deficits of autistic people may thus have been constructed through a neurotypical bias in autism research, which has come to be scrutinized for "dehumanization, objectification, and stigmatization".[101] Recent research has proposed that autistics' lack of readability and a neurotypical lack of effort to interpret atypical signals may cause a negative interaction loop, increasingly driving both groups apart into two distinct groups with different social interaction styles.[100]

 

Differences in verbal communication begin to be noticeable in childhood, as many autistic children develop language skills at an uneven pace. Verbal communication may be delayed or never developed (nonverbal autism), while reading ability may be present before school age (hyperlexia).[102][103] Reduced joint attention seem to distinguish autistic from non-autistic infants.[104] Infants may show delayed onset of babbling, unusual gestures, diminished responsiveness, and vocal patterns that are not synchronized with the caregiver. In the second and third years, autistic children may have less frequent and less diverse babbling, consonants, words, and word combinations; their gestures are less often integrated with words. Autistic children are less likely to make requests or share experiences and are more likely to simply repeat others' words (echolalia).[105] The CDC estimated in 2015 that around 40% of autistic children do not speak at all.[106] Autistic adults' verbal communication skills largely depend on when and how well speech is acquired during childhood.[102]

 

Autistic people display atypical nonverbal behaviors or show differences in nonverbal communication. They may make infrequent eye contact, even when called by name, or avoid it altogether. This may be due to the high amount of sensory input received when making eye contact.[107] Autistic people often recognize fewer emotions and their meaning from others' facial expressions, and may not respond with facial expressions expected by their non-autistic peers.[108][103] Temple Grandin, an autistic woman involved in autism activism, described her inability to understand neurotypicals' social communication as leaving her feeling "like an anthropologist on Mars".[109] Autistic people struggle to understand the social context and subtext of neurotypical conversational or printed situations, and form different conclusions about the content.[110] Autistic people may not control the volume of their voice in different social settings.[111] At least half of autistic children have atypical prosody.[111]

 

What may look like self-involvement or indifference to non-autistic people stems from autistic differences in recognizing how other people have their own personalities, perspectives, and interests.[110][112] Most published research focuses on the interpersonal relationship difficulties between autistic people and their non-autistic counterparts and how to solve them through teaching neurotypical social skills, but newer research has also evaluated what autistic people want from friendships, such as a sense of belonging and good mental health.[113][114] Children with ASD are more frequently involved in bullying situations than their non-autistic peers, and predominantly experience bullying as victims rather than perpetrators or victim-perpetrators, especially after controlling for comorbid psychopathology.[115] Prioritizing dependability and intimacy in friendships during adolescence, coupled with lowered friendship quantity and quality, often lead to increased loneliness in autistic people.[116] As they progress through life, autistic people observe and form a model of social patterns, and develop coping mechanisms, referred to as "masking",[117][118] which have recently been found to come with psychological costs and a higher increased risk of suicidality.[100]

 

Restricted and repetitive behaviors

Sleeping boy beside a dozen or so toys arranged in a line

A young autistic boy who has arranged his toys in a row

ASD includes a wide variety of characteristics. Some of these include behavioral characteristics, which widely range from slow development of social and learning skills to difficulties creating connections with other people. Autistic people may experience these challenges with forming connections due to anxiety or depression, which they are more likely to experience, and as a result isolate themselves.[119][120]

 

Other behavioral characteristics include abnormal responses to sensations (such as sights, sounds, touch, taste and smell) and problems keeping a consistent speech rhythm. The latter problem influences social skills, leading to potential problems in understanding for interlocutors. Autistic people's behavioral characteristics typically influence development, language, and social competence. Their behavioral characteristics can be observed as perceptual disturbances, disturbances of development rate, relating, speech and language, and motility.[121]

 

The second core symptom of autism spectrum is a pattern of restricted and repetitive behaviors, activities, and interests. In order to be diagnosed with ASD under the DSM-5-TR, a person must have at least two of the following behaviors:[69][122]

  

An autistic boy arranging brads on a cork coaster

Repetitive behaviors – Repetitive behaviors such as rocking, hand flapping, finger flicking, head banging, or repeating phrases or sounds.[123] These behaviors may occur constantly or only when the person gets stressed, anxious, or upset. These behaviors are also known as stimming.

Resistance to change – A strict adherence to routines such as eating certain foods in a specific order or taking the same path to school every day.[123] The person may become distressed if there is a change or disruption to their routine.

Restricted interests – An excessive interest in a particular activity, topic, or hobby, and devoting all their attention to it. For example, young children might completely focus on things that spin and ignore everything else. Older children might try to learn everything about a single topic, such as the weather or sports, and perseverate or talk about it constantly.[123]

Sensory reactivity – An unusual reaction to certain sensory inputs, such as negative reaction to specific sounds or textures, fascination with lights or movements, or apparent indifference to pain or heat.[124]

Autistic people can display many forms of repetitive or restricted behavior, which the Repetitive Behavior Scale-Revised (RBS-R) categorizes as follows.[125]

 

Stereotyped behaviors: Repetitive movements, such as hand flapping, head rolling, or body rocking.

Compulsive behaviors: Time-consuming behaviors intended to reduce anxiety, that a person feels compelled to perform repeatedly or according to rigid rules, such as placing objects in a specific order, checking things, or handwashing.

Sameness: Resistance to change; for example, insisting that the furniture not be moved or refusing to be interrupted.

Ritualistic behavior: Unvarying pattern of daily activities, such as an unchanging menu or a dressing ritual. This is closely associated with sameness and an independent validation has suggested combining the two factors.[125]

Self-injurious behaviors: Behaviors such as eye-poking, skin-picking, hand-biting and head-banging.[104]

Self-injury and suicide

Self-injurious behaviors are relatively common in autistic people, and can include head-banging, self-cutting, self-biting, and hair-pulling.[126] Some of these can result in serious injury or death.[126] Autistic people are about three times as likely as non-autistic people to engage in self-injury.[127]

 

Theories about the cause of self-injurious behavior in children with developmental delay, including autistic children, include:[128]

 

Frequency or continuation of self-injurious behavior can be influenced by environmental factors (e.g., reward in return for halting self-injurious behavior). This theory does not apply to younger children with autism. There is some evidence that frequency of self-injurious behavior can be reduced by removing or modifying environmental factors that reinforce the behavior.[128]: 10–12 

Higher rates of self-injury are noted in socially isolated autistic people. Studies have shown that socialization skills are related factors to self-injurious behavior for autistic people.[129]

Self-injury could be a response to modulate pain perception when chronic pain or other health problems that cause pain are present.[128]: 12–13 

Abnormal basal ganglia connectivity may predispose to self-injurious behavior.[128]: 13 

Risk factors for self-harm and suicidality include circumstances that could affect anyone, such as mental health problems (e.g., anxiety disorder) and social problems (e.g., unemployment and social isolation), plus factors that affect only autistic people, such as actively trying to behave like like a neurotypical person, which is called masking.[130]

 

Rates of suicidality vary significantly depending upon what is being measured.[130] This is partly because questionnaires developed for neurotypical subjects are not always valid for autistic people.[130] As of 2023, the Suicidal Behaviours Questionnaire–Autism Spectrum Conditions (SBQ-ASC) is the only test validated for autistic people.[130] According to some estimates, about a quarter of autistic youth[131] and a third of all autistic people[130][132] have experienced suicidal ideation at some point. Rates of suicidal ideation are the same for people formally diagnosed with autism and people who have typical intelligence and are believed to have autism but have not been diagnosed.[130]

 

Although most people who attempt suicide are not autistic,[130] autistic people are about three times as likely as non-autistic people to make a suicide attempt.[127][133] Less than 10% of autistic youth have attempted suicide,[131] but 15% to 25% autistic adults have.[130][132] The rates of suicide attempts are the same among people formally diagnosed with autism and those who have typical intelligence and are believed to have autism but have not been diagnosed.[130] The suicide risk is lower among cisgender autistic males and autistic people with intellectual disabilities.[130][133] The rate of suicide results in a global excess mortality among autistic people equal to approximately 2% of all suicide deaths each year.[133]

 

Burnout

Main article: Autistic burnout

 

This section should include a summary of Autistic burnout. See Wikipedia:Summary style for information on how to incorporate it into this article's main text. (August 2024)

Studies have supported the common belief that autistic people become exhausted or burnt out in some situations.[134][135][136][137]

  

In 2021, screenwriter and actor Wentworth Miller revealed his autism diagnosis in a now-deleted Instagram post, stating it was "a shock" but "not a surprise".[138]

Other features

Autistic people may have symptoms that do not contribute to the official diagnosis, but that can affect the person or the family.[139]

 

Some autistic people show unusual or notable abilities, ranging from splinter skills (such as the memorization of trivia) to rare talents in mathematics, music, or artistic reproduction, which in exceptional cases are considered a part of the savant syndrome.[140][141][142] One study describes how some autistic people show superior skills in perception and attention relative to the general population.[143] Sensory abnormalities are found in over 90% of autistic people, and are considered core features by some.[144]

More generally, autistic people tend to show a "spiky skills profile", with strong abilities in some areas contrasting with much weaker abilities in others.[145]

Autistic people are less likely to show cognitive or emotional biases, and usually process information more rationally.[146] On the other hand, most autistic people exhibit lower levels of emotional intelligence, the ability to understand nonverbal clues about other people's feelings.[147]

Differences between the previously recognized disorders under the autism spectrum are greater for under-responsivity (for example, walking into things) than for over-responsivity (for example, distress from loud noises) or for sensation seeking (for example, rhythmic movements).[148] An estimated 60–80% of autistic people have motor signs that include poor muscle tone, poor motor planning, and toe walking;[144][149] deficits in motor coordination are pervasive across ASD and are greater in autism proper.[150][151]

Pathological demand avoidance can occur. People with this set of autistic symptoms are more likely to refuse to do what is asked or expected of them, even to activities they enjoy.

Unusual or atypical eating behavior occurs in about three-quarters of children with ASD, to the extent that it was formerly a diagnostic indicator.[139] Selectivity is the most common problem, although eating rituals and food refusal also occur.[152]

Problematic digital media use

See also: Screen time, Internet addiction disorder, and Video game addiction

This section is an excerpt from Digital media use and mental health § Autism.[edit]

In September 2018, the Review Journal of Autism and Developmental Disorders published a systematic review of 47 studies published from 2005 to 2016 that concluded that associations between autism spectrum disorder (ASD) and screen time was inconclusive.[153] In May 2019, the Journal of Developmental and Behavioral Pediatrics published a systematic review of 16 studies that found that children and adolescents with ASD are exposed to more screen time than typically developing peers and that the exposure starts at a younger age.[154] In April 2021, Research in Autism Spectrum Disorders published a systematic review of 12 studies of video game addiction in ASD subjects that found that children, adolescents, and adults with ASD are at greater risk of video game addiction than those without ASD, and that the data from the studies suggested that internal and external factors (sex, attention and oppositional behavior problems, social aspects, access and time spent playing video games, parental rules, and game genre) were significant predictors of video game addiction in ASD subjects.[155] In March 2022, the Review Journal of Autism and Developmental Disorders published a systematic review of 21 studies investigating associations between ASD, problematic internet use, and gaming disorder where the majority of the studies found positive associations between the disorders.[156]

 

In August 2022, the International Journal of Mental Health and Addiction published a review of 15 studies that found that high rates of video game use in boys and young males with ASD was predominantly explained by video game addiction, but also concluded that greater video game use could be a function of ASD restricted interest and that video game addiction and ASD restricted interest could have an interactive relationship.[157] In December 2022, the Review Journal of Autism and Developmental Disorders published a systematic review of 10 studies researching the prevalence of problematic internet use with ASD that found that ASD subjects had more symptoms of problematic internet use than control group subjects, had higher screen time online and an earlier age of first-time use of the internet, and also greater symptoms of depression and ADHD.[158] In July 2023, Cureus published a systematic review of 11 studies that concluded that earlier and longer screen time exposure for children was associated with higher probability of a child "developing" ASD.[159] In December 2023, JAMA Network Open published a meta-analysis of 46 studies comprising 562,131 subjects that concluded that while screen time may be a developmental cause of ASD in childhood, associations between ASD and screen time were not statistically significant when accounting for publication bias.[160]

Possible causes

Main article: Causes of autism

Exactly what causes autism remains unknown.[161][162][163][164] It was long mostly presumed that there is a common cause at the genetic, cognitive, and neural levels for the social and non-social components of ASD's symptoms, described as a triad in the classic autism criteria.[165] But it is increasingly suspected that autism is instead a complex disorder whose core aspects have distinct causes that often cooccur.[165][166] It is unlikely that ASD has a single cause;[166] many risk factors identified in the research literature may contribute to ASD. These include genetics, prenatal and perinatal factors (meaning factors during pregnancy or very early infancy), neuroanatomical abnormalities, and environmental factors. It is possible to identify general factors, but much more difficult to pinpoint specific ones. Given the current state of knowledge, prediction can only be of a global nature and so requires the use of general markers.[clarification needed][167]

 

Biological subgroups

Research into causes has been hampered by the inability to identify biologically meaningful subgroups within the autistic population[168] and by the traditional boundaries between the disciplines of psychiatry, psychology, neurology and pediatrics.[169] Newer technologies such as fMRI and diffusion tensor imaging can help identify biologically relevant phenotypes (observable traits) that can be viewed on brain scans, to help further neurogenetic studies of autism;[170] one example is lowered activity in the fusiform face area of the brain, which is associated with impaired perception of people versus objects.[171] It has been proposed to classify autism using genetics as well as behavior.[172]

 

Syndromic autism and non-syndromic autism

Main article: Syndromic autism

Autism spectrum disorder (ASD) can be classified into two categories: "syndromic autism" and "non-syndromic autism".

 

Syndromic autism refers to cases where ASD is one of the characteristics associated with a broader medical condition or syndrome, representing about 25% of ASD cases. The causes of syndromic autism are often known, and monogenic disorders account for approximately 5% of these cases.

 

Non-syndromic autism, also known as classic or idiopathic autism, represents the majority of cases, and its cause is typically polygenic and unknown.

 

Genetics

Main articles: Heritability of autism and Epigenetics of autism

See also: Missing heritability problem

 

Hundreds of different genes are implicated in susceptibility to developing autism,[173] most of which alter the brain structure in a similar way.

Autism has a strong genetic basis, although the genetics of autism are complex and it is unclear whether ASD is explained more by rare mutations with major effects, or by rare multi-gene interactions of common genetic variants.[174][175] Complexity arises due to interactions among multiple genes, the environment, and epigenetic factors which do not change DNA sequencing but are heritable and influence gene expression.[176] Many genes have been associated with autism through sequencing the genomes of affected people and their parents.[177] But most of the mutations that increase autism risk have not been identified. Typically, autism cannot be traced to a Mendelian (single-gene) mutation or to a single chromosome abnormality, and none of the genetic syndromes associated with ASD have been shown to selectively cause ASD.[174] Numerous genes have been found, with only small effects attributable to any particular gene.[174] Most loci individually explain less than 1% of cases of autism.[178] As of 2018, it appeared that between 74% and 93% of ASD risk is heritable.[122] After an older child is diagnosed with ASD, 7% to 20% of subsequent children are likely to be as well.[122] If parents have one autistic child, they have a 2% to 8% chance of having a second child who is autistic. If the autistic child is an identical twin, the other will be affected 36% to 95% of the time. A fraternal twin is affected up to 31% of the time.[179] The large number of autistic people with unaffected family members may result from spontaneous structural variation, such as deletions, duplications or inversions in genetic material during meiosis.[180][181] Hence, a substantial fraction of autism cases may be traceable to genetic causes that are highly heritable but not inherited: that is, the mutation that causes the autism is not present in the parental genome.[182]

 

As of 2018, understanding of genetic risk factors had shifted from a focus on a few alleles to an understanding that genetic involvement in ASD is probably diffuse, depending on a large number of variants, some of which are common and have a small effect, and some of which are rare and have a large effect. The most common gene disrupted with large effect rare variants appeared to be CHD8, but less than 0.5% of autistic people have such a mutation. The gene CHD8 encodes the protein chromodomain helicase DNA binding protein 8, which is a chromatin regulator enzyme that is essential during fetal development. CHD8 is an adenosine triphosphate (ATP)–dependent enzyme.[183][184][185] The protein contains an Snf2 helicase domain that is responsible for the hydrolysis of ATP to adenosine diphosphate (ADP).[185] CHD8 encodes a DNA helicase that functions as a repressor of transcription, remodeling chromatin structure by altering the position of nucleosomes. CHD8 negatively regulates Wnt signaling. Wnt signaling is important in the vertebrate early development and morphogenesis. It is believed that CHD8 also recruits the linker histone H1 and causes the repression of β-catenin and p53 target genes.[183] The importance of CHD8 can be observed in studies where CHD8-knockout mice died after 5.5 embryonic days because of widespread p53-induced apoptosis. Some studies have determined the role of CHD8 in autism spectrum disorder (ASD). CHD8 expression significantly increases during human mid-fetal development.[183] The chromatin remodeling activity and its interaction with transcriptional regulators have shown to play an important role in ASD aetiology.[184] The developing mammalian brain has conserved CHD8 target regions that are associated with ASD risk genes.[186] The knockdown of CHD8 in human neural stem cells results in dysregulation of ASD risk genes that are targeted by CHD8.[187] Recently CHD8 has been associated with the regulation of long non-coding RNAs (lncRNAs),[188] and the regulation of X chromosome inactivation (XCI) initiation, via regulation of Xist long non-coding RNA,[ambiguous] the master regulator of XCI,[ambiguous] though competitive binding to Xist regulatory regions.[189]

 

Some ASD is associated with clearly genetic conditions, like fragile X syndrome, but only around 2% of autistic people have fragile X.[122] Hypotheses from evolutionary psychiatry suggest that these genes persist because they are linked to human inventiveness, intelligence or systemising.[190][191]

 

Current research suggests that genes that increase susceptibility to ASD are ones that control protein synthesis in neuronal cells in response to cell needs, activity and adhesion of neuronal cells, synapse formation and remodeling, and excitatory to inhibitory neurotransmitter balance. Therefore, although up to 1,000 different genes are thought to increase the risk of ASD, all of them eventually affect normal neural development and connectivity between different functional areas of the brain in a similar manner that is characteristic of an ASD brain. Some of these genes are known to modulate production of the GABA neurotransmitter, the nervous system's main inhibitory neurotransmitter. These GABA-related genes are under-expressed in an ASD brain. On the other hand, genes controlling expression of glial and immune cells in the brain, e.g. astrocytes and microglia, respectively, are overexpressed, which correlates with increased number of glial and immune cells found in postmortem ASD brains. Some genes under investigation in ASD pathophysiology are those that affect the mTOR signaling pathway, which supports cell growth and survival.[192]

 

All these genetic variants contribute to the development of the autism spectrum, but it cannot be guaranteed that they are determinants for the development.[193]

 

ASD may be under-diagnosed in women and girls due to an assumption that it is primarily a male condition,[194] but genetic phenomena such as imprinting and X linkage have the ability to raise the frequency and severity of conditions in males, and theories have been put forward for a genetic reason why males are diagnosed more often, such as the imprinted brain hypothesis and the extreme male brain theory.[195][196][197]

 

Early life

See also: Refrigerator mother theory

Several prenatal and perinatal complications have been reported as possible risk factors for autism. These risk factors include maternal gestational diabetes, maternal and paternal age over 30,[198][199][200] bleeding during pregnancy after the first trimester, use of certain prescription medication (e.g. valproate) during pregnancy, and meconium in the amniotic fluid. Research is not conclusive on the relation of these factors to autism, but each of them has been identified more frequently in children with autism compared to their siblings who do not have autism and other typically developing youth.[201] While it is unclear if any single factors during the prenatal phase affect the risk of autism,[202] complications during pregnancy may be a risk.[202]

 

There are also studies being done to test whether certain types of regressive autism have an autoimmune basis.[203]

 

Maternal nutrition and inflammation during preconception and pregnancy influences fetal neurodevelopment. Intrauterine growth restriction is associated with ASD, in both term and preterm infants.[204] Maternal inflammatory and autoimmune diseases may damage fetal tissues, aggravating a genetic problem or damaging the nervous system.[205] Systematic reviews and meta-analyses have found that maternal prenatal infections, prenatal antibiotic exposure, and post-term pregnancies are associated with increased risk of ASD in children.[206][207][208]

 

Exposure to air pollution during child pregnancy, especially heavy metals and particulates, may increase the risk of autism.[209][210] Environmental factors that have been claimed without evidence to contribute to or exacerbate autism include certain foods, infectious diseases, solvents, PCBs, phthalates and phenols used in plastic products, pesticides, brominated flame retardants, alcohol, smoking, illicit drugs, vaccines,[211] and prenatal stress. Some, such as the MMR vaccine, have been completely disproven.[212][213][214][215]

 

Disproven vaccine hypothesis

Main articles: Vaccines and autism and MMR vaccine and autism

Parents may first become aware of ASD symptoms in their child around the time of a routine vaccination. This has led to unsupported and disproven theories blaming vaccine "overload", the vaccine preservative thiomersal, or the MMR vaccine for causing autism spectrum disorder.[216] In 1998, British physician and academic Andrew Wakefield led a fraudulent, litigation-funded study that suggested that the MMR vaccine may cause autism.[217][218][219][220][221]

 

Two versions of the vaccine causation hypothesis were that autism results from brain damage caused by either the MMR vaccine itself, or by mercury used as a vaccine preservative.[222] No convincing scientific evidence supports these claims.[39] They are biologically implausible,[216] and further evidence continues to refute them, including the observation that the rate of autism continues to climb despite elimination of thimerosal from most routine vaccines given to children from birth to 6 years of age.[223][224][225][226][227]

 

A 2014 meta-analysis examined ten major studies on autism and vaccines involving 1.25 million children worldwide; it concluded that neither the vaccine preservative thimerosal (mercury), nor the MMR vaccine, which has never contained thimerosal,[228] lead to the development of ASDs.[229] Despite this, misplaced parental concern has led to lower rates of childhood immunizations, outbreaks of previously controlled childhood diseases in some countries, and the preventable deaths of several children.[230][231]

 

Etiological hypotheses

Several hypotheses have been presented that try to explain how and why autism develops by integrating known causes (genetic and environmental effects) and findings (neurobiological and somatic). Some are more comprehensive, such as the Pathogenetic Triad, which proposes and operationalizes three core features (an autistic personality, cognitive compensation, neuropathological burden) that interact to cause autism,[232] and the Intense World Theory, which explains autism through a hyper-active neurobiology that leads to an increased perception, attention, memory, and emotionality.[233] There are also simpler hypotheses that explain only individual parts of the neurobiology or phenotype of autism, such as mind-blindness (a decreased ability for theory of mind), the weak central coherence theory, or the extreme male brain and empathising–systemising theory.

 

Evolutionary hypotheses

See also: Evolutionary psychology and Pleiotropy § Autism and schizophrenia

Research exploring the evolutionary benefits of autism and associated genes has suggested that autistic people may have played a "unique role in technological spheres and understanding of natural systems" in the course of human development.[234][235] It has been suggested that autism may have arisen as "a slight trade off for other traits that are seen as highly advantageous", providing "advantages in tool making and mechanical thinking", with speculation that the condition may "reveal itself to be the result of a balanced polymorphism, like sickle cell anemia, that is advantageous in a certain mixture of genes and disadvantageous in specific combinations".[236] In 2011, a paper in Evolutionary Psychology proposed that autistic traits, including increased spatial intelligence, concentration and memory, could have been naturally selected to enable self-sufficient foraging in a more (although not completely) solitary environment. This is called the "Solitary Forager Hypothesis".[237][238][239] A 2016 paper examines Asperger syndrome as "an alternative prosocial adaptive strategy" that may have developed as a result of the emergence of "collaborative morality" in the context of small-scale hunter-gathering, i.e., where "a positive social reputation for making a contribution to group wellbeing and survival" becomes more important than complex social understanding.[240]

 

Some research suggests that recent human evolution may be a driving force in the rise of autism in recent human populations. Studies in evolutionary medicine indicate that as cultural evolution outpaces biological evolution, disorders linked to bodily dysfunction increase in prevalence due to lack of contact with pathogens and negative environmental conditions that once widely affected ancestral populations. Because natural selection favors reproduction over health and longevity, the lack of this impetus to adapt to certain harmful circumstances creates a tendency for genes in descendant populations to over-express themselves, which may cause a wide array of maladies, ranging from mental disorders to autoimmune diseases.[241] Conversely, noting the failure to find specific alleles that reliably cause autism or rare mutations that account for more than 5% of the heritable variation in autism established by twin and adoption studies, research in evolutionary psychiatry has concluded that it is unlikely that there is selection pressure for autism when considering that, like schizophrenics, autistic people and their siblings tend to have fewer offspring on average than non-autistic people, and instead that autism is probably better explained as a by-product of adaptive traits caused by antagonistic pleiotropy and by genes that are retained due to a fitness landscape with an asymmetric distribution.[242][243][244]

 

Pathophysiology

Main articles: Mechanism of autism and Pathophysiology of autism

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Diagnosis

Main article: Diagnosis of autism

 

This section should include a summary of Diagnosis of autism. See Wikipedia:Summary style for information on how to incorporate it into this article's main text. (August 2024)

This section is an excerpt from Diagnosis of autism.[edit]

The diagnosis of autism is based on a person's reported and directly observed behavior.[245] There are no known biomarkers for autism spectrum conditions that allow for a conclusive diagnosis.[246]

 

In most cases, diagnostic criteria codified in the World Health Organization's International Classification of Diseases (ICD) or the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) are used. These reference manuals are regularly updated based on advances in research, systematic evaluation of clinical experience, and healthcare considerations. Currently, the DSM-5 published in 2013 and the ICD-10 that came into effect in 1994 are used, with the latter in the process of being replaced by the ICD-11 that came into effect in 2022 and is now implemented by healthcare systems across the world. Which autism spectrum diagnoses can be made and which criteria are used depends on the local healthcare system's regulations.

 

According to the DSM-5-TR (2022), in order to receive a diagnosis of autism spectrum disorder, one must present with "persistent deficits in social communication and social interaction" and "restricted, repetitive patterns of behavior, interests, or activities."[247] These behaviors must begin in early childhood and affect one's ability to perform everyday tasks. Furthermore, the symptoms must not be fully explainable by intellectual developmental disorder or global developmental delay.

Conditions correlated or comorbid to autism

Main article: Conditions comorbid to autism spectrum disorders

 

Euler diagram showing overlapping clinical phenotypes in genes associated with monogenic forms of autism spectrum disorder (ASD), dystonia, epilepsy and schizophrenia:

Genes associated with epilepsy

Genes associated with schizophrenia

Genes associated with autism spectrum disorder

Genes associated with dystonia

Autism is correlated or comorbid with several personality traits/disorders.[171] Comorbidity may increase with age and may worsen the course of youth with ASDs and make intervention and treatment more difficult. Distinguishing between ASDs and other diagnoses can be challenging because the traits of ASDs often overlap with symptoms of other disorders, and the characteristics of ASDs make traditional diagnostic procedures difficult.[248][249]

 

Correlations

Research indicates that autistic people are significantly more likely to be LGBT than the general population.[33] There is tentative evidence that gender dysphoria occurs more frequently in autistic people.[250][251] A 2021 anonymized online survey of 16- to 90-year-olds revealed that autistic males are more likely to identify as bisexual than their non-autistic peers, while autistic females are more likely to identify as homosexual than non-autistic females do.[252][non-primary source needed]

 

People on the autism spectrum are significantly more likely to be non-theistic than members of the general population.[253]

 

Comorbidities

 

A 2024 Danish cohort study found increased risks for a multitude of comorbid physical diseases, especially in infancy.

The most common medical condition occurring in autistic people is seizure disorder or epilepsy, which occurs in 11–39% of autistic people.[254] The risk varies with age, cognitive level, and type of language disorder.[255]

Tuberous sclerosis, an autosomal dominant genetic condition in which non-malignant tumors grow in the brain and on other vital organs, is present in 1–4% of autistic people.[256]

Intellectual disabilities are some of the most common comorbid disorders with ASDs. As diagnosis is increasingly being given to people with higher functioning autism, there is a tendency for the proportion with comorbid intellectual disability to decrease over time. In a 2019 study, it was estimated that approximately 30–40% of people diagnosed with ASD also have intellectual disability.[257] Recent research has suggested that autistic people with intellectual disability tend to have rarer, more harmful, genetic mutations than those found in people solely diagnosed with autism.[258] A number of genetic syndromes causing intellectual disability may also be comorbid with ASD, including fragile X, Down, Prader-Willi, Angelman, Williams syndrome,[259] branched-chain keto acid dehydrogenase kinase deficiency,[260][261] and SYNGAP1-related intellectual disability.[262][263]

Learning disabilities are also highly comorbid in people with an ASD. Approximately 25–75% of people with an ASD also have some degree of a learning disability.[264] In particular, attention deficit disorder, which is generally more prevalent than autism (ca. 8% vs. 1%), is not directly related, though it is sometimes comorbid with autism.[265]

Various anxiety disorders tend to co-occur with ASDs, with overall comorbidity rates of 7–84%.[266] They are common among children with ASD; there are no firm data, but studies have reported prevalences ranging from 11% to 84%. Many anxiety disorders have symptoms that are better explained by ASD itself or are hard to distinguish from ASD's symptoms.[267]

Rates of comorbid depression in people with an ASD range from 4–58%.[268]

The relationship between ASD and schizophrenia remains a controversial subject under continued investigation, and recent meta-analyses have examined genetic, environmental, infectious, and immune risk factors that may be shared between the two conditions.[269][270][271] Oxidative stress, DNA damage and DNA repair have been postulated to play a role in the aetiopathology of both ASD and schizophrenia.[272]

Deficits in ASD are often linked to behavior problems, such as difficulties following directions, being cooperative, and doing things on other people's terms.[273] Symptoms similar to those of ADHD can be part of an ASD diagnosis.[274]

Sensory processing disorder is also comorbid with ASD, with comorbidity rates of 42–88%.[275]

Starting in adolescence, some people with Asperger syndrome (26% in one sample)[276] fall under the criteria for the similar condition schizoid personality disorder, which is characterized by a lack of interest in social relationships, a tendency towards a solitary or sheltered lifestyle, secretiveness, emotional coldness, detachment and apathy.[276][277][278] Asperger syndrome was traditionally called "schizoid disorder of childhood".

Genetic disorders – about 10–15% of autism cases have an identifiable Mendelian (single-gene) condition, chromosome abnormality, or other genetic syndromes.[279]

Several metabolic defects, such as phenylketonuria, are associated with autistic symptoms.[280]

Gastrointestinal problems are one of the most commonly co-occurring medical conditions in autistic people.[281] These are linked to greater social impairment, irritability, language impairments, mood changes, and behavior and sleep problems.[281][282][283] A 2015 review proposed that immune, gastrointestinal inflammation, malfunction of the autonomic nervous system, gut flora alterations, and food metabolites may cause brain neuroinflammation and dysfunction.[282] A 2016 review concludes that enteric nervous system abnormalities might play a role in neurological disorders such as autism. Neural connections and the immune system are a pathway that may allow diseases originated in the intestine to spread to the brain.[283]

Sleep problems affect about two-thirds of autistic people at some point in childhood. These most commonly include symptoms of insomnia, such as difficulty falling asleep, frequent nocturnal awakenings, and early morning awakenings. Sleep problems are associated with difficult behaviors and family stress, and are often a focus of clinical attention over and above the primary ASD diagnosis.[284]

Dysautonomia is common in ASD, affecting heart rate and blood pressure and causing symptoms such as brain fog, blurry vision, and bowel dysfunction.[285] It can be diagnosed through a Tilt table test.[286]

The frequency of ASD is 10 times higher in mast cell activation syndrome patients than in the general population. This immunological condition causes cardiovascular, dermatological, gastrointestinal, neurological, and respiratory problems.[287]

Management

Main article: Autism therapies

See also: Autism-friendly

There is no treatment as such for autism,[288] and many sources advise that this is not an appropriate goal,[289][290] although treatment of co-occurring conditions remains an important goal.[291] There is no cure for autism, nor can any of the known treatments significantly reduce brain mutations caused by autism, although those who require little to no support are more likely to experience a lessening of symptoms over time.[292][293][294] Several interventions can help children with autism,[295] and no single treatment is best, with treatment typically tailored to the child's needs.[296] Studies of interventions have methodological problems that prevent definitive conclusions about efficacy,[297] but the development of evidence-based interventions has advanced.[298]

 

The main goals of treatment are to lessen associated deficits and family distress, and to increase quality of life and functional independence. In general, higher IQs are correlated with greater responsiveness to treatment and improved treatment outcomes.[299][298] Behavioral, psychological, education, and skill-building interventions may be used to assist autistic people to learn life skills necessary for living independently,[300] as well as other social, communication, and language skills. Therapy also aims to reduce challenging behaviors and build upon strengths.[301]

 

Intensive, sustained special education programs and behavior therapy early in life may help children acquire self-care, language, and job skills.[296] Although evidence-based interventions for autistic children vary in their methods, many adopt a psychoeducational approach to enhancing cognitive, communication, and social skills while minimizing problem behaviors. While medications have not been found to help with core symptoms, they may be used for associated symptoms, such as irritability, inattention, or repetitive behavior patterns.[302]

 

Non-pharmacological interventions

Intensive, sustained special education or remedial education programs and behavior therapy early in life may help children acquire self-care, social, and job skills. Available approaches include applied behavior analysis, developmental models, structured teaching, speech and language therapy, cognitive behavioral therapy,[303] social skills therapy, and occupational therapy.[304] Among these approaches, interventions either treat autistic features comprehensively, or focus treatment on a specific area of deficit.[298] Generally, when educating those with autism, specific tactics may be used to effectively relay information to these people. Using as much social interaction as possible is key in targeting the inhibition autistic people experience concerning person-to-person contact. Additionally, research has shown that employing semantic groupings, which involves assigning words to typical conceptual categories, can be beneficial in fostering learning.[305]

 

There has been increasing attention to the development of evidence-based interventions for autistic young children. Three theoretical frameworks outlined for early childhood intervention include applied behavior analysis (ABA), the developmental social-pragmatic model (DSP) and cognitive behavioral therapy (CBT).[303][298] Although ABA therapy has a strong evidence base, particularly in regard to early intensive home-based therapy, ABA's effectiveness may be limited by diagnostic severity and IQ of the person affected by ASD.[306] The Journal of Clinical Child and Adolescent Psychology has published a paper deeming two early childhood interventions "well-established": individual comprehensive ABA, and focused teacher-implemented ABA combined with DSP.[298]

 

Many people have criticized ABA, calling it unhelpful and unethical.[307][308][309] Sandoval-Norton et al. also discuss the "unintended but damaging consequences, such as prompt dependency, psychological abuse and compliance" that result in autistic people facing challenges as they transition into adulthood.[307] Some ABA advocates have responded to such critiques that, instead of stopping ABA, there should be movement to increase protections and ethical compliance when working with autistic children.[310]

 

Another evidence-based intervention that has demonstrated efficacy is a parent training model, which teaches parents how to implement various ABA and DSP techniques themselves.[298] Various DSP programs have been developed to explicitly deliver intervention systems through at-home parent implementation.

 

In October 2015, the American Academy of Pediatrics (AAP) proposed new evidence-based recommendations for early interventions in ASD for children under 3.[311] These recommendations emphasize early involvement with both developmental and behavioral methods, support by and for parents and caregivers, and a focus on both the core and associated symptoms of ASD.[311] But a Cochrane review found no evidence that early intensive behavioral intervention (EIBI) is effective in reducing behavioral problems associated with autism in most autistic children, though it did improve IQ and language skills. The Cochrane review acknowledged that this may be due to the low quality of studies available on EIBI and therefore providers should recommend EIBI based on their clinical judgment and the family's preferences. No adverse effects of EIBI treatment were found.[312] A meta-analysis in that same database indicates that due to the heterology in ASD, children progress to differing early intervention modalities based on ABA.[313]

 

ASD treatment generally focuses on behavioral and educational interventions to target its two core symptoms: social communication deficits and restricted, repetitive behaviors. If symptoms continue after behavioral strategies have been implemented, some medications can be recommended to target specific symptoms or co-existing problems such as restricted and repetitive behaviors (RRBs), anxiety, depression, hyperactivity/inattention and sleep disturbance.[314] Melatonin, for example, can be used for sleep problems.[315]

 

Several parent-mediated behavioral therapies target social communication deficits in children with autism, but their efficacy in treating RRBs is uncertain.[316]

 

Education

A young child points, in front of a woman who smiles and points in the same direction.

An autistic three-year-old points to fish in an aquarium, as part of an experiment on the effect of intensive shared-attention training on language development.[317]

Educational interventions often used include applied behavior analysis (ABA), developmental models, structured teaching, speech and language therapy and social skills therapy.[296] Among these approaches, interventions either treat autistic features comprehensively, or focalize treatment on a specific area of deficit.[298]

 

The quality of research for early intensive behavioral intervention (EIBI)—a treatment procedure incorporating over 30 hours per week of the structured type of ABA that is carried out with very young children—is low; more vigorous research designs with larger sample sizes are needed.[312] Two theoretical frameworks outlined for early childhood intervention include structured and naturalistic ABA interventions, and developmental social pragmatic models (DSP).[298] One interventional strategy utilizes a parent training model, which teaches parents how to implement various ABA and DSP techniques, allowing for parents to disseminate interventions themselves.[298] Various DSP programs have been developed to explicitly deliver intervention systems through at-home parent implementation. Despite the recent development of parent training models, these interventions have demonstrated effectiveness in numerous studies, being evaluated as a probable efficacious mode of treatment.[298] Early, intensive ABA therapy has demonstrated effectiveness in enhancing communication and adaptive functioning in preschool children;[296][318] it is also well-established for improving the intellectual performance of that age group.[296]

 

In 2018, a Cochrane meta-analysis database concluded that some recent research is beginning to suggest that because of the heterology of ASD, there are two different ABA teaching approaches to acquiring spoken language: children with higher receptive language skills respond to 2.5 to 20 hours per week of the naturalistic approach, whereas children with lower receptive language skills require 25 hou

cross section: human pineal gland

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Expressing thymidine kinase in GFAP+ hippocampal stem cells allows us to kill them by feeding mice valganciclovir. And see what happens when mice no longer have adult neurogenesis.

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Neurons and astrocytes isolated from rat hippocampus stained for DNA (blue), neuronal-specific βIII-tubulin (green) and astrocyte-specific GFAP (red).

Neurobiology

 

Human neural stem cells from fetal cortex stained for DNA (blue), neuronal (green), and astrocyte (red) markers.

Depression, Post tramatic stress disorder, Anxiety, Cognition

 

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Hometown: Wolfeboro, N.H.

Degree: PhD, Experimental Molecular Medicine

 

Kyla Rodgers earned her BS in biochemistry and molecular biology from Gettysburg College in 2011, after which she began working as a research assistant in the Chou Laboratory at Dartmouth. In August 2013, she joined the Program in Experimental Molecular Medicine, where she continued her work in the Chou Lab, studying the innate immune functions of astrocytes and their implications for neurological conditions (i.e. Alzheimer’s disease). During her studies, she served as both a departmental representative and president of the Graduate Student Council, winning the Graduate Community Award in 2018. She is now completing her first year of her MD at the Geisel School of Medicine, and will serve as a Dickey Center Global Health Fellow this summer at the Comprehensive Rural Health Project in Jamkhed, India.

 

Favorite Place: Occom Pond and the DOC House

 

“I love the fine dining of Moosilauke Ravine Lodge. I adore the quiet splendor of an evening, lying on the docks and spotting shooting stars, then waking up to the call of the loons on a foggy summer morning at Hinman and Armington cabins. But I will never forget all of the loops I ran around Occom Pond when the yellow-green buds poked out their heads in the spring, or when the warm summer breeze rippled its surface, or when the scarlet- and canary-colored leaves dropped and crunched under my feet in the fall. I come here to find my peace.”