COVID-19

During the initial outbreak in Wuhan, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus",^[20][21][22] with the disease sometimes called "Wuhan pneumonia".^[23][24] In the past, many diseases have been named after geographical locations, such as the Spanish flu,^[25] Middle East respiratory syndrome, and Zika virus.^[26] In January 2020, the World Health Organization (WHO) recommended 2019-nCoV^[27] and 2019-nCoV acute respiratory disease^[28] as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations or groups of people in disease and virus names to prevent social stigma.^[29][30][31] The official names COVID‑19 and SARS-CoV-2 were issued by the WHO on 11 February 2020 with COVID-19 being shorthand for "coronavirus disease 2019".^[32][33] The WHO additionally uses "the COVID‑19 virus" and "the virus responsible for COVID‑19" in public communications.^[32][34]

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COVID-19 naming

COVID-19 naming

During the early days of the COVID-19 pandemic, the disease and virus were sometimes called "coronavirus", "Wuhan coronavirus", or "Wuhan pneumonia".

Wuhan

Wuhan

Wuhan is the capital of Hubei Province in the People's Republic of China. It is the largest city in Hubei and the most populous city in Central China, with a population of over eleven million, the ninth-most populous Chinese city and one of the nine National Central Cities of China.

Spanish flu

Spanish flu

The 1918 flu pandemic, also known as the Great Influenza epidemic or by the common misnomer of the Spanish flu, was an exceptionally deadly global influenza pandemic caused by the H1N1 influenza A virus. The earliest documented case was March 1918 in Kansas, United States, with further cases recorded in France, Germany and the United Kingdom in April. Two years later, nearly a third of the global population, or an estimated 500 million people, had been infected in four successive waves. Estimates of deaths range from 17 million to 50 million, and possibly as high as 100 million, making it one of the deadliest pandemics in history.

Zika virus

Zika virus

Zika virus is a member of the virus family Flaviviridae. It is spread by daytime-active Aedes mosquitoes, such as A. aegypti and A. albopictus. Its name comes from the Ziika Forest of Uganda, where the virus was first isolated in 1947. Zika virus shares a genus with the dengue, yellow fever, Japanese encephalitis, and West Nile viruses. Since the 1950s, it has been known to occur within a narrow equatorial belt from Africa to Asia. From 2007 to 2016, the virus spread eastward, across the Pacific Ocean to the Americas, leading to the 2015–2016 Zika virus epidemic.

World Health Organization

World Health Organization

The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. Headquartered in Geneva, Switzerland, it has six regional offices and 150 field offices worldwide.

Social stigma

Social stigma

Social stigma is the disapproval of, or discrimination against, an individual or group based on perceived characteristics that serve to distinguish them from other members of a society. Social stigmas are commonly related to culture, gender, race, socioeconomic class, age, sexual orientation, body image, physical disability, intelligence or lack thereof, and health. Some stigma may be obvious, while others are known as concealable stigmas that must be revealed through disclosure. Stigma can also be against oneself, stemming from negatively viewed personal attributes in a way that can result in a "spoiled identity".

Symptoms of COVID-19

The symptoms of COVID-19 are variable depending on the type of variant contracted, ranging from mild symptoms to a potentially fatal illness.^[35][36] Common symptoms include coughing, fever, loss of smell (anosmia) and taste (ageusia), with less common ones including headaches, nasal congestion and runny nose, muscle pain, sore throat, diarrhea, eye irritation,^[37] and toes swelling or turning purple,^[38] and in moderate to severe cases, breathing difficulties.^[39] People with the COVID-19 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; and a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea.^[39] In people without prior ear, nose, or throat disorders, loss of taste combined with loss of smell is associated with COVID-19 and is reported in as many as 88% of symptomatic cases.^[40][41][42]

Of people who show symptoms, 81% develop only mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) that require hospitalization, and 5% of patients develop critical symptoms (respiratory failure, septic shock, or multiorgan dysfunction) requiring ICU admission.^[43] At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time.^[44][45] These asymptomatic carriers tend not to get tested and can still spread the disease.^{[45][46][47][48]} Other infected people will develop symptoms later (called "pre-symptomatic") or have very mild symptoms and can also spread the virus.^[48]

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^[49] possibly being infectious on 1-4 of those days.^[50] Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.^[49][51]

Most people recover from the acute phase of the disease. However, some people—over half of a cohort of home-isolated young adults identified in June 2021^[52][53] continued to experience a range of effects, such as fatigue, for months even after recovery. This is the result of a condition called long COVID, which can be described as a range of persistent symptoms that continue for weeks and/or months at a time.^[54] Long-term damage to organs has also been observed after the onset of COVID-19. Multi-year studies are underway to further investigate the potential long-term effects of the disease.^[55]

The Omicron variant became dominant in the U.S. in December 2021. Symptoms with the Omicron variant are less severe than they are with other variants.^[56]

Complications

Mechanisms of SARS-CoV-2 cytokine storm and complications

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death.^{[57][58][59][60]} Cardiovascular complications may include heart failure, arrhythmias (including atrial fibrillation), heart inflammation, and thrombosis, particularly venous thromboembolism.^{[61][62][63][64][65][66]} Approximately 20–30% of people who present with COVID‑19 have elevated liver enzymes, reflecting liver injury.^[67][68]

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions).^[69][70] Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal.^[71][72] 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.^[73]

According to the US Centers for Disease Control and Prevention, pregnant women are at increased risk of becoming seriously ill from COVID‑19.^[74] This is because pregnant women with COVID‑19 appear to be more likely to develop respiratory and obstetric complications that can lead to miscarriage, premature delivery and intrauterine growth restriction.^[74]

Fungal infections such as aspergillosis, candidiasis, cryptococcosis and mucormycosis have been recorded in patients recovering from COVID‑19.^[75][76]

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Signs and symptoms

Signs and symptoms

Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. Signs are objective and externally observable; symptoms are the patient's reported subjective experiences. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showing on a medical scan. A symptom is something out of the ordinary that is experienced by an individual such as feeling feverish, a headache or other pain or pains in the body.

Cough

Cough

A cough is a sudden expulsion of air through the large breathing passages which can help clear them of fluids, irritants, foreign particles and microbes. As a protective reflex, coughing can be repetitive with the cough reflex following three phases: an inhalation, a forced exhalation against a closed glottis, and a violent release of air from the lungs following opening of the glottis, usually accompanied by a distinctive sound.

Fever

Fever

Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using values between 37.2 and 38.3 °C in humans. The increase in set point triggers increased muscle contractions and causes a feeling of cold or chills. This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat. Rarely a fever may trigger a febrile seizure, with this being more common in young children. Fevers do not typically go higher than 41 to 42 °C.

Anosmia

Anosmia

Anosmia, also known as smell blindness, is the loss of the ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells.

Ageusia

Ageusia

Ageusia is the loss of taste functions of the tongue, particularly the inability to detect sweetness, sourness, bitterness, saltiness, and umami. It is sometimes confused with anosmia – a loss of the sense of smell. Because the tongue can only indicate texture and differentiate between sweet, sour, bitter, salty, and umami, most of what is perceived as the sense of taste is actually derived from smell. True ageusia is relatively rare compared to hypogeusia – a partial loss of taste – and dysgeusia – a distortion or alteration of taste.

Headache

Headache

Headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches.

Nasal congestion

Nasal congestion

Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels.

Rhinorrhea

Rhinorrhea

Rhinorrhea, rhinorrhoea, or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is a common condition. It is a common symptom of allergies or certain viral infections, such as the common cold or COVID-19. It can be a side effect of crying, exposure to cold temperatures, cocaine abuse, or drug withdrawal, such as from methadone or other opioids. Treatment for rhinorrhea is not usually undertaken, but there are a number of medical treatments and preventive techniques.

Diarrhea

Diarrhea

Diarrhea, also spelled diarrhoea or diarrhœa, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin with loss of the normal stretchiness of the skin and irritable behaviour. This can progress to decreased urination, loss of skin color, a fast heart rate, and a decrease in responsiveness as it becomes more severe. Loose but non-watery stools in babies who are exclusively breastfed, however, are normal.

Shortness of breath

Shortness of breath

Shortness of breath (SOB), also medically known as dyspnea or dyspnoea, is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity", and recommends evaluating dyspnea by assessing the intensity of its distinct sensations, the degree of distress and discomfort involved, and its burden or impact on the patient's activities of daily living. Distinct sensations include effort/work to breathe, chest tightness or pain, and "air hunger". The tripod position is often assumed to be a sign.

Hypogeusia

Hypogeusia

Hypogeusia is a reduced ability to taste things. The complete lack of taste is referred to as ageusia. Causes of hypogeusia include the chemotherapy drug bleomycin, an antitumor antibiotic, Bell's Palsy, and zinc deficiency among others.

Hyposmia

Hyposmia

Hyposmia, or microsmia, is a reduced ability to smell and to detect odors. A related condition is anosmia, in which no odors can be detected. Some of the causes of olfaction problems are allergies, nasal polyps, viral infections and head trauma. In 2012 an estimated 9.8 million people aged 40 and older in the United States had hyposmia and an additional 3.4 million had anosmia/severe hyposmia.

COVID‑19 is caused by infection with a strain of coronavirus known as 'Severe Acute Respiratory Syndrome coronavirus 2' (SARS-CoV-2).^[77]

Transmission

Transmission of COVID‑19

Virology

Illustration of SARSr-CoV virion

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.^[95] All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature,^[96] particularly in Rhinolophus sinicus aka Chinese horseshoe bats.^[97]

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.^[98]

SARS-CoV-2 is closely related to the original SARS-CoV.^[99] 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).^{[100][101][102]} 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.^[103]

SARS-CoV-2 variants

The many thousands of SARS-CoV-2 variants are grouped into either clades or lineages.^[104][105] The WHO, in collaboration with partners, expert networks, national authorities, institutions and researchers, have established nomenclature systems for naming and tracking SARS-CoV-2 genetic lineages by GISAID, Nextstrain and Pango. The expert group convened by the WHO recommended the labelling of variants using letters of the Greek alphabet, for example, Alpha, Beta, Delta, and Gamma, giving the justification that they "will be easier and more practical to discussed by non-scientific audiences."^[106] 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).^[107] The Pango tool groups variants into lineages, with many circulating lineages being classed under the B.1 lineage.^[105][108]

Several notable variants of SARS-CoV-2 emerged throughout 2020.^[109][110] Cluster 5 emerged among minks and mink farmers in Denmark.^[111] After strict quarantines and a mink euthanasia campaign, the cluster was assessed to no longer be circulating among humans in Denmark as of 1 February 2021.^[112]

As of December 2021^[update], there are five dominant variants of SARS-CoV-2 spreading among global populations: the Alpha variant (B.1.1.7, formerly called the UK variant), first found in London and Kent, the Beta variant (B.1.351, formerly called the South Africa variant), the Gamma variant (P.1, formerly called the Brazil variant), the Delta variant (B.1.617.2, formerly called the India variant),^[113] and the Omicron variant (B.1.1.529), which had spread to 57 countries as of 7 December.^[114][115]

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Coronavirus

Coronavirus

Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold, while more lethal varieties can cause SARS, MERS and COVID-19, which is causing the ongoing pandemic. In cows and pigs they cause diarrhea, while in mice they cause hepatitis and encephalomyelitis.

SARS-CoV-2

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a provisional name, 2019 novel coronavirus (2019-nCoV), and has also been called the human coronavirus 2019. First identified in the city of Wuhan, Hubei, China, the World Health Organization declared the outbreak a public health emergency of international concern on January 30, 2020, and a pandemic on March 11, 2020. SARS‑CoV‑2 is a positive-sense single-stranded RNA virus that is contagious in humans.

Transmission of COVID-19

Transmission of COVID-19

The transmission of COVID-19 is the passing of coronavirus disease 2019 from person to person. COVID-19 is mainly transmitted when people breathe in air contaminated by droplets/aerosols and small airborne particles containing the virus. Infected people exhale those particles as they breathe, talk, cough, sneeze, or sing. Transmission is more likely the more physically close people are. However, infection can occur over longer distances, particularly indoors.

Drop (liquid)

Drop (liquid)

A drop or droplet is a small column of liquid, bounded completely or almost completely by free surfaces. A drop may form when liquid accumulates at the lower end of a tube or other surface boundary, producing a hanging drop called a pendant drop. Drops may also be formed by the condensation of a vapor or by atomization of a larger mass of solid. Water vapor will condense into droplets depending on the temperature. The temperature at which droplets form is called the dew point.

Aerosol

Aerosol

An aerosol is a suspension of fine solid particles or liquid droplets in air or another gas. Aerosols can be natural or anthropogenic. Examples of natural aerosols are fog or mist, dust, forest exudates, and geyser steam. Examples of anthropogenic aerosols include particulate air pollutants, mist from the discharge at hydroelectric dams, irrigation mist, perfume from atomizers, smoke, dust, steam from a kettle, sprayed pesticides, and medical treatments for respiratory illnesses. When a person inhales the contents of a vape pen or e-cigarette, they are inhaling an anthropogenic aerosol.

Airborne transmission

Airborne transmission

Airborne transmission or aerosol transmission is transmission of an infectious disease through small particles suspended in the air. Infectious diseases capable of airborne transmission include many of considerable importance both in human and veterinary medicine. The relevant infectious agent may be viruses, bacteria, or fungi, and they may be spread through breathing, talking, coughing, sneezing, raising of dust, spraying of liquids, flushing toilets, or any activities which generate aerosol particles or droplets. This is the transmission of diseases via transmission of an infectious agent, and does not include diseases caused by air pollution.

Infectivity

Infectivity

In epidemiology, infectivity is the ability of a pathogen to establish an infection. More specifically, infectivity is a pathogen's capacity for horizontal transmission — that is, how frequently it spreads among hosts that are not in a parent–child relationship. The measure of infectivity in a population is called incidence.

Asymptomatic

Asymptomatic

Asymptomatic is an adjective categorising the medical conditions that patients carry but without experiencing their symptoms, despite an explicit diagnosis.

Respiratory droplet

Respiratory droplet

A respiratory droplet is a small aqueous droplet produced by exhalation, consisting of saliva or mucus and other matter derived from respiratory tract surfaces. Respiratory droplets are produced naturally as a result of breathing, speaking, sneezing, coughing, or vomiting, so they are always present in our breath, but speaking and coughing increase their number.

Basic reproduction number

Basic reproduction number

In epidemiology, the basic reproduction number, or basic reproductive number, denoted , of an infection is the expected number of cases directly generated by one case in a population where all individuals are susceptible to infection. The definition assumes that no other individuals are infected or immunized. Some definitions, such as that of the Australian Department of Health, add the absence of "any deliberate intervention in disease transmission". The basic reproduction number is not necessarily the same as the effective reproduction number , which is the number of cases generated in the current state of a population, which does not have to be the uninfected state. is a dimensionless number and not a time rate, which would have units of time−1, or units of time like doubling time.

Disease cluster

Disease cluster

A disease cluster is an unusually large aggregation of a relatively uncommon medical condition or event within a particular geographical location or period. Recognition of a cluster depends on its size being seen as greater than would be expected by the play of chance. Identification of a suspected disease cluster may initially depend on anecdotal evidence. Epidemiologists and biostatisticians need to assess whether the suspected cluster corresponds to an actual increase of disease in the area. Typically, when clusters are recognized, they are reported to public health departments in the local area. If clusters are of sufficient size and importance, they may be re-evaluated as outbreaks.

Superspreading event

Superspreading event

A superspreading event (SSEV) is an event in which an infectious disease is spread much more than usual, while an unusually contagious organism infected with a disease is known as a superspreader. In the context of a human-borne illness, a superspreader is an individual who is more likely to infect others, compared with a typical infected person. Such superspreaders are of particular concern in epidemiology.

COVID‑19 pathogenesis

The SARS-CoV-2 virus can infect a wide range of cells and systems of the body. COVID‑19 is most known for affecting the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs).^[116] The lungs are the organs most affected by COVID‑19 because the virus accesses host cells via the receptor for the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant on the surface of type II alveolar cells of the lungs.^[117] The virus uses a special surface glycoprotein called a "spike" to connect to the ACE2 receptor and enter the host cell.^[118]

Respiratory tract

Following viral entry, COVID‑19 infects the ciliated epithelium of the nasopharynx and upper airways.^[119]

Nervous system

One common symptom, loss of smell, results from infection of the support cells of the olfactory epithelium, with subsequent damage to the olfactory neurons.^[120] The involvement of both the central and peripheral nervous system in COVID‑19 has been reported in many medical publications.^[121] It is clear that many people with COVID-19 exhibit neurological or mental health issues. The virus is not detected in the central nervous system (CNS) of the majority of COVID-19 patients 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.^[122] 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.^{[123][124][125]} 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.^[122]

Tropism and multiple organ injuries in SARS-CoV-2 infection

Research conducted when Alpha was the dominant variant has suggested COVID-19 may cause brain damage. It is unknown if such damage is temporary or permanent, and whether Omicron has similar effects.^[126][127] Observed individuals infected with COVID-19 (most with mild cases) experienced an additional 0.2% to 2% of brain tissue lost in regions of the brain connected to the sense of smell compared with uninfected individuals, and the overall effect on the brain was equivalent on average to at least one extra year of normal ageing; infected individuals also scored lower on several cognitive tests. All effects were more pronounced among older ages.^[128]

Gastrointestinal tract

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium^[129] as well as endothelial cells and enterocytes of the small intestine.^[130]

Cardiovascular system

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system.^[131][132] An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China,^[133] and is more frequent in severe disease.^[134] 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.^[132] ACE2 receptors are highly expressed in the heart and are involved in heart function.^[132][135]

A high incidence of thrombosis and venous thromboembolism occurs in people transferred to intensive care units with COVID‑19 infections, and may be related to poor prognosis.^[136] Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) may have a significant role in mortality, incidents of clots leading to pulmonary embolisms, and ischaemic events (strokes) within the brain found as complications leading to death in people infected with COVID‑19.^[137] Infection may initiate a chain of vasoconstrictive responses within the body, including pulmonary vasoconstriction – a possible mechanism in which oxygenation decreases during pneumonia.^[137] Furthermore, damage of arterioles and capillaries was found in brain tissue samples of people who died from COVID‑19.^[138][139]

COVID‑19 may also cause substantial structural changes to blood cells, sometimes persisting for months after hospital discharge.^[140] A low level of blood lymphocytes may result from the virus acting through ACE2-related entry into lymphocytes.^[141]

Other organs

Another common cause of death is complications related to the kidneys.^[137] Early reports show that up to 30% of hospitalised patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.^[142]

Autopsies of people who died of COVID‑19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.^[143]

Immunopathology

Key components of the adaptive immune response to SARS-CoV-2

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 gamma-induced protein 10 (IP‑10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1‑alpha (MIP‑1‑alpha), and tumour necrosis factor (TNF‑α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.^[133]

Interferon alpha plays a complex, Janus-faced role in the pathogenesis of COVID-19. Although it promotes the elimination of virus-infected cells, it also upregulates the expression of ACE-2, thereby facilitating the SARS-Cov2 virus to enter cells and to replicate.^[144][145] A competition of negative feedback loops (via protective effects of interferon alpha) and positive feedback loops (via upregulation of ACE-2) is assumed to determine the fate of patients suffering from COVID-19.^[146]

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.^[147]

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.^[148] Lymphocytic infiltrates have also been reported at autopsy.^[143]

Viral and host factors

Virus proteins

The association between SARS-CoV-2 and the Renin-Angiotensin-Aldosterone System (RAAS)

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.^[149]

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.^[150] The N and E protein are accessory proteins that interfere with the host's immune response.^[150]

Host factors

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-CoV-2 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.^[151]

The effect of the virus 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.^[152]

Among healthy adults not exposed to SARS-CoV-2, about 35% have CD4⁺ T cells that recognise the SARS-CoV-2 S protein (particularly the S2 subunit) and about 50% react to other proteins of the virus, suggesting cross-reactivity from previous common colds caused by other coronaviruses.^[153]

It is unknown whether different persons use similar antibody genes in response to COVID‑19.^[154]

Host cytokine response

Mild versus severe immune response during virus infection

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm.^[155] 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.^[156]

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 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 involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.^[157]

Pregnancy response

There are many unknowns for pregnant women during the COVID-19 pandemic. Given that they are prone to have complications and severe disease infection with other types of coronaviruses, they have been identified as a vulnerable group and advised to take supplementary preventive measures.^[158]

Physiological responses to pregnancy can include:

• Immunological: The immunological response to COVID-19, like other viruses, depends on a working immune system. It adapts during pregnancy to allow the development of the foetus whose genetic load is only partially shared with their mother, leading to a different immunological reaction to infections during the course of pregnancy.^[158]
• Respiratory: Many factors can make pregnant women more vulnerable to hard respiratory infections. One of them is the total reduction of the lungs' capacity and inability to clear secretions.^[158]
• Coagulation: During pregnancy, there are higher levels of circulating coagulation factors, and the pathogenesis of SARS-CoV-2 infection can be implicated. The thromboembolic events with associated mortality are a risk for pregnant women.^[158]

However, from the evidence base, it is difficult to conclude whether pregnant women are at increased risk of grave consequences of this virus.^[158]

In addition to the above, other clinical studies have proved that SARS-CoV-2 can affect the period of pregnancy in different ways. On the one hand, there is little evidence of its impact up to 12 weeks gestation. On the other hand, COVID-19 infection may cause increased rates of unfavourable outcomes in the course of the pregnancy. Some examples of these could be foetal growth restriction, preterm birth, and perinatal mortality, which refers to the foetal death past 22 or 28 completed weeks of pregnancy as well as the death among live-born children up to seven completed days of life.^[158]

Unvaccinated women in later stages of pregnancy with COVID-19 are more likely than other patients to need very intensive care. Babies born to mothers with COVID-19 are more likely to have breathing problems. Pregnant women are strongly encouraged to get vaccinated.^[159]

Discover more about Pathophysiology related topics

Angiotensin-converting enzyme 2

Angiotensin-converting enzyme 2

Angiotensin-converting enzyme 2 (ACE2) is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines, kidney, testis, gallbladder, and heart or in a soluble form (sACE2). Both membrane bound and soluble ACE2 are integral parts of the renin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. While mACE2 does not appear to factor into the harmful phase of RAAS, its existence is vital in order for the enzyme ADAM17 to cleave its extracellular domain to create soluble ACE2 (sACE2). Soluble ACE2 lowers blood pressure by catalyzing the hydrolysis of angiotensin II into angiotensin (1–7) which in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. This decrease in blood pressure makes the entire process a promising drug target for treating cardiovascular diseases.

Coronavirus spike protein

Coronavirus spike protein

Spike (S) glycoprotein is the largest of the four major structural proteins found in coronaviruses. The spike protein assembles into trimers that form large structures, called spikes or peplomers, that project from the surface of the virion. The distinctive appearance of these spikes when visualized using negative stain transmission electron microscopy, "recalling the solar corona", gives the virus family its main name.

Central nervous system

Central nervous system

The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all parts of the bodies of bilaterally symmetric and triploblastic animals—that is, all multicellular animals except sponges and diploblasts. It is a structure composed of nervous tissue positioned along the rostral to caudal axis of the body and may have an enlarged section at the rostral end which is a brain. Only arthropods, cephalopods and vertebrates have a true brain.

Impact of the COVID-19 pandemic on neurological, psychological and other mental health outcomes

Impact of the COVID-19 pandemic on neurological, psychological and other mental health outcomes

There is increasing evidence suggesting that COVID-19 causes both acute and chronic neurological or psychological symptoms. Caregivers of COVID-19 patients also show a higher than average prevalence of mental health concerns. These symptoms result from multiple different factors.

Cerebrospinal fluid

Cerebrospinal fluid

Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.

Host tropism

Host tropism

Host tropism is the infection specificity of certain pathogens to particular hosts and host tissues. This explains why most pathogens are only capable of infecting a limited range of host organisms.

Multiple organ dysfunction syndrome

Multiple organ dysfunction syndrome

Multiple organ dysfunction syndrome (MODS) is altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis.

Gland

Gland

In animals, a gland is a group of cells in an animal's body that synthesizes substances for release into the bloodstream or into cavities inside the body or its outer surface.

Duodenum

Duodenum

The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In mammals it may be the principal site for iron absorption. The duodenum precedes the jejunum and ileum and is the shortest part of the small intestine.

Epithelium

Epithelium

Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellular matrix. Epithelial tissues line the outer surfaces of organs and blood vessels throughout the body, as well as the inner surfaces of cavities in many internal organs. An example is the epidermis, the outermost layer of the skin.

Endothelium

Endothelium

The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Enterocyte

Enterocyte

Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its surface area. This facilitates transport of numerous small molecules into the enterocyte from the intestinal lumen. These include broken down proteins, fats, and sugars, as well as water, electrolytes, vitamins, and bile salts. Enterocytes also have an endocrine role, secreting hormones such as leptin.

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.^[19][160] Along with laboratory testing, chest CT scans may be helpful to diagnose COVID‑19 in individuals with a high clinical suspicion of infection.^[161] Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.^[19]

Viral testing

Demonstration of a nasopharyngeal swab for COVID‑19 testing

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests,^[19][162] which detects the presence of viral RNA fragments.^[163] As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited."^[164] The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used.^[165][166] Results are generally available within hours.^[19] The WHO has published several testing protocols for the disease.^[167]

Several 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.^[168]

The University of Oxford's CEBM has pointed to mounting evidence^[169][170] 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"^[171] In September 2020, 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".^[172]

Imaging

A CT scan of a person with COVID-19 shows lesions (bright regions) in the lungs

CT scan of rapid progression stage of COVID-19

Chest X-ray showing COVID‑19 pneumonia

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.^[161][173] Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection.^[161][174] Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses.^[161][175] Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.^[176]

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.^[177] Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID‑19.^[176] 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.^[160]

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.^[178]

Pathology

The main pathological findings at autopsy are:

• Macroscopy: pericarditis, lung consolidation and pulmonary oedema^[143]
• Lung findings:
  • minor serous exudation, minor fibrin exudation^[143]
  • pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation^[143]
  • diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxaemia.^[143]
  • organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis^[143]
  • plasmocytosis in BAL^[179]
• Blood and vessels: disseminated intravascular coagulation (DIC);^[180] leukoerythroblastic reaction,^[181] endotheliitis,^[182] hemophagocytosis^[182]
• Heart: cardiac muscle cell necrosis^[182]
• Liver: microvesicular steatosis^[143]
• Nose: shedding of olfactory epithelium^[120]
• Brain: infarction^[182]
• Kidneys: acute tubular damage.^[182]
• Spleen: white pulp depletion.^[182]

Discover more about Diagnosis related topics

COVID-19 testing

COVID-19 testing

COVID-19 testing involves analyzing samples to assess the current or past presence of SARS-CoV-2. The two main types of tests detect either the presence of the virus or antibodies produced in response to infection. Molecular tests for viral presence through its molecular components are used to diagnose individual cases and to allow public health authorities to trace and contain outbreaks. Antibody tests instead show whether someone once had the disease. They are less useful for diagnosing current infections because antibodies may not develop for weeks after infection. It is used to assess disease prevalence, which aids the estimation of the infection fatality rate.

Reverse transcription polymerase chain reaction

Reverse transcription polymerase chain reaction

Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA and amplification of specific DNA targets using polymerase chain reaction (PCR). It is primarily used to measure the amount of a specific RNA. This is achieved by monitoring the amplification reaction using fluorescence, a technique called real-time PCR or quantitative PCR (qPCR). Combined RT-PCR and qPCR are routinely used for analysis of gene expression and quantification of viral RNA in research and clinical settings.

Nucleic acid test

Nucleic acid test

A nucleic acid test (NAT) is a technique used to detect a particular nucleic acid sequence and thus usually to detect and identify a particular species or subspecies of organism, often a virus or bacterium that acts as a pathogen in blood, tissue, urine, etc. NATs differ from other tests in that they detect genetic materials rather than antigens or antibodies. Detection of genetic materials allows an early diagnosis of a disease because the detection of antigens and/or antibodies requires time for them to start appearing in the bloodstream. Since the amount of a certain genetic material is usually very small, many NATs include a step that amplifies the genetic material—that is, makes many copies of it. Such NATs are called nucleic acid amplification tests (NAATs). There are several ways of amplification, including polymerase chain reaction (PCR), strand displacement assay (SDA), or transcription mediated assay (TMA).

Serology

Serology

Serology is the scientific study of serum and other body fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum. Such antibodies are typically formed in response to an infection, against other foreign proteins, or to one's own proteins. In either case, the procedure is simple.

Antibody

Antibody

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

Nasopharyngeal swab

Nasopharyngeal swab

A nasopharyngeal swab is a device used for collecting a sample of nasal secretions from the back of the nose and throat. The sample is then analyzed for the presence of organisms or other clinical markers for disease. This diagnostic method is commonly used in suspected cases of whooping cough, diphtheria, influenza, and various types of diseases caused by the coronavirus family of viruses, including SARS, MERS, and COVID-19.

Public Health England

Public Health England

Public Health England (PHE) was an executive agency of the Department of Health and Social Care in England which began operating on 1 April 2013 to protect and improve health and wellbeing and reduce health inequalities. Its formation came as a result of the reorganisation of the National Health Service (NHS) in England outlined in the Health and Social Care Act 2012. It took on the role of the Health Protection Agency, the National Treatment Agency for Substance Misuse and a number of other health bodies. It was an executive agency of the Department of Health and Social Care, and a distinct delivery organisation with operational autonomy.

University of Oxford

University of Oxford

The University of Oxford is a collegiate research university in Oxford, England. There is evidence of teaching as early as 1096, making it the oldest university in the English-speaking world and the world's second-oldest university in continuous operation. It grew rapidly from 1167 when Henry II banned English students from attending the University of Paris. After disputes between students and Oxford townsfolk in 1209, some academics fled north-east to Cambridge where they established what became the University of Cambridge. The two English ancient universities share many common features and are jointly referred to as Oxbridge.

Ground-glass opacity

Ground-glass opacity

Ground-glass opacity (GGO) is a finding seen on chest x-ray (radiograph) or computed tomography (CT) imaging of the lungs. It is typically defined as an area of hazy opacification (x-ray) or increased attenuation (CT) due to air displacement by fluid, airway collapse, fibrosis, or a neoplastic process. When a substance other than air fills an area of the lung it increases that area's density. On both x-ray and CT, this appears more grey or hazy as opposed to the normally dark-appearing lungs. Although it can sometimes be seen in normal lungs, common pathologic causes include infections, interstitial lung disease, and pulmonary edema.

Crazy paving (medicine)

Crazy paving (medicine)

Crazy paving refers to a pattern seen on computed tomography of the chest, involving lobular septal thickening with variable alveolar filling. The finding is seen in pulmonary alveolar proteinosis, and other diseases. Its name comes from its resemblance to irregular paving stones, called crazy pavings.

Pulmonary consolidation

Pulmonary consolidation

A pulmonary consolidation is a region of normally compressible lung tissue that has filled with liquid instead of air. The condition is marked by induration of a normally aerated lung. It is considered a radiologic sign. Consolidation occurs through accumulation of inflammatory cellular exudate in the alveoli and adjoining ducts. The liquid can be pulmonary edema, inflammatory exudate, pus, inhaled water, or blood. Consolidation must be present to diagnose pneumonia: the signs of lobar pneumonia are characteristic and clinically referred to as consolidation.

Pleural effusion

Pleural effusion

A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per kilogram weight per hour, and is cleared by lymphatic absorption leaving behind only 5–15 millilitres of fluid, which helps to maintain a functional vacuum between the parietal and visceral pleurae. Excess fluid within the pleural space can impair inspiration by upsetting the functional vacuum and hydrostatically increasing the resistance against lung expansion, resulting in a fully or partially collapsed lung.

Without pandemic containment measures – such as social distancing, vaccination, and face masks – pathogens can spread exponentially.^[183] This graphic shows how early adoption of containment measures tends to protect wider swaths of the population.

Preventive measures to reduce the chances of infection include getting vaccinated, staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, managing potential exposure durations,^[184] washing hands with soap and water often and for at least twenty seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.^[185][186]

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.^[187][188]

The first COVID‑19 vaccine was granted regulatory approval on 2 December 2020 by the UK medicines regulator MHRA.^[189] It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries.^[190] 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.^[191][68] 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".^[192] This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of active cases, and delaying additional cases until effective treatments or a vaccine become available.^[192][193]

Vaccine

Different vaccine candidate types in development for SARS-CoV-2

Face masks and respiratory hygiene

Masks with an exhalation valve. The valves are a weak point that can transmit the viruses outwards.

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.^[194][195] 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.^[195][196] Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing.^[195][196] 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.^[197] However, if the mask includes an exhalation valve, a wearer that is infected (and possibly asymptomatic) may transmit the virus through the valve. 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.^[198]

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease.^[199] 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.^[200]

Indoor ventilation and avoiding crowded indoor spaces

The CDC recommends that crowded indoor spaces should be avoided.^[201] When indoors, increasing the rate of air change, decreasing recirculation of air and increasing the use of outdoor air can reduce transmission.^[201][202] The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.^{[203][204][205]}

Exhaled respiratory particles can build-up within enclosed spaces with inadequate ventilation. The risk of COVID‑19 infection increases especially in spaces where people engage in physical exertion or raise their voice (e.g., exercising, shouting, singing) as this increases exhalation of respiratory droplets. Prolonged exposure to these conditions, typically more than 15 minutes, leads to higher risk of infection.^[201]

Displacement ventilation with large natural inlets can move stale air directly to the exhaust in laminar flow while significantly reducing the concentration of droplets and particles. Passive ventilation reduces energy consumption and maintenance costs but may lack controllability and heat recovery. Displacement ventilation can also be achieved mechanically with higher energy and maintenance costs. The use of large ducts and openings helps to prevent mixing in closed environments. Recirculation and mixing should be avoided because recirculation prevents dilution of harmful particles and redistributes possibly contaminated air, and mixing increases the concentration and range of infectious particles and keeps larger particles in the air.^[206]

Hand-washing and hygiene

Students in Rwanda hand washing and wearing face masks during the COVID‑19 pandemic in the country.

Thorough hand hygiene after any cough or sneeze is required.^[207] The WHO also recommends that individuals wash hands often with soap and water for at least twenty seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose.^[208] When soap and water are not available, the CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol.^[209] 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.^[210]

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.^[211] Many governments are mandating or recommending social distancing in regions affected by the outbreak.^[212]

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing.^[213][214] In the United States, the prisoner population is ageing 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.^[213]

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 and cause infection.^[215] Evidence indicates that contact with infected surfaces is not the main driver of COVID‑19,^{[216][217][218]} 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.^[219][220] Deep cleaning and other surface sanitation has been criticised as hygiene theatre, giving a false sense of security against something primarily spread through the air.^[221][222]

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity.^[223] Coronaviruses die very quickly when exposed to the UV light in sunlight.^[223] 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 ([223]

On many surfaces, including 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.^[223][224] On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours.^[223] The virus dies faster on porous surfaces than on non-porous surfaces due to capillary action within pores and faster aerosol droplet evaporation.^{[225][218][223]} However, 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.^[223]

The CDC says that in most situations, cleaning surfaces with soap or detergent, not disinfecting, is enough to reduce risk of transmission.^[226][227] 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 ATMs used by the ill persons should be disinfected.^[228] Surfaces may be decontaminated with 62–71 per cent ethanol, 50–100 per cent isopropanol, 0.1 per cent sodium hypochlorite, 0.5 per cent hydrogen peroxide, 0.2–7.5 per cent povidone-iodine, or 50–200 ppm hypochlorous acid. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used,^[203] although popular devices require 5–10 min exposure and may deteriorate some materials over time.^[229] A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inoculum volumes) can be seen in the supplementary material of.^[219]

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.^[230] 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.^[231] 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.^[232]

International travel-related control measures

A 2021 Cochrane rapid review found that based upon low-certainty evidence, international travel-related control measures such as restricting cross-border travel may help to contain the spread of COVID‑19.^[233] Additionally, symptom/exposure-based screening measures at borders may miss many positive cases.^[233] While test-based border screening measures may be more effective, it could also miss many positive cases if only conducted upon arrival without follow-up. The review concluded that a minimum 10-day quarantine may be beneficial in preventing the spread of COVID‑19 and may be more effective if combined with an additional control measure like border screening.^[233]

Discover more about Prevention related topics

Pandemic prevention

Pandemic prevention

Pandemic prevention is the organization and management of preventive measures against pandemics. Those include measures to reduce causes of new infectious diseases and measures to prevent outbreaks and epidemics from becoming pandemics.

Non-pharmaceutical intervention (epidemiology)

Non-pharmaceutical intervention (epidemiology)

In epidemiology, a non-pharmaceutical intervention (NPI) is any method used to reduce the spread of an epidemic disease without requiring pharmaceutical drug treatments. Examples of non-pharmaceutical interventions that reduce the spread of infectious diseases include wearing a face mask and staying away from sick people.

Pandemic predictions and preparations prior to the COVID-19 pandemic

Pandemic predictions and preparations prior to the COVID-19 pandemic

Planning and preparing for pandemics has happened in countries and international organizations. The World Health Organization writes recommendations and guidelines, though there is no sustained mechanism to review countries' preparedness for epidemics and their rapid response abilities. National action depends on national governments. In 2005–2006, before the 2009 swine flu pandemic and during the decade following it, the governments in the United States, France, UK, and others managed strategic health equipment stocks, but they often reduced stocks after the 2009 pandemic in order to reduce costs.

COVID-19 surveillance

COVID-19 surveillance

COVID-19 surveillance involves monitoring the spread of the coronavirus disease in order to establish the patterns of disease progression. The World Health Organization (WHO) recommends active surveillance, with focus of case finding, testing and contact tracing in all transmission scenarios. COVID-19 surveillance is expected to monitor epidemiological trends, rapidly detect new cases, and based on this information, provide epidemiological information to conduct risk assessment and guide disease preparedness.

COVID-19 apps

COVID-19 apps

COVID-19 apps include mobile-software applications for digital contact-tracing - i.e. the process of identifying persons ("contacts") who may have been in contact with an infected individual - deployed during the COVID-19 pandemic.

Medicines and Healthcare products Regulatory Agency

Medicines and Healthcare products Regulatory Agency

The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are acceptably safe.

National Institutes of Health

National Institutes of Health

The National Institutes of Health, commonly referred to as NIH, is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late 1880s and is now part of the United States Department of Health and Human Services. Many NIH facilities are located in Bethesda, Maryland, and other nearby suburbs of the Washington metropolitan area, with other primary facilities in the Research Triangle Park in North Carolina and smaller satellite facilities located around the United States. The NIH conducts its own scientific research through the NIH Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program.

Epidemic curve

Epidemic curve

An epidemic curve, also known as an epi curve or epidemiological curve, is a statistical chart used in epidemiology to visualise the onset of a disease outbreak. It can help with the identification of the mode of transmission of the disease. It can also show the disease's magnitude, whether cases are clustered or if there are individual case outliers, its trend over time, and its incubation period. It can give outbreak investigators an idea as to whether an outbreak is likely to be from a point source, a continuous common source, or a propagated source.

COVID-19 vaccine

COVID-19 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 that causes coronavirus disease 2019 (COVID‑19).

Vaccine

Vaccine

A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future.

SARS-CoV-2

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a provisional name, 2019 novel coronavirus (2019-nCoV), and has also been called the human coronavirus 2019. First identified in the city of Wuhan, Hubei, China, the World Health Organization declared the outbreak a public health emergency of international concern on January 30, 2020, and a pandemic on March 11, 2020. SARS‑CoV‑2 is a positive-sense single-stranded RNA virus that is contagious in humans.

Face masks during the COVID-19 pandemic

Face masks during the COVID-19 pandemic

During the COVID-19 pandemic, face masks or coverings, including N95, FFP2, surgical, and cloth masks, have been employed as public and personal health control measures against the spread of SARS-CoV-2, the virus that causes COVID-19.

An overview of COVID-19 therapeutics and drugs

Discover more about Treatment related topics

Nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged oral medication, developed by Pfizer and used as a treatment for COVID-19. It contains the antiviral medications nirmatrelvir and ritonavir.

Remdesivir

Remdesivir

Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. It is administered via injection into a vein. During the COVID‑19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in numerous countries.

Symptomatic treatment

Symptomatic treatment

Symptomatic treatment, supportive care, supportive therapy, or palliative treatment is any medical therapy of a disease that only affects its symptoms, not the underlying cause. It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae of these signs and symptoms of the disease. In many diseases, even in those whose etiologies are known, symptomatic treatment is the only treatment available so far. For more detail, see supportive therapy. For conditions like cancer, arthritis, neuropathy, tendinopathy, and injury, it can be useful to distinguish treatments that are supportive/palliative and cannot alter the natural history of the disease.

Fluid replacement

Fluid replacement

Fluid replacement or fluid resuscitation is the medical practice of replenishing bodily fluid lost through sweating, bleeding, fluid shifts or other pathologic processes. Fluids can be replaced with oral rehydration therapy (drinking), intravenous therapy, rectally such as with a Murphy drip, or by hypodermoclysis, the direct injection of fluid into the subcutaneous tissue. Fluids administered by the oral and hypodermic routes are absorbed more slowly than those given intravenously.

Paracetamol

Paracetamol

Paracetamol is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.

Obligate nasal breathing

Obligate nasal breathing

Obligate nasal breathing describes a physiological necessity to breathe through the nose as opposed to breathing through the mouth.

Healthy diet

Healthy diet

A healthy diet is a diet that maintains or improves overall health. A healthy diet provides the body with essential nutrition: fluid, macronutrients such as protein, micronutrients such as vitamins, and adequate fibre and food energy.

Centers for Disease Control and Prevention

Centers for Disease Control and Prevention

The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services, and is headquartered in Atlanta, Georgia.

Glucocorticoid

Glucocorticoid

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The name "glucocorticoid" is a portmanteau and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure.

Dexamethasone

Dexamethasone

Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cava syndrome, and along with antibiotics in tuberculosis. In adrenocortical insufficiency, it may be used in combination with a mineralocorticoid medication such as fludrocortisone. In preterm labor, it may be used to improve outcomes in the baby. It may be given by mouth, as an injection into a muscle, as an injection into a vein, as a topical cream or ointment for the skin or as a topical ophthalmic solution to the eye. The effects of dexamethasone are frequently seen within a day and last for about three days.

Intensive care unit

Intensive care unit

An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensive care medicine.

Mechanical ventilation

Mechanical ventilation

Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move air into and out of the lungs, with the main goal of helping the delivery of oxygen and removal of carbon dioxide. Mechanical ventilation is used for many reasons, including to protect the airway due to mechanical or neurologic cause, to ensure adequate oxygenation, or to remove excess carbon dioxide from the lungs. Various healthcare providers are involved with the use of mechanical ventilation and people who require ventilators are typically monitored in an intensive care unit.

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 hospitalisation.^[253] 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.^[100] 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.^[254] Abnormal sodium levels during hospitalization with COVID-19 are associated with poor prognoses: high sodium with a greater risk of death, and low sodium with an increased chance of needing ventilator support.^[255][256] 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.^[257][258]

Some early studies suggest 10% to 20% of people with COVID‑19 will experience symptoms lasting longer than a month.^[259][260] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath.^[261] 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 therefore concluded that a strategy of achieving herd immunity by infection, rather than vaccination, is "morally unconscionable and unfeasible".^[262]

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within two months of discharge. The average to readmit was eight 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.^[263][264]

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers.^[265][266] Acting on the same ACE2 pulmonary receptors affected by smoking, air pollution has been correlated with the disease.^[266] Short term^[267] and chronic^[268] exposure to air pollution seems to enhance morbidity and mortality from COVID‑19.^{[269][270][271]} Pre-existing heart and lung diseases^[272] and also obesity, especially in conjunction with fatty liver disease, contributes to an increased health risk of COVID‑19.^{[266][273][274][275]}

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2.^[276] One research study that looked into the COVID‑19 infections in hospitalised kidney transplant recipients found a mortality rate of 11%.^[277]

Men with untreated hypogonadism were 2.4 times more likely than men with eugonadism to be hospitalized if they contracted COVID-19; Hypogonad men treated with testosterone were less likely to be hospitalized for COVID-19 than men who were not treated for hypogonadism.^[278]

Genetic risk factors

Genetics plays an important role in the ability to fight off Covid.^[279] For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID‑19.^[280][281] Genetic screening is able to detect interferon effector genes.^[282] Some genetic variants are risk factors in specific populations. For instance, and allele of the DOCK2 gene (dedicator of cytokinesis 2 gene) is a common risk factor in Asian populations but much less common in Europe. The mutation leads to lower expression of DOCK2 especially in younger patients with severe Covid.^[283] In fact, many other genes and genetic variants have been found that determine the outcome of SARS-CoV-2 infections.^[284]

Children

While very young children have experienced lower rates of infection, older children have a rate of infection that is similar to the population as a whole.^[285][286] Children are likely to have milder symptoms and are at lower risk of severe disease than adults.^[287] The CDC reports that in the US roughly a third of hospitalised children were admitted to the ICU,^[288] while a European multinational study of hospitalised children from June 2020, found that about 8% of children admitted to a hospital needed intensive care.^[289] Four of the 582 children (0.7%) in the European study died, but the actual mortality rate may be "substantially lower" since milder cases that did not seek medical help were not included in the study.^[290][291]

Longer-term effects

Some early studies suggest that 10–20% of people with COVID‑19 will experience symptoms lasting longer than a month.^[292][260] A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath.^[293] About 5–10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.^[294]

By a variety of mechanisms, the lungs are the organs most affected in COVID‑19.^[295] In people requiring hospital admission, up to 98% of CT scans performed show lung abnormalities after 28 days of illness even if they had clinically improved.^[296]

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long-lasting effects, including pulmonary fibrosis.^[297] Overall, approximately one-third of those investigated after four weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in asymptomatic people, but with the suggestion of continuing improvement with the passing of more time.^[295] After severe disease, lung function can take anywhere from three months to a year or more to return to previous levels.^[298]

The risks of cognitive deficit, dementia, psychotic disorders, and epilepsy or seizures persists at an increased level two years after infection.^[299]

Immunity

Human antibody response to SARS-CoV-2 infection

The immune response by humans to SARS-CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production,^[300] just as with most other infections.^[301] B cells interact with T cells and begin dividing before selection into the plasma cell, partly on the basis of their affinity for antigen.^[302] 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.^[303] The presence of neutralising antibodies in blood strongly correlates with protection from infection, but the level of neutralising antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralising antibody two months after infection. In another study, the level of neutralising antibodies fell four-fold one to four months after the onset of symptoms. However, the lack of antibodies in the blood does not mean antibodies 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 six months after the appearance of symptoms.^[303]

As of August 2021, reinfection with COVID‑19 was possible but uncommon. The first case of reinfection was documented in August 2020.^[304] A systematic review found 17 cases of confirmed reinfection in medical literature as of May 2021.^[304] With the Omicron variant, as of 2022, reinfections have become common, albeit it is unclear how common.^[305] COVID-19 reinfections are thought to likely be less severe than primary infections, especially if one was previously infected by the same variant.^[305]

Discover more about Prognosis and risk factors related topics

COVID-19 pandemic death rates by country

COVID-19 pandemic death rates by country

This article contains the current number of confirmed COVID-19 deaths per population by country. It also has cumulative death totals by country. For these numbers over time see the tables, graphs, and maps at COVID-19 pandemic deaths and COVID-19 pandemic by country and territory.

Common cold

Common cold

The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposure to the virus. These may include coughing, sore throat, runny nose, sneezing, headache, and fever. People usually recover in seven to ten days, but some symptoms may last up to three weeks. Occasionally, those with other health problems may develop pneumonia.

Istituto Superiore di Sanità

Istituto Superiore di Sanità

The Istituto Superiore di Sanità, also ISS, is an Italian public institution that, as the leading technical-scientific body of the Italian National Health Service, performs research, trials, control, counseling, documentation and training for public health. The Institute is under the supervision of the Ministero della Salute.

C-reactive protein

C-reactive protein

C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells in order to activate the complement system via C1q.

Long COVID

Long COVID

Long COVID or long-haul COVID is a condition characterized by long-term health problems persisting or appearing after the typical recovery period of COVID-19. Although studies into long COVID are under way, as of May 2022 there is no consensus on the definition of the term.

Herd immunity

Herd immunity

Herd immunity is a form of indirect protection that applies only to contagious diseases. It occurs when a sufficient percentage of a population has become immune to an infection, whether through previous infections or vaccination, thereby reducing the likelihood of infection for individuals who lack immunity.

Fatty liver disease

Fatty liver disease

Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complications may include cirrhosis, liver cancer, and esophageal varices.

Hypogonadism

Hypogonadism

Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

Genetics

Genetics

Genetics is the study of genes, genetic variation, and heredity in organisms. It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar working in the 19th century in Brno, was the first to study genetics scientifically. Mendel studied "trait inheritance", patterns in the way traits are handed down from parents to offspring over time. He observed that organisms inherit traits by way of discrete "units of inheritance". This term, still used today, is a somewhat ambiguous definition of what is referred to as a gene.

Autoantibody

Autoantibody

An autoantibody is an antibody produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases are associated with such antibodies.

Allele

Allele

An allele is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.The word "Allele" is a short form of "allelomorph". "The chromosomal or genomic location of a gene or any other genetic element is called a locus and alternative DNA sequences at a locus are called alleles."

Impact of the COVID-19 pandemic on children

Impact of the COVID-19 pandemic on children

A systematic review notes that children with COVID-19 have milder effects and better prognoses than adults. However, children are susceptible to "multisystem inflammatory syndrome in children" (MIS-C), a rare but life-threatening systemic illness involving persistent fever and extreme inflammation following exposure to the SARS-CoV-2 virus.

Several measures are commonly used to quantify mortality.^[306] 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.^[307]

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.^{[308][309][310]} In fact, one relevant factor of mortality rates is the age structure of the countries' populations. For example, the case fatality rate for COVID‑19 is lower in India than in the US since India's younger population represents a larger percentage than in the US.^[311]

Case fatality rate

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 1.02% (6,881,955/676,609,955) as of 10 March 2023.^[4] The number varies by region.^[312][313]

• 

  Total confirmed cases over time

• 

  Total confirmed cases of COVID‑19 per million people^[314]

• 

  Total confirmed deaths over time

• 

  Total confirmed deaths due to COVID‑19 per million people^[315]

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.^{[316][317][318]} 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.^[319]

Estimates

The red line shows the estimate of infection fatality rate (IFR), in percentage terms, as a function of age. The shaded region depicts the 95% confidence interval for that estimate. Markers denotes specific observations used in the meta-analysis.^[320]

The same relationship plotted on a log scale

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.^[320] 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.^[320] These results were also highlighted in a December 2020 report issued by the WHO.^[321]

An analysis of those IFR rates indicates that COVID‑19 is hazardous not only for the elderly but also for middle-aged adults, for whom the infection fatality rate of COVID-19 is two orders of magnitude greater than the annualised risk of a fatal automobile accident and far more dangerous than seasonal influenza.^[320]

Earlier estimates of IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.^[322][323] 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%.^[324][325] In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%.^[326] 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. (After sufficient time however, people can get reinfected).^[327] 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).^[328] Antibody testing in New York City suggested an IFR of ≈0.9%,^[329] and ≈1.4%.^[330] In Bergamo province, 0.6% of the population has died.^[331] In September 2020, the U.S. Centers for Disease Control and Prevention (CDC) reported preliminary estimates of age-specific IFRs for public health planning purposes.^[332]

Sex differences

COVID‑19 case fatality rates are higher among men than women in most countries. However, in a few countries like India, Nepal, Vietnam, and Slovenia the fatality cases are higher in women than men.^[311] Globally, men are more likely to be admitted to the ICU and more likely to die.^[334][335] One meta-analysis found that globally, men were more likely to get COVID‑19 than women; there were approximately 55 men and 45 women per 100 infections (CI: 51.43–56.58).^[336]

The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women.^[337] Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders.^[338][339] 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.^[340] Smoking, which in some countries like China is mainly a male activity, is a habit that contributes to increasing significantly the case fatality rates among men.^[311] 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.^[341] In Europe as of February 2020, 57% of the infected people were men and 72% of those died with COVID‑19 were men.^[342] As of April 2020, the US government is not tracking sex-related data of COVID‑19 infections.^[343] Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.^[343]

Ethnic differences

In the US, a greater proportion of deaths due to COVID‑19 have occurred among African Americans and other minority groups.^[344] Structural factors that prevent them from practising 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 of underlying conditions such as diabetes,^[345] hypertension, and heart disease also increase their risk of death.^[346] Similar issues affect Native American and Latino communities.^[344] On the one hand, in the Dominican Republic there is a clear example of both gender and ethnic inequality. In this Latin American territory, there is great inequality and precariousness that especially affects Dominican women, with greater emphasis on those of Haitian descent.^[347] 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.^[348] 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.^[349]

Leaders have called for efforts to research and address the disparities.^[350] In the UK, a greater proportion of deaths due to COVID‑19 have occurred in those of a Black, Asian, and other ethnic minority background.^{[351][352][353]} More severe impacts upon patients including the relative incidence of the necessity of hospitalisation 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.^[354] The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet.^[354] 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.^[354]

Comorbidities

Biological factors (immune response) and the general behaviour (habits) can strongly determine the consequences of COVID‑19.^[311] Most of those who die of COVID‑19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus,^[345] and cardiovascular disease.^[355] According to March data from the United States, 89% of those hospitalised had preexisting conditions.^[356] 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.^[254] According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), ischaemic 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 US Centers for Disease Control and Prevention (CDC), are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis.^[357] Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes.^[358][359] When someone with existing respiratory problems is infected with COVID‑19, they might be at greater risk for severe symptoms.^[360] COVID‑19 also poses a greater risk to people who misuse opioids and amphetamines, insofar as their drug use may have caused lung damage.^[361]

In August 2020, the CDC issued a caution that tuberculosis (TB) 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 could not 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.^[362]

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COVID-19 pandemic

COVID-19 pandemic

The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identified in an outbreak in the Chinese city of Wuhan in December 2019. Attempts to contain it there failed, allowing the virus to spread to other areas of Asia and later worldwide. The World Health Organization (WHO) declared the outbreak a public health emergency of international concern on 30 January 2020, and a pandemic on 11 March 2020. As of 10 March 2023, the pandemic had caused more than 676 million cases and 6.88 million confirmed deaths, making it one of the deadliest in history.

COVID-19 pandemic death rates by country

COVID-19 pandemic death rates by country

This article contains the current number of confirmed COVID-19 deaths per population by country. It also has cumulative death totals by country. For these numbers over time see the tables, graphs, and maps at COVID-19 pandemic deaths and COVID-19 pandemic by country and territory.

Case fatality rate

Case fatality rate

In epidemiology, case fatality rate (CFR) – or sometimes more accurately case-fatality risk – is the proportion of people diagnosed with a certain disease, who end up dying of it. Unlike a disease's mortality rate, the CFR does not take into account the time period between disease onset and death. A CFR is generally expressed as a percentage. It represents a measure of disease lethality and may change with different treatments. CFRs are most often used for with discrete, limited-time courses, such as acute infections.

Centers for Disease Control and Prevention

Centers for Disease Control and Prevention

The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services, and is headquartered in Atlanta, Georgia.

Gendered impact of the COVID-19 pandemic

Gendered impact of the COVID-19 pandemic

COVID-19 affects men and women differently both in terms of the outcome of infection and the effect of the disease upon society. The mortality due to COVID-19 is higher in men. Slightly more men than women contract COVID with a ratio of 10:9.

COVID-19 pandemic in France

COVID-19 pandemic in France

The COVID-19 pandemic in France has resulted in 38,623,552 confirmed cases of COVID-19 and 161,700 deaths.

COVID-19 pandemic on Diamond Princess

COVID-19 pandemic on Diamond Princess

The Diamond Princess is a British-registered luxury and cruise ship that is operated by Princess Cruises, a holiday company based in the United States and Bermuda. In February 2020, during a cruise of the Western Pacific, cases of COVID-19 were detected on board. The vessel was quarantined off Japan for two weeks, after which all remaining passengers and crew were evacuated. Of the 3,711 people on board, 712 became infected with the virus – 567 of 2,666 passengers, and 145 of 1,045 crew. Figures for total deaths vary from early to later assessments, and because of difficulties in establishing causation. As many as 14 are reported to have died from the virus, all of them older passengers - an overall mortality rate for those infected of 2%.

Credible interval

Credible interval

In Bayesian statistics, a credible interval is an interval within which an unobserved parameter value falls with a particular probability. It is an interval in the domain of a posterior probability distribution or a predictive distribution. The generalisation to multivariate problems is the credible region.

Confidence interval

Confidence interval

In frequentist statistics, a confidence interval (CI) is a range of estimates for an unknown parameter. A confidence interval is computed at a designated confidence level; the 95% confidence level is most common, but other levels, such as 90% or 99%, are sometimes used. The confidence level represents the long-run proportion of CIs that theoretically contain the true value of the parameter. For example, out of all intervals computed at the 95% level, 95% of them should contain the parameter's true value.

Chinese Center for Disease Control and Prevention

Chinese Center for Disease Control and Prevention

The Chinese Center for Disease Control and Prevention is an institution directly under the National Health Commission, based in Changping District, Beijing, China.

Health insurance

Health insurance

Health insurance or medical insurance is a type of insurance that covers the whole or a part of the risk of a person incurring medical expenses. As with other types of insurance, risk is shared among many individuals. By estimating the overall risk of health risk and health system expenses over the risk pool, an insurer can develop a routine finance structure, such as a monthly premium or payroll tax, to provide the money to pay for the health care benefits specified in the insurance agreement. The benefit is administered by a central organization, such as a government agency, private business, or not-for-profit entity.

Diabetes

Diabetes

Diabetes, also known as diabetes mellitus, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced. Diabetes, if left untreated, leads to many health complications. Untreated or poorly treated diabetes accounts for approximately 1.5 million deaths per year.

The virus is thought to be of natural animal origin, most likely through spillover infection.^{[96][363][364]} A joint-study conducted in early 2021 by the People's Republic of China and the World Health Organization indicated that the virus descended from a coronavirus that infects wild bats, and likely spread to humans through an intermediary wildlife host.^[365] There are several theories about where the index case originated and investigations into the origin of the pandemic are ongoing.^[366] According to articles published in July 2022 in Science, virus transmission into humans occurred through two spillover events in November 2019 and was likely due to live wildlife trade on the Huanan wet market in the city of Wuhan (Hubei, China).^{[367][368][369]} Doubts about the conclusions have mostly centered on the precise site of spillover.^[370] Earlier phylogenetics estimated that SARS-CoV-2 arose in October or November 2019.^{[371][372][373]} A phylogenetic algorithm analysis suggested that the virus may have been circulating in Guangdong before Wuhan.^[374]

Most scientists believe the virus spilled into human populations through natural zoonosis, similar to the SARS-CoV-1 and MERS-CoV outbreaks, and consistent with other pandemics in human history.^[375][376] Available evidence suggests that the SARS-CoV-2 virus was originally harbored by bats, and spread to humans multiple times from infected wild animals at the Huanan Seafood Market in Wuhan in December 2019.^[375][376] A minority of scientists and some members of the U.S intelligence community believe the virus may have been unintentionally leaked from a laboratory such as the Wuhan Institute of Virology.^[377][378] The US intelligence community has mixed views on the issue,^[379][380] but overall agrees with the scientific consensus that the virus was not developed as a biological weapon and is unlikely to have been genetically engineered.^{[381][382][383][384]} There is no evidence SARS-CoV-2 existed in any laboratory prior to the pandemic.^{[385][386][387]}

The first confirmed human infections were in Wuhan. 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.^{[388][389][390]} Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019.^[391] Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020.^[392][393] According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals.^[394] 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.^[395] Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.^[396]

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission.^[337][397] The number of COVID-19 cases in Hubei gradually increased, reaching sixty by 20 December,^[398] and at least 266 by 31 December.^[399] 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.^[400] 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.^[401] 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.^[402] Eight of these doctors, including Li Wenliang (punished on 3 January),^[403] were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.^[404]

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases^{[405][406][407]} – enough to trigger an investigation.^[408]

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days.^[409] 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.^[100] On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen.^[410] Later official data shows 6,174 people had already developed symptoms by then,^[337] and more may have been infected.^[411] 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".^[133][412] On 30 January, the WHO declared COVID-19 a Public Health Emergency of International Concern.^[411] By this time, the outbreak spread by a factor of 100 to 200 times.^[413]

Italy had its first confirmed cases on 31 January 2020, two tourists from China.^[414] Italy overtook China as the country with the most deaths on 19 March 2020.^[415] By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world.^[416] 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.^[417] Retesting of prior samples found a person in France who had the virus on 27 December 2019,^[418][419] and a person in the United States who died from the disease on 6 February 2020.^[420]

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.^[421] 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.^[422]

As of 1 October 2021^[update], Reuters reported that it had estimated the worldwide total number of deaths due to COVID‑19 to have exceeded five million.^[423]

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Timeline of the COVID-19 pandemic

Timeline of the COVID-19 pandemic

The timeline of the COVID-19 pandemic lists the articles containing the chronology and epidemiology of SARS-CoV-2, the virus that causes the coronavirus disease 2019 (COVID-19) and is responsible for the COVID-19 pandemic.

Investigations into the origin of COVID-19

Investigations into the origin of COVID-19

There are several ongoing efforts by scientists, governments, international organisations, and others to determine the origin of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Most scientists agree that as with other pandemics in human history, the virus is likely of zoonotic origin in a natural setting, and ultimately originated from a bat-borne virus. Many other explanations, including several conspiracy theories, have been proposed about the origins of the virus. Some scientists and politicians have speculated that SARS-CoV-2 was accidentally released from a laboratory, but this theory is unsupported by evidence. Another fringe theory about the origins of the virus, centered around an incident in the Mojiang mine in 2012 in which three miners fell ill and died, has also been found to have no supporting evidence.

Spillover infection

Spillover infection

Spillover infection, also known as pathogen spillover and spillover event, occurs when a reservoir population with a high pathogen prevalence comes into contact with a novel host population. The pathogen is transmitted from the reservoir population and may or may not be transmitted within the host population. Due to climate change and land use expansion, the risk of viral spillover is predicted to significantly increase.

Index case

Index case

The index case or patient zero is the first documented patient in a disease epidemic within a population, or the first documented patient included in an epidemiological study. It can also refer to the first case of a condition or syndrome to be described in the medical literature, whether or not the patient is thought to be the first person affected. An index case can achieve the status of a "classic" case study in the literature, as did Phineas Gage, the first known person to exhibit a definitive personality change as a result of a brain injury.

Science (journal)

Science (journal)

Science, also widely referred to as Science Magazine, is the peer-reviewed academic journal of the American Association for the Advancement of Science (AAAS) and one of the world's top academic journals. It was first published in 1880, is currently circulated weekly and has a subscriber base of around 130,000. Because institutional subscriptions and online access serve a larger audience, its estimated readership is over 400,000 people.

Huanan Seafood Wholesale Market

Huanan Seafood Wholesale Market

The Wuhan Huanan Seafood Wholesale Market, simply known as the Huanan Seafood Market, was a live animal and seafood market in Jianghan District, Wuhan City, the capital of Hubei Province, in Central China.

Phylogenetics

Phylogenetics

In biology, phylogenetics is the study of the evolutionary history and relationships among or within groups of organisms. These relationships are determined by phylogenetic inference methods that focus on observed heritable traits, such as DNA sequences, protein amino acid sequences, or morphology. The result of such an analysis is a phylogenetic tree—a diagram containing a hypothesis of relationships that reflects the evolutionary history of a group of organisms.

Guangdong

Guangdong

Guangdong, alternatively romanized as Canton or Kwangtung, is a coastal province in South China on the north shore of the South China Sea. The capital of the province is Guangzhou. With a population of 126.01 million across a total area of about 179,800 km2 (69,400 sq mi), Guangdong is the most populous province of China and the 15th-largest by area as well as the second-most populous country subdivision in the world. Its economy is larger than that of any other province in the nation and the fifth largest sub-national economy in the world with a GDP (nominal) of 1.95 trillion USD in 2021. The Pearl River Delta Economic Zone, a Chinese megalopolis, is a core for high technology, manufacturing and foreign trade. Located in this zone are two of the four top Chinese cities and the top two Chinese prefecture-level cities by GDP; Guangzhou, the capital of the province, and Shenzhen, the first special economic zone in the country. These two are among the most populous and important cities in China, and have now become two of the world's most populous megacities and leading financial centres in the Asia-Pacific region.

SARS-CoV-1

SARS-CoV-1

Severe acute respiratory syndrome coronavirus 1 is a strain of coronavirus that causes severe acute respiratory syndrome (SARS), the respiratory illness responsible for the 2002–2004 SARS outbreak. It is an enveloped, positive-sense, single-stranded RNA virus that infects the epithelial cells within the lungs. The virus enters the host cell by binding to angiotensin-converting enzyme 2. It infects humans, bats, and palm civets. The SARS-CoV-1 outbreak was largely brought under control by simple public health measures. Testing people with symptoms, isolating and quarantining suspected cases, and restricting travel all had an effect. SARS-CoV-1 was most transmissible when patients were sick, and so by isolating those with symptoms, you could effectively prevent onward spread.

United States Intelligence Community

United States Intelligence Community

The United States Intelligence Community (IC) is a group of separate United States government intelligence agencies and subordinate organizations that work both separately and collectively to conduct intelligence activities which support the foreign policy and national security interests of the United States. Member organizations of the IC include intelligence agencies, military intelligence, and civilian intelligence and analysis offices within federal executive departments.

COVID-19 lab leak theory

COVID-19 lab leak theory

The COVID-19 lab leak theory, or lab leak hypothesis, is the idea that SARS-CoV-2, the virus that caused the COVID-19 pandemic, is the result of a laboratory leak. Most scientists believe the virus spilled into human populations through natural zoonosis, similar to the SARS-CoV-1 and MERS-CoV outbreaks, and consistent with other pandemics in human history. Available evidence suggests that the SARS-CoV-2 virus was originally harbored by bats, and spread to humans multiple times from infected wild animals at the Huanan Seafood Market in Wuhan, Hubei, China, in December 2019. There is no evidence SARS-CoV-2 existed in any laboratory prior to the pandemic. An original animal reservoir has not yet been confirmed, though several candidate species have been identified.

Biological agent

Biological agent

A biological agent is a bacterium, virus, protozoan, parasite, fungus, or toxin that can be used purposefully as a weapon in bioterrorism or biological warfare (BW). In addition to these living or replicating pathogens, toxins and biotoxins are also included among the bio-agents. More than 1,200 different kinds of potentially weaponizable bio-agents have been described and studied to date.

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.^{[424][425][426]}

In September 2020, the US Centers for Disease Control and Prevention (CDC) published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.^[427][428]

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COVID-19 misinformation

COVID-19 misinformation

False information, including intentional disinformation and conspiracy theories, about the scale of the COVID-19 pandemic and the origin, prevention, diagnosis, and treatment of the disease has been spread through social media, text messaging, and mass media. False information has been propagated by celebrities, politicians, and other prominent public figures. Many countries have passed laws against "fake news", and thousands of people have been arrested for spreading COVID-19 misinformation. The spread of COVID-19 misinformation by governments has also been significant.

Misinformation

Misinformation

Misinformation is incorrect or misleading information. It differs from disinformation, which is deliberately deceptive. Rumors are information not attributed to any particular source, and so are unreliable and often unverified, but can turn out to be either true or false. Even if later retracted, misinformation can continue to influence actions and memory. People may be more prone to believe misinformation because they are emotionally connected to what they are listening to or are reading. The role of social media has made information readily available to society at anytime, and it connects vast groups of people along with their information at one time. Advances in technology has impacted the way people communicate information and the way misinformation is spread. Misinformation has impacts on societies' ability to receive information which then influences our communities, politics, and medical field.

Disinformation

Disinformation

Disinformation is false information deliberately spread to deceive people. It is sometimes confused with misinformation, which is false information but is not deliberate. Disinformation is presented in the form of fake news.

Centers for Disease Control and Prevention

Centers for Disease Control and Prevention

The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services, and is headquartered in Atlanta, Georgia.

Humans appear to be capable of spreading the virus to some other animals,^[429][430] a type of disease transmission referred to as zooanthroponosis.^[431][432]

Some pets, especially cats and ferrets, can catch this virus from infected humans.^[433][434] Symptoms in cats include respiratory (such as a cough) and digestive symptoms.^[433] 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.^[433][435] Compared to cats, dogs are less susceptible to this infection.^[435] Behaviours which increase the risk of transmission include kissing, licking, and petting the animal.^[435]

The virus does not appear to be able to infect pigs, ducks, or chickens at all.^[433] Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.^[435]

Tigers and lions in zoos have become infected as a result of contact with infected humans.^[435] As expected, monkeys and great ape species such as orangutans can also be infected with the COVID‑19 virus.^[435]

Minks, which are in the same family as ferrets, have been infected.^[435] Minks may be asymptomatic, and can also spread the virus to humans.^[435] Multiple countries have identified infected animals in mink farms.^[436] Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations,^[436] following an outbreak referred to as Cluster 5. A vaccine for mink and other animals is being researched.^[436]

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Ferret

Ferret

The ferret is a small, domesticated species belonging to the family Mustelidae. The ferret is most likely a domesticated form of the wild European polecat, evidenced by their interfertility. Other mustelids include the stoat, badger and mink.

Domestic duck

Domestic duck

The domestic duck or domestic mallard is a subspecies of mallard that has been domesticated by humans and raised for meat, eggs, and down feathers. A few are also kept for show, as pets, or for their ornamental value. Almost all varieties of domesticated ducks, apart from the domestic Muscovy duck, are descended from the mallard.

Mouse

Mouse

A mouse is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse. Mice are also popular as pets. In some places, certain kinds of field mice are locally common. They are known to invade homes for food and shelter.

Orangutan

Orangutan

Orangutans are great apes native to the rainforests of Indonesia and Malaysia. They are now found only in parts of Borneo and Sumatra, but during the Pleistocene they ranged throughout Southeast Asia and South China. Classified in the genus Pongo, orangutans were originally considered to be one species. From 1996, they were divided into two species: the Bornean orangutan and the Sumatran orangutan. A third species, the Tapanuli orangutan, was identified definitively in 2017. The orangutans are the only surviving species of the subfamily Ponginae, which diverged genetically from the other hominids between 19.3 and 15.7 million years ago.

Denmark

Denmark

Denmark is a Nordic constituent country in Northern Europe. It is the most populous and politically central constituent of the Kingdom of Denmark, a constitutionally unitary state that includes the autonomous territories of the Faroe Islands and Greenland in the North Atlantic Ocean. Metropolitan Denmark is the southernmost of the Scandinavian countries, lying south-west and south of Sweden, south of Norway, and north of Germany, with which it shares a short land border, its only land border.

Cluster 5

Cluster 5

Cluster 5 is a designation used by the Danish Statens Serum Institut for a virus variant described by the institute in autumn 2020, in connection with investigations of SARS-CoV-2 infection among mink and humans in the north of Jutland, Denmark.

International research on vaccines and medicines in COVID‑19 is underway by government organisations, academic groups, and industry researchers.^[437][438] The CDC has classified it to require a BSL3 grade laboratory.^[439] There has been a great deal of COVID‑19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.^[440]

As of December 2020^[update], hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica.^[441] As of November 2020^[update], more than 200 possible treatments have been studied in humans.^[442]

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission,^[443] diagnosis and prognosis of infection,^[444] estimation of the impact of interventions,^[445][446] or allocation of resources.^[447] Modelling studies are mostly based on compartmental models in epidemiology,^[448] 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 pandemic including computational fluid dynamics models to study the flow physics of COVID‑19,^[449] retrofits of crowd movement models to study occupant exposure,^[450] mobility-data based models to investigate transmission,^[451] or the use of macroeconomic models to assess the economic impact of the pandemic.^[452] Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID‑19 on organisations worldwide.^[453][454]

Treatment-related research

Seven possible drug targets in viral replication process and drugs

Repurposed antiviral drugs make up most of the research into COVID‑19 treatments.^[455][456] Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.^[456]

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.^[457][458] More than 300 active clinical trials are underway as of April 2020.^[68]

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best,^[459][460] and that they may reduce the antiviral activity of remdesivir.^[461] By May 2020^[update], France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID‑19 treatment.^[462]

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.^[463] 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.^[464][465] 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.^[466]

In September 2020, the WHO released updated guidance on using corticosteroids for COVID‑19.^[467][468] 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).^[467] The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID‑19 (conditional recommendation, based on low certainty evidence).^[467] The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID‑19 patients.^[469][470]

In September 2020, the European Medicines Agency (EMA) endorsed the use of dexamethasone in adults and adolescents from twelve years of age and weighing at least 40 kilograms (88 lb) who require supplemental oxygen therapy.^[471][472] Dexamethasone can be taken by mouth or given as an injection or infusion (drip) into a vein.^[471]

In November 2020, the US Food and Drug Administration (FDA) issued an emergency use authorization for the investigational monoclonal antibody therapy bamlanivimab for the treatment of mild-to-moderate COVID‑19.^[473] Bamlanivimab is authorised for people with positive results of direct SARS-CoV-2 viral testing who are twelve years of age and older weighing at least 40 kilograms (88 lb), and who are at high risk for progressing to severe COVID‑19 or hospitalisation.^[473] This includes those who are 65 years of age or older, or who have chronic medical conditions.^[473]

In February 2021, the FDA issued an emergency use authorization (EUA) for bamlanivimab and etesevimab administered together for the treatment of mild to moderate COVID‑19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) who test positive for SARS‑CoV‑2 and who are at high risk for progressing to severe COVID‑19. The authorised use includes treatment for those who are 65 years of age or older or who have certain chronic medical conditions.^[474]

In April 2021, the FDA revoked the emergency use authorization (EUA) that allowed for the investigational monoclonal antibody therapy bamlanivimab, when administered alone, to be used for the treatment of mild-to-moderate COVID‑19 in adults and certain paediatric patients.^[475]

Cytokine storm

Various therapeutic strategies for targeting cytokine storm

A cytokine storm can be a complication in the later stages of severe COVID‑19. A cytokine storm is a potentially deadly immune reaction where a large amount of pro-inflammatory cytokines and chemokines are released too quickly. A cytokine storm can lead to ARDS and multiple organ failure.^[476] Data collected from Jin Yin-tan Hospital in Wuhan, China indicates that patients who had more severe responses to COVID‑19 had greater amounts of pro-inflammatory cytokines and chemokines in their system than patients who had milder responses. These high levels of pro-inflammatory cytokines and chemokines indicate presence of a cytokine storm.^[477]

Tocilizumab has been included in treatment guidelines by China's National Health Commission after a small study was completed.^[478][479] It is undergoing a Phase II non-randomised trial at the national level in Italy after showing positive results in people with severe disease.^[480][481] Combined with a serum ferritin blood test to identify a cytokine storm (also called cytokine storm syndrome, not to be confused with cytokine release syndrome), it is meant to counter such developments, which are thought to be the cause of death in some affected people.^[482] The interleukin-6 receptor (IL-6R) antagonist was approved by the FDA to undergo a Phase III clinical trial assessing its effectiveness on COVID‑19 based on retrospective case studies for the treatment of steroid-refractory cytokine release syndrome induced by a different cause, CAR T cell therapy, in 2017.^[483] There is no randomised, controlled evidence that tocilizumab is an efficacious treatment for CRS. Prophylactic tocilizumab has been shown to increase serum IL-6 levels by saturating the IL-6R, driving IL-6 across the blood–brain barrier, and exacerbating neurotoxicity while having no effect on the incidence of CRS.^[484]

Lenzilumab, an anti-GM-CSF monoclonal antibody, is protective in murine models for CAR T cell-induced CRS and neurotoxicity and is a viable therapeutic option due to the observed increase of pathogenic GM-CSF secreting T cells in hospitalised patients with COVID‑19.^[485]

Passive antibodies

Overview of the application and use of convalescent plasma therapy

Transferring purified and concentrated antibodies produced by the immune systems of those who have recovered from COVID‑19 to people who need them is being investigated as a non-vaccine method of passive immunisation.^[486][487] Viral neutralisation is the anticipated mechanism of action by which passive antibody therapy can mediate defence against SARS-CoV-2. The spike protein of SARS-CoV-2 is the primary target for neutralising antibodies.^[488] As of 8 August 2020, eight neutralising antibodies targeting the spike protein of SARS-CoV-2 have entered clinical studies.^[489] It has been proposed that selection of broad-neutralising antibodies against SARS-CoV-2 and SARS-CoV might be useful for treating not only COVID‑19 but also future SARS-related CoV infections.^[488] Other mechanisms, however, such as antibody-dependant cellular cytotoxicity or phagocytosis, may be possible.^[486] Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development.^[486]

The use of passive antibodies to treat people with active COVID‑19 is also being studied. This involves the production of convalescent serum, which consists of the liquid portion of the blood from people who recovered from the infection and contains antibodies specific to this virus, which is then administered to active patients.^[486] This strategy was tried for SARS with inconclusive results.^[486] An updated Cochrane review in May 2021 found high certainty evidence that, for the treatment of people with moderate to severe COVID‑19, convalescent plasma did not reduce mortality or bring about symptom improvement.^[487] There continues to be uncertainty about the safety of convalescent plasma administration to people with COVID‑19 and differing outcomes measured in different studies limits their use in determining efficacy.^[487]

Bioethics

Since the outbreak of the COVID‑19 pandemic, scholars have explored the bioethics, normative economics, and political theories of healthcare policies related to the public health crisis.^[490] Academics have pointed to the moral distress of healthcare workers, ethics of distributing scarce healthcare resources such as ventilators,^[491] and the global justice of vaccine diplomacies. The socio-economic inequalities between genders,^[492] races,^[493] groups with disabilities,^[494] communities,^[495] regions, countries,^[496] and continents have also drawn attention in academia and the general public.

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COVID-19 drug development

COVID-19 drug development

COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research, with 419 potential COVID-19 drugs in clinical trials, as of April 2021.

Clinical trial

Clinical trial

Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted.

COVID-19 pandemic in Antarctica

COVID-19 pandemic in Antarctica

The COVID-19 pandemic in Antarctica is part of the worldwide pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2. Due to its remoteness and sparse population, Antarctica was the last continent to have confirmed cases of COVID-19 and was one of the last regions of the world affected directly by the pandemic. The first cases were reported in December 2020, almost a year after the first cases of COVID-19 were detected in China. At least 36 people are confirmed to have been infected. Even before the first cases on the continent were reported, human activity in Antarctica was indirectly impacted.

COVID-19 vaccine

COVID-19 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 that causes coronavirus disease 2019 (COVID‑19).

Compartmental models in epidemiology

Compartmental models in epidemiology

Compartmental models are a very general modelling technique. They are often applied to the mathematical modelling of infectious diseases. The population is assigned to compartments with labels – for example, S, I, or R,. People may progress between compartments. The order of the labels usually shows the flow patterns between the compartments; for example SEIS means susceptible, exposed, infectious, then susceptible again.

Computational fluid dynamics

Computational fluid dynamics

Computational fluid dynamics (CFD) is a branch of fluid mechanics that uses numerical analysis and data structures to analyze and solve problems that involve fluid flows. Computers are used to perform the calculations required to simulate the free-stream flow of the fluid, and the interaction of the fluid with surfaces defined by boundary conditions. With high-speed supercomputers, better solutions can be achieved, and are often required to solve the largest and most complex problems. Ongoing research yields software that improves the accuracy and speed of complex simulation scenarios such as transonic or turbulent flows. Initial validation of such software is typically performed using experimental apparatus such as wind tunnels. In addition, previously performed analytical or empirical analysis of a particular problem can be used for comparison. A final validation is often performed using full-scale testing, such as flight tests.

COVID-19 drug repurposing research

COVID-19 drug repurposing research

Drug repositioning is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.

Antiviral drug

Antiviral drug

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural viricides are produced by some plants such as eucalyptus and Australian tea trees.

Corticosteroid

Corticosteroid

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

Bevacizumab

Bevacizumab

Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, glioblastoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).

Experimental drug

Experimental drug

An experimental drug is a medicinal product that has not yet received approval from governmental regulatory authorities for routine use in human or veterinary medicine. A medicinal product may be approved for use in one disease or condition but still be considered experimental for other diseases or conditions. In 2018 federal "Right to Try" laws were enacted in the United States, which allows individuals who fit into the criteria to try experimental drugs that are not yet deemed safe.

Antimalarial medication

Antimalarial medication

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

The use of social distancing and the wearing of surgical masks and similar precautions against COVID‑19 may have caused a drop in the spread of the common cold and the flu.^[497][498]

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Social distancing

Social distancing

In public health, social distancing, also called physical distancing, is a set of non-pharmaceutical interventions or measures intended to prevent the spread of a contagious disease by maintaining a physical distance between people and reducing the number of times people come into close contact with each other. It usually involves keeping a certain distance from others and avoiding gathering together in large groups.

Surgical mask

Surgical mask

A surgical mask, also known by other names such as a medical face mask or procedure mask, is a personal protective equipment used by healthcare professionals that serves as a mechanical barrier that interferes with direct airflow in and out of respiratory orifices. This helps reduce airborne transmission of pathogens and other aerosolized contaminants between the wearer and nearby people via respiratory droplets ejected when sneezing, coughing, forceful expiration or unintentionally spitting when talking, etc. Surgical masks may be labeled as surgical, isolation, dental or medical procedure masks.

Common cold

Common cold

The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposure to the virus. These may include coughing, sore throat, runny nose, sneezing, headache, and fever. People usually recover in seven to ten days, but some symptoms may last up to three weeks. Occasionally, those with other health problems may develop pneumonia.