# Coronavirus disease 2019

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Coronavirus disease 2019 (COVID-19)
Other names
• Coronavirus
• Corona
• COVID
• 2019-nCoV acute respiratory disease
• Novel coronavirus pneumonia[1][2]
• Severe pneumonia with novel pathogens[3]
Symptoms of COVID-19
Pronunciation
SpecialtyInfectious disease
SymptomsFever, persistent cough (usually dry), fatigue, shortness of breath, loss of smell; sometimes no symptoms at all[5][6][7]
ComplicationsPneumonia, viral sepsis, acute respiratory distress syndrome, kidney failure, cytokine release syndrome
Usual onset2–14 days (typically 5) from infection
CausesSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Risk factorsTravel, viral exposure
Diagnostic methodrRT-PCR testing, CT scan
PreventionHand washing, face coverings, quarantine, social distancing[8]
TreatmentSymptomatic and supportive
Frequency6,152,160[9] confirmed cases
Deaths371,700 (6.0% of confirmed cases)[9]

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[10] It was first identified in December 2019 in Wuhan, China, and since spread globally, resulting in an ongoing pandemic.[11][12] The first case may be traced back to 17 November 2019.[13] As of 1 June 2020, more than 6.15 million cases have been reported across 188 countries and territories, resulting in more than 371,000 deaths. More than 2.63 million people have recovered.[9]

Common symptoms include fever, cough, fatigue, shortness of breath, and loss of smell and taste.[6][7][14] While the majority of cases result in mild symptoms, some progress to acute respiratory distress syndrome (ARDS) likely precipitated by a cytokine storm,[15] multi-organ failure, septic shock, and blood clots.[16][17][18] The time from exposure to onset of symptoms is typically around five days but may range from two to fourteen days.[6][19]

The virus is primarily spread between people during close contact,[a] most often via small droplets produced by coughing,[b] sneezing, and talking.[7][20][22] The droplets usually fall to the ground or onto surfaces rather than travelling through air over long distances.[7] Less commonly, people may become infected by touching a contaminated surface and then touching their face.[7][20] It is most contagious during the first three days after the onset of symptoms, although spread is possible before symptoms appear, and from people who do not show symptoms.[7][20] The standard method of diagnosis is by real-time reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab.[23] Chest CT imaging may also be helpful for diagnosis in individuals where there is a high suspicion of infection based on symptoms and risk factors; however, guidelines do not recommend using CT imaging for routine screening.[24][25]

Recommended measures to prevent infection include frequent hand washing, maintaining physical distance from others (especially from those with symptoms), quarantine (especially for those with symptoms), covering coughs, and keeping unwashed hands away from the face.[8][26][27] The use of cloth face coverings such as a scarf or a bandana is recommended in public settings to minimise the risk of transmissions, with some authorities requiring their use.[28][29] Medical grade facemasks such as N95 masks should only be used by healthcare workers, first responders and those who care for infected individuals.[30][31]

According to the World Health Organization (WHO), there are no vaccines nor specific antiviral treatments for COVID-19.[7] On 1 May 2020, the United States gave emergency use authorization to the antiviral remdesivir for people hospitalized with severe COVID‑19.[32] Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.[33] The World Health Organization (WHO) declared the COVID‑19 outbreak a public health emergency of international concern (PHEIC)[34][35] on 30 January 2020 and a pandemic on 11 March 2020.[12] Local transmission of the disease has occurred in most countries across all six WHO regions.[36]

Video summary (script)

## Signs and symptoms

Symptoms of COVID-19[5]
Symptom Range
Fever 83–99%
Cough 59–82%
Loss of appetite 40–84%
Fatigue 44–70%
Shortness of breath 31–40%
Coughing up sputum 28–33%
Muscle aches and pains 11–35%

Fever is the most common symptom, but it is highly variable in severity and presentation, with some older, immunocompromised, or critically ill people not having fever at all.[5][37][38] In one study, only 44% of people had fever when they presented to the hospital, while 89% went on to develop fever at some point during their hospitalization.[5][39] A lack of fever does not verify someone is disease free.

Other common symptoms include cough, loss of appetite, fatigue, shortness of breath, sputum production, and muscle and joint pains.[1][5][6][40] Symptoms such as nausea, vomiting, and diarrhoea have been observed in varying percentages.[41][42][43] Less common symptoms include sneezing, runny nose, sore throat, and skin lesions.[44] Some cases in China initially presented with only chest tightness and palpitations.[45] A decreased sense of smell or disturbances in taste may occur.[46][47] Loss of smell was a presenting symptom in 30% of confirmed cases in South Korea.[14][48]

As is common with infections, there is a delay between the moment a person is first infected and the time he or she develops symptoms. This is called the incubation period. The average incubation period for COVID‑19 is five to six days but commonly ranges from one to 14 days,[7][49] with approximately 10% of cases exceeding that time.[50][51][52]

A minority of cases do not develop noticeable symptoms at any point in time.[53][54] These asymptomatic carriers tend not to get tested, and their role in transmission is not yet fully known.[55][56] However, preliminary evidence suggests they may contribute to the spread of the disease.[57]

### Complications

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death.[11][16][58][59] Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots.[60] Approximately 20-30% of people who present with COVID‑19 have elevated liver enzymes reflecting liver injury.[61][62] Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions).[63] Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal.[64][65]

## Cause

### Transmission

Respiratory droplets produced when a man sneezes, visualised using Tyndall scattering
A video discussing the basic reproduction number and case fatality rate in the context of the pandemic (10:19 min)

COVID-19 spreads primarily when people are in close contact and one person inhales small droplets produced by an infected person (symptomatic or not) coughing, sneezing, or talking.[22] WHO recommends 1 metre (3 ft) of social distance;[7] the U.S. CDC recommends 2 metres (6 ft).[20] People can transmit the virus without showing symptoms, but it is unclear how often this happens.[7][20][22] One estimate of the number of those infected who are asymptomatic is 40%.[66]

People are most infectious when they show symptoms (even mild or non-specific symptoms), but may be infectious for up to two days before symptoms appear (pre-symptomatic transmission).[22] They remain infectious an estimated seven to twelve days in moderate cases and an average of two weeks in severe cases.[22]

When the contaminated droplets fall to floors or surfaces they can, though less commonly, remain infectious if people touch contaminated surfaces and then their eyes, nose or mouth with unwashed hands.[7] On surfaces the amount of active virus decreases over time until it can no longer cause infection,[22] and surfaces are thought not to be the main way the virus spreads.[20] It is unknown what amount of virus on surfaces is required to cause infection via this method, but it can be detected for up to four hours on copper, up to one day on cardboard, and up to three days on plastic (polypropylene) and stainless steel (AISI 304).[22][67][68] Surfaces are easily decontaminated with household disinfectants which kill the virus outside the human body or on the hands.[7] Disinfectants or bleach are not a treatment for COVID‑19, and cause health problems when not used properly, such as when used inside the human body.[69]

Sputum and saliva carry large amounts of virus.[7][20][22][70] Although COVID‑19 is not a sexually transmitted infection, kissing, intimate contact, and faecal-oral routes are suspected to transmit the virus.[71][72] Some medical procedures are aerosol-generating[73] and result in the virus being transmitted more easily than normal.[7][22]

COVID‑19 is a new disease, and many of the details of its spread are still under investigation.[7][20][22] It spreads easily between people—easier than influenza but not as easily as measles.[20] Estimates of the number of people infected by one person with COVID-19 (the R0) have varied widely. The WHO's initial estimates of the R0 were 1.4-2.5 (average 1.95), however a more recent review found the basic R0 (without control measures) to be higher at 3.28 and the median R0 to be 2.79.[74]

### Virology

Illustration of SARSr-CoV virion

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus, first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan.[75] All features of the novel SARS-CoV-2 virus occur in related coronaviruses in nature.[76] Outside the human body, the virus is killed by household soap, which bursts its protective bubble.[24]

SARS-CoV-2 is closely related to the original SARS-CoV.[77] 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).[44] In February 2020, Chinese researchers found that there is only one amino acid difference in the binding domain of the S protein between the coronaviruses from pangolins and those from humans; however, whole-genome comparison to date found that at most 92% of genetic material was shared between pangolin coronavirus and SARS-CoV-2, which is insufficient to prove pangolins to be the intermediate host.[78]

## Pathophysiology

The lungs are the organs most affected by COVID‑19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs.[79] The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell.[80] The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and some have suggested decreasing ACE2 activity might be protective,[81][82][unreliable medical source?] though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective.[83] As the alveolar disease progresses, respiratory failure might develop and death may follow.[82][unreliable medical source?]

SARS-CoV-2 may also cause respiratory failure through affecting the brainstem as other coronaviruses have been found to invade the central nervous system (CNS). While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain.[84][85][unreliable medical source?]

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium[86] as well as endothelial cells and enterocytes of the small intestine.[87][unreliable medical source?]

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system.[88] An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China,[42] and is more frequent in severe disease.[89][unreliable medical source?] 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.[88] ACE2 receptors are highly expressed in the heart and are involved in heart function.[88][90] A high incidence of thrombosis (31%) and venous thromboembolism (25%) have been found in ICU patients with COVID‑19 infections and may be related to poor prognosis.[91][unreliable medical source?][92][unreliable medical source?] Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in patients infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia.[93][better source needed]

Another common cause of death is complications related to the kidneys.[93][better source needed] Early reports show that up to 30% of hospitalized patients in both China and New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.[94]

Autopsies of people who died of COVID‑19 have found diffuse alveolar damage (DAD), and lymphocyte-containing inflammatory infiltrates within the lung.[95][unreliable medical source?]

### Immunopathology

Although SARS-COV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, patients with severe COVID‑19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.[42]

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.[96]

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 COVID‑19 patients.[citation needed] Lymphocytic infiltrates have also been reported at autopsy.[95][unreliable medical source?]

## Diagnosis

Demonstration of a nasopharyngeal swab for COVID-19 testing
CDC rRT-PCR test kit for COVID-19[97]

The WHO has published several testing protocols for the disease.[98] The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR).[99] The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used.[23][100] Results are generally available within a few hours to two days.[101][102] Blood tests can be used, but these require two blood samples taken two weeks apart, and the results have little immediate value.[103] Chinese scientists were able to isolate a strain of the coronavirus and publish the genetic sequence so laboratories across the world could independently develop polymerase chain reaction (PCR) tests to detect infection by the virus.[11][104][105] As of 4 April 2020, antibody tests (which may detect active infections and whether a person had been infected in the past) were in development, but not yet widely used.[106][107][108] The Chinese experience with testing has shown the accuracy is only 60 to 70%.[109] The FDA in the United States approved the first point-of-care test on 21 March 2020 for use at the end of that month.[110]

Diagnostic guidelines released by Zhongnan Hospital of Wuhan University suggested methods for detecting infections based upon clinical features and epidemiological risk. These involved identifying people who had at least two of the following symptoms in addition to a history of travel to Wuhan or contact with other infected people: fever, imaging features of pneumonia, normal or reduced white blood cell count, or reduced lymphocyte count.[111]

A study asked hospitalised COVID‑19 patients to cough into a sterile container, thus producing a saliva sample, and detected the virus in eleven of twelve patients using RT-PCR. This technique has the potential of being quicker than a swab and involving less risk to health care workers (collection at home or in the car).[70]

Along with laboratory testing, 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.[24][25] Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection.[24] Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses.[24][112]

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.[113]

Typical CT imaging findings
CT imaging of rapid progression stage

### Pathology

Few data are available about microscopic lesions and the pathophysiology of COVID‑19.[114][115] The main pathological findings at autopsy are:

## Prevention

Progressively stronger mitigation efforts to reduce the number of active cases at any given time—"flattening the curve"—allows healthcare services to better manage the same volume of patients.[119][120][121] Likewise, progressively greater increases in healthcare capacity—called raising the line—such as by increasing bed count, personnel, and equipment, helps to meet increased demand.[122]
Mitigation attempts that are inadequate in strictness or duration—such as premature relaxation of distancing rules or stay-at-home orders—can allow a resurgence after the initial surge and mitigation.[120][123]

Preventive measures to reduce the chances of infection include staying at home, avoiding crowded places, keeping distance from others, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.[124][125][126] The U.S. Centers for Disease Control and Prevention (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.[124] Proper hand hygiene after any cough or sneeze is encouraged.[124] The CDC has recommended cloth face coverings in public settings where other social distancing measures are difficult to maintain, in part to limit transmission by asymptomatic individuals.[127] The U.S. 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.[128]

Social distancing strategies aim to reduce contact of infected persons with large groups by closing schools and workplaces, restricting travel, and cancelling large public gatherings.[129] Distancing guidelines also include that people stay at least 6 feet (1.8 m) apart.[130] There is no medication known to be effective at preventing COVID‑19.[131] After the implementation of social distancing and stay-at-home orders, many regions have been able to sustain an effective transmission rate ("Rt") of less than one, meaning the disease is in remission in those areas.[132] In a simple model ${\textstyle \ln(R_{t})\approx R_{t}-1}$ needs on average over time be kept at or below zero to avoid exponential growth.[citation needed]

As a COVID-19 vaccine is not expected until 2021 at the earliest,[133] a key part of managing COVID‑19 is trying to decrease and delay the epidemic peak, known as "flattening the curve".[120] This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.[120][123]

According to the WHO, the use of masks is recommended only if a person is coughing or sneezing or when one is taking care of someone with a suspected infection.[134] For the European Centre for Disease Prevention and Control (ECDC) face masks "... could be considered especially when visiting busy closed spaces ..." but "... only as a complementary measure ..."[135] The U.S. CDC recommends masks in public places where 6-foot social distancing is difficult to maintain, primarily in case you yourself are asymptomatic and to prevent unknowingly spreading the infection.[136]

Several countries have recommended that healthy individuals wear face masks or cloth face coverings (like scarves or bandanas) at least in certain public settings, including China,[137] Hong Kong,[138] Spain,[139] Italy (Lombardy region),[140] Russia,[141] and the United States.[127]

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.[30][142] The CDC also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose, coughing or sneezing. It further recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available.[124]

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.[143]

## Management

People are managed with supportive care, which may include fluid therapy, oxygen support, and supporting other affected vital organs.[144][145][146] The CDC recommends those who suspect they carry the virus wear a simple face mask.[30] Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.[39][147] Personal hygiene and a healthy lifestyle and diet have been recommended to improve immunity.[148] Supportive treatments may be useful in those with mild symptoms at the early stage of infection.[149]

The WHO, the Chinese National Health Commission, and the United States' National Institutes of Health have published recommendations for taking care of people who are hospitalised with COVID‑19.[128][150][151] Intensivists and pulmonologists in the U.S. have compiled treatment recommendations from various agencies into a free resource, the IBCC.[152][153]

### Medications

Per the World Health Organization, as of April 2020, there is no specific treatment for COVID‑19.[7] On 1 May 2020, the United States gave emergency use authorization (not full approval) for remdesivir in people hospitalized with severe COVID‑19 after a study suggested it reduced the duration of recovery.[32][154] Researchers continue working on more effective treatments and many vaccine candidates are in development or testing phases.[citation needed]

For symptoms, some medical professionals recommend paracetamol (acetaminophen) over ibuprofen for first-line use.[155][156][157] The WHO and NIH do not oppose the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for symptoms,[128][158] and the FDA says currently there is no evidence that NSAIDs worsen COVID‑19 symptoms.[159]

While theoretical concerns have been raised about ACE inhibitors and angiotensin receptor blockers, as of 19 March 2020, these are not sufficient to justify stopping these medications.[128][160][161][162] One study from 22 April found that people with COVID‑19 and hypertension had lower all-cause mortality when on these medications.[163]

Steroids, such as methylprednisolone, are not recommended unless the disease is complicated by acute respiratory distress syndrome.[164][165]

The Australasian Society of Clinical Immunology and Allergy recommends that tocilizumab be considered an off-label treatment option for those with COVID‑19-related acute respiratory distress syndrome. It recommends this because of its known benefit in cytokine storm caused by a specific cancer treatment, and that cytokine storm may be a significant contributor to mortality in severe COVID‑19.[15]

Medications to prevent blood clotting have been suggested for treatment,[91] and anticoagulant therapy with low molecular weight heparin appears to be associated with better outcomes in severe COVID‐19 showing signs of coagulopathy (elevated D-dimer).[166]

### Protective equipment

The U.S. Centers for Disease Control and Prevention (CDC) recommends four steps to putting on personal protective equipment (PPE).[167]

Precautions must be taken to minimise the risk of virus transmission, especially in healthcare settings when performing procedures that can generate aerosols, such as intubation or hand ventilation.[168] For healthcare professionals caring for people with COVID‑19, the CDC recommends placing the person in an Airborne Infection Isolation Room (AIIR) in addition to using standard precautions, contact precautions, and airborne precautions.[169]

The CDC outlines the guidelines for the use of personal protective equipment (PPE) during the pandemic. The recommended gear is a PPE gown, respirator or facemask, eye protection, and medical gloves.[170][171]

When available, respirators (instead of face masks) are preferred.[172] N95 respirators are approved for industrial settings but the FDA has authorised the masks for use under an emergency use authorization (EUA). They are designed to protect from airborne particles like dust but effectiveness against a specific biological agent is not guaranteed for off-label uses.[173] When masks are not available, the CDC recommends using face shields or, as a last resort, homemade masks.[174]

### Mechanical ventilation

Most cases of COVID‑19 are not severe enough to require mechanical ventilation or alternatives, but a percentage of cases are.[175][176] The type of respiratory support for individuals with COVID‑19 related respiratory failure is being actively studied for people in the hospital, with some evidence that intubation can be avoided with a high flow nasal cannula or bi-level positive airway pressure.[177] Whether either of these two leads to the same benefit for people who are critically ill is not known.[178] Some doctors prefer staying with invasive mechanical ventilation when available because this technique limits the spread of aerosol particles compared to a high flow nasal cannula.[175]

Mechanical ventilation had been performed in 79% of critically ill people in hospital including 62% who previously received other treatment. Of these 41% died, according to one study in the United States.[179]

Severe cases are most common in older adults (those older than 60 years,[175] and especially those older than 80 years).[53] Many developed countries do not have enough hospital beds per capita, which limits a health system's capacity to handle a sudden spike in the number of COVID‑19 cases severe enough to require hospitalisation.[180] This limited capacity is a significant driver behind calls to flatten the curve.[180] One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died.[39] In China, approximately 30% of people in hospital with COVID‑19 are eventually admitted to ICU.[5]

### Acute respiratory distress syndrome

Mechanical ventilation becomes more complex as acute respiratory distress syndrome (ARDS) develops in COVID‑19 and oxygenation becomes increasingly difficult.[181] Ventilators capable of pressure control modes and high PEEP[182] are needed to maximise oxygen delivery while minimising the risk of ventilator-associated lung injury and pneumothorax.[183] High PEEP may not be available on older ventilators.[citation needed]

Options for ARDS[181]
Therapy Recommendations
High-flow nasal oxygen For SpO2 <93%. May prevent the need for intubation and ventilation
Tidal volume 6mL per kg and can be reduced to 4mL/kg
Plateau airway pressure Keep below 30 cmH2O if possible (high respiratory rate (35 per minute) may be required)
Positive end-expiratory pressure Moderate to high levels
Prone positioning For worsening oxygenation
Fluid management Goal is a negative balance of 0.5–1.0L per day
Antibiotics For secondary bacterial infections
Glucocorticoids Not recommended

### Experimental treatment

Research into potential treatments started in January 2020,[184] and several antiviral drugs are in clinical trials.[185][186] Remdesivir appears to be the most promising.[131] Although new medications may take until 2021 to develop,[187] several of the medications being tested are already approved for other uses or are already in advanced testing.[188] Antiviral medication may be tried in people with severe disease.[144] The WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments.[189]

The FDA has granted temporary authorisation to convalescent plasma as an experimental treatment in cases where the person's life is seriously or immediately threatened. It has not undergone the clinical studies needed to show it is safe and effective for the disease.[190][191][192]

### Information technology

In February 2020, China launched a mobile app to deal with the disease outbreak.[193] Users are asked to enter their name and ID number. The app can detect 'close contact' using surveillance data and therefore a potential risk of infection. Every user can also check the status of three other users. If a potential risk is detected, the app not only recommends self-quarantine, it also alerts local health officials.[194]

Big data analytics on cellphone data, facial recognition technology, mobile phone tracking, and artificial intelligence are used to track infected people and people whom they contacted in South Korea, Taiwan, and Singapore.[195][196] In March 2020, the Israeli government enabled security agencies to track mobile phone data of people supposed to have coronavirus. According to the Israeli government, the measure was taken to enforce quarantine and protect those who may come into contact with infected citizens. The Association for Civil Rights in Israel, however, said the move was "a dangerous precedent and a slippery slope".[197] Also in March 2020, Deutsche Telekom shared aggregated phone location data with the German federal government agency, Robert Koch Institute, to research and prevent the spread of the virus.[198] Russia deployed facial recognition technology to detect quarantine breakers.[199] Italian regional health commissioner Giulio Gallera said he has been informed by mobile phone operators that "40% of people are continuing to move around anyway".[200] The German Government conducted a 48-hour weekend hackathon, which had more than 42,000 participants.[201][202] Three million people in the UK used an app developed by King's College London and Zoe to track people with COVID‑19 symptoms.[203][204] The president of Estonia, Kersti Kaljulaid, made a global call for creative solutions against the spread of coronavirus.[205]

### Psychological support

Individuals may experience distress from quarantine, travel restrictions, side effects of treatment, or fear of the infection itself. To address these concerns, the National Health Commission of China published a national guideline for psychological crisis intervention on 27 January 2020.[206][207]

The Lancet published a 14-page call for action focusing on the UK and stated conditions were such that a range of mental health issues was likely to become more common. BBC quoted Rory O'Connor in saying, "Increased social isolation, loneliness, health anxiety, stress, and an economic downturn are a perfect storm to harm people's mental health and wellbeing."[208][209]

## Prognosis

The severity of diagnosed COVID-19 cases in China[210]
Case fatality rates by age group:
China, as of 11 February 2020[211]
South Korea, as of 20 May 2020[212]
Spain, as of 18 May 2020[213]
Italy, as of 14 May 2020[214]
Case fatality rate in China depending on other health problems. Data through 11 February 2020.[211]
The number of deaths vs total cases by country and approximate case fatality rate[215]

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. 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.[44]

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years.[22] They are likely to have milder symptoms and a lower chance of severe disease than adults; in those younger than 50 years the risk of death is less than 0.5%, while in those older than 70 it is more than 8%.[216][217][218] Pregnant women may be at higher risk for severe infection with COVID‑19 based on data from other similar viruses, like Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), but data for COVID‑19 is lacking.[219][220] In China, children acquired infections mainly through close contact with their parents or other family members who lived in Wuhan or had traveled there.[216]

Some studies have found that the neutrophil to lymphocyte ratio (NLR) may be helpful in early screening for severe illness.[221]

Most of those who die of COVID‑19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease.[222] The Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 97% of people had at least one comorbidity with the average person having 2.7 diseases.[223] According to the same report, the median time between the onset of symptoms and death was ten days, with five being spent hospitalised. However, people transferred to an ICU had a median time of seven days between hospitalisation and death.[223] In a study of early cases, the median time from exhibiting initial symptoms to death was 14 days, with a full range of six to 41 days.[224] In a study by the National Health Commission (NHC) of China, men had a death rate of 2.8% while women had a death rate of 1.7%.[225] Histopathological examinations of post-mortem lung samples show diffuse alveolar damage with cellular fibromyxoid exudates in both lungs. Viral cytopathic changes were observed in the pneumocytes. The lung picture resembled acute respiratory distress syndrome (ARDS).[44] In 11.8% of the deaths reported by the National Health Commission of China, heart damage was noted by elevated levels of troponin or cardiac arrest.[45] According to March data from the United States, 89% of those hospitalised had preexisting conditions.[226]

The availability of medical resources and the socioeconomics of a region may also affect mortality.[227] Estimates of the mortality from the condition vary because of those regional differences,[228] but also because of methodological difficulties. The under-counting of mild cases can cause the mortality rate to be overestimated.[229] However, the fact that deaths are the result of cases contracted in the past can mean the current mortality rate is underestimated.[230][231] Smokers were 1.4 times more likely to have severe symptoms of COVID‑19 and approximately 2.4 times more likely to require intensive care or die compared to non-smokers.[232][233] According to a number of studies, air pollution is similarly associated with risk factors.[233] According to three scientific reviews, obesity contributes to an increased risk and poorer prognosis of COVID-19.[233][234][235]

Concerns have been raised about long-term sequelae of the disease. The Hong Kong Hospital Authority found a drop of 20% to 30% in lung capacity in some people who recovered from the disease, and lung scans suggested organ damage.[236] This may also lead to post-intensive care syndrome following recovery.[237]

Case fatality rates (%) by age and country
Age 0–9 10–19 20–29 30–39 40–49 50–59 60–69 70–79 80–89 90+
Argentina as of 7 May[238] 0.0 0.0 0.1 0.4 1.3 3.6 12.9 18.8 28.4
Australia as of 20 May[239] 0.0 0.0 0.0 0.0 0.1 0.2 1.0 4.2 17.7 40.8
Canada as of 19 May[240] 0.0 0.1 0.7 7.7 25.3
Chile as of 17 May[241] 0.0 0.5 0.8 3.4 10.4 22.3
China as of 11 February[211] 0.0 0.2 0.2 0.2 0.4 1.3 3.6 8.0 14.8
Colombia as of 20 May[242] 0.0 0.0 0.3 0.4 1.7 3.6 11.0 19.5 28.1 38.3
Denmark as of 19 May[243] 0.2 4.1 16.6 27.6 48.1
Finland as of 29 May[244] 0.0 0.0 0.2 0.8 3.8 18.1 41.1
Germany as of 21 May[245] 0.0 0.0 0.1 1.9 19.2 30.3
Israel as of 3 May[246] 0.0 0.0 0.0 0.9 0.9 3.1 9.7 22.9 30.8 31.3
Italy as of 27 May[247] 0.2 0.0 0.1 0.3 0.9 2.7 10.6 25.8 32.0 29.2
Japan as of 7 May[248] 0.0 0.0 0.0 0.1 0.3 0.6 2.5 6.8 14.8
Mexico as of 24 May[249] 3.0 0.7 1.2 2.7 7.3 13.8 23.0 30.6 34.3 32.7
Netherlands as of 20 May[250] 0.0 0.2 0.1 0.3 0.5 1.7 8.1 25.5 32.7 33.9
Norway as of 20 May[251] 0.0 0.0 0.0 0.0 0.3 0.4 2.0 9.2 22.9 57.1
Philippines as of 20 May[252] 3.1 1.2 0.5 1.1 3.3 6.7 15.4 22.4 33.0
Portugal as of 20 May[253] 0.0 0.0 0.0 0.0 0.3 0.8 3.4 10.1 19.4
South Africa as of 28 May[254] 0.3 0.1 0.1 0.4 1.1 3.8 9.2 15.0 12.3
South Korea as of 24 May[212] 0.0 0.0 0.0 0.2 0.2 0.8 2.8 10.9 26.3
Spain as of 17 May[213] 0.2 0.3 0.2 0.3 0.6 1.4 4.9 14.3 21.0 22.3
Sweden as of 20 May[255] 0.7 0.0 0.3 0.3 0.8 2.1 7.2 23.5 34.6 39.0
Switzerland as of 20 May[256] 0.0 0.0 0.0 0.1 0.1 0.6 3.3 11.5 27.9
United States
Colorado as of 20 May[257] 0.0 0.2 0.2 0.2 0.8 1.9 6.3 17.7 38.6
Connecticut as of 20 May[258] 0.2 0.1 0.1 0.4 0.9 2.2 7.6 20.0 36.1
Idaho as of 20 May[259] 0.0 0.0 0.0 0.0 0.0 0.5 3.0 9.2 30.5
Indiana as of 20 May[260] 0.2 0.1 0.3 0.7 1.9 7.2 16.9 28.3
Kentucky as of 20 May[261] 0.0 0.0 0.0 0.2 0.5 1.9 5.9 14.2 29.1
Maryland as of 20 May[262] 0.0 0.1 0.2 0.3 0.7 1.9 6.1 14.6 28.8
Massachusetts as of 20 May[263] 0.0 0.0 0.1 0.1 0.4 1.5 5.2 16.8 28.9
Minnesota as of 13 May[264] 0.0 0.0 0.0 0.1 0.3 1.6 5.4 26.9
Mississippi as of 19 May[265] 0.0 0.1 0.5 0.9 2.1 8.1 16.1 19.4 27.2
Missouri as of 19 May[266] 0.0 0.0 0.1 0.2 0.8 2.2 6.3 14.3 22.5
Nevada as of 20 May[267] 0.0 0.3 0.3 0.4 1.7 2.6 7.7 22.3
N. Hampshire as of 12 May[268] 0.0 0.0 0.4 0.0 1.2 0.0 2.2 12.0 21.2
Oregon as of 12 May[269] 0.0 0.0 0.0 0.0 0.5 0.8 5.6 12.1 28.9
Texas as of 20 May[270] 0.0 0.5 0.4 0.3 0.8 2.1 5.5 10.1 30.6
Virginia as of 19 May[271] 0.0 0.0 0.0 0.1 0.4 1.0 4.4 12.9 24.9
Washington as of 10 May[272] 0.0 0.2 1.3 9.8 31.2
Wisconsin as of 20 May[273] 0.0 0.0 0.2 0.2 0.6 2.0 5.0 14.7 19.9 30.4
Estimated prognosis by age and sex based on cases from France and Diamond Princess ship[274]
Percent of infected people who are hospitalized
0–19 20–29 30–39 40–49 50–59 60–69 70–79 80+ Total
Female 0.2
(0.1–0.3)
0.6
(0.3–0.9)
1.1
(0.7–1.8)
1.6
(0.9–2.4)
3.2
(1.9–4.9)
6.2
(3.7–9.6)
9.6
(5.7–14.8)
23.6
(14.0–36.4)
3.2
(1.9–5.0)
Male 0.2
(0.1–0.3)
0.7
(0.4–1.1)
1.4
(0.9–2.2)
1.9
(1.1–3.0)
3.9
(2.3–6.1)
8.1
(4.8–12.6)
13.4
(8.0–20.7)
45.9
(27.3–70.9)
4.0
(2.4–6.2)
Total 0.2
(0.1–0.3)
0.6
(0.4–1.0)
1.3
(0.8–2.0)
1.7
(1.0–2.7)
3.5
(2.1–5.4)
7.1
(4.2–11.0)
11.3
(6.7–17.5)
32.0
(19.0–49.4)
3.6
(2.1–5.6)
Percent of hospitalized people who go to Intensive Care Unit
0–19 20–29 30–39 40–49 50–59 60–69 70–79 80+ Total
Female 16.7
(14.4–19.2)
8.6
(7.5–9.9)
11.9
(10.9–13.0)
16.6
(15.6–17.7)
20.7
(19.8–21.7)
23.1
(22.2–24.0)
18.7
(18.0–19.5)
4.2
(4.0–4.5)
14.3
(13.9–14.7)
Male 26.9
(23.2–31.0)
14.0
(12.2–15.9)
19.2
(17.6–20.9)
26.9
(25.3–28.5)
33.4
(32.0–34.8)
37.3
(36.0–38.6)
30.2
(29.2–31.3)
6.8
(6.5–7.2)
23.1
(22.6–23.6)
Total 22.2
(19.2–25.5)
11.5
(10.1–13.2)
15.9
(14.6–17.3)
22.2
(21.0–23.5)
27.6
(26.5–28.7)
30.8
(29.8–31.8)
24.9
(24.1–25.8)
5.6
(5.3–5.9)
19.0
(18.7–19.44)
Percent of hospitalized people who die
0–19 20–29 30–39 40–49 50–59 60–69 70–79 80+ Total
Female 0.5
(0.2–1.1)
0.9
(0.5–1.3)
1.5
(1.2–1.9)
2.6
(2.3–3.0)
5.2
(4.8–5.6)
10.1
(9.5–10.6)
16.7
(16.0–17.4)
25.2
(24.4–26.0)
14.4
(14.0–14.9)
Male 0.7
(0.3–1.5)
1.3
(0.8–1.9)
2.2
(1.7–2.7)
3.8
(3.4–4.4)
7.6
(7.0–8.2)
14.8
(14.1–15.6)
24.6
(23.7–25.6)
37.1
(36.1–38.2)
21.22
(20.8–21.7)
Total 0.6
(0.3–1.3)
1.1
(0.7–1.6)
1.9
(1.5–2.3)
3.3
(2.9–3.7)
6.5
(6.0–7.0)
12.6
(12.0–13.2)
21.0
(20.3–21.8)
31.6
(30.9–32.4)
18.1
(17.8–18.4)
Percent of infected people who die – infection fatality rate (IFR)
0–19 20–29 30–39 40–49 50–59 60–69 70–79 80+ Total
Female 0.001
(<0.001–0.002)
0.005
(0.002–0.009)
0.02
(0.01–0.03)
0.04
(0.02–0.07)
0.2
(0.1–0.3)
0.6
(0.4–1.0)
1.6
(1.0–2.5)
5.9
(3.5–9.2)
0.5
(0.3–0.7)
Male 0.001
(<0.001–0.003)
0.008
(0.004–0.02)
0.03
(0.02–0.05)
0.07
(0.04–0.1)
0.3
(0.2–0.5)
1.2
(0.7–1.9)
3.3
(2.0–5.1)
17.1
(10.1–26.3)
0.8
(0.5–1.3)
Total 0.001
(<0.001–0.002)
0.007
(0.003–0.01)
0.02
(0.01–0.04)
0.06
(0.03–0.09)
0.2
(0.1–0.36)
0.9
(0.5–1.4)
2.4
(1.4–3.7)
10.1
(6.0–15.6)
0.7
(0.4–1.0)
Numbers in parentheses are 95% credible intervals for the estimates.

### Existing respiratory problems

When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms.[275] COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.[276]

### Immunity

It is unknown (as of April 2020) if past infection provides effective and long-term immunity in people who recover from the disease.[277][278] Some of the infected have been reported to develop protective antibodies, so acquired immunity is presumed likely, based on the behaviour of other coronaviruses.[279] Cases in which recovery from COVID‑19 was followed by positive tests for coronavirus at a later date have been reported.[280][281][282][283] However, these cases are believed to be lingering infection rather than reinfection,[283] or false positives due to remaining RNA fragments.[284] An investigation by the Korean CDC of 285 individuals who tested positive for SARS-CoV-2 in PCR tests administered days or weeks after recovery from COVID-19 found no evidence that these individuals were contagious at this later time.[285] Some other coronaviruses circulating in people are capable of reinfection after roughly a year.[286][287]

## History

The virus is thought to be natural and has an animal origin,[76] through spillover infection.[288] The actual origin is unknown, but the first known cases of infection happened in China. By December 2019, the spread of infection was almost entirely driven by human-to-human transmission.[211][289] A study of the first 41 cases of confirmed COVID‑19, published in January 2020 in The Lancet, revealed the earliest date of onset of symptoms as 1 December 2019.[290][291][292] Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019.[293] Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020.[294][295]

## Epidemiology

Several measures are commonly used to quantify mortality.[296] 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.[297]

The death-to-case ratio 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 6.0% (371,700/6,152,160) as of 1 June 2020.[9] The number varies by region.[298]

Other measures include the case fatality rate (CFR), which reflects the percent of diagnosed individuals who die from a disease, and the infection fatality rate (IFR), which reflects the percent of infected individuals (diagnosed and undiagnosed) who die from a disease. These statistics are not time-bound and follow a specific population from infection through case resolution. Many academics have attempted to calculate these numbers for specific populations.[299]

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing.[300][301] In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID‑19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.[300]

Total confirmed cases over time
Total deaths over time
Total confirmed cases of COVID‑19 per million people[302]
Total confirmed deaths due to COVID‑19 per million people[303]

### Infection fatality rate

Our World in Data states that, as of 25 March 2020, the infection fatality rate (IFR) cannot be accurately calculated.[304] In February, one research group estimated the IFR at 0.94%, with a confidence interval between 0.37 percent to 2.9 percent.[305] The University of Oxford Centre for Evidence-Based Medicine (CEBM) estimated a global CFR of 0.8 to 9.6 percent (last revised 30 April) and IFR of 0.10 to 0.41 percent (last revised 2 May).[306] According to CEBM, random antibody testing in Germany suggested an IFR of 0.37% (0.12% to 0.87%) there, but there have been concerns about false positives.[306][307][308][309][unreliable medical source?] Firm lower limits of infection fatality rates have been established in a number of locations. As of 7 May, in New York City, with a population of 8.4 million, 14,162 have died from COVID-19 (0.17% of the population).[310] In Bergamo province, 0.57% of the population has died.[311][312][unreliable medical source?] To get a better view on the number of people infected, initial antibody testing has been carried out, but there are no valid scientific reports based on any of them as of yet.[313][314] On 1 May antibody testing in New York suggested an IFR of 0.86%.[315]

### Sex differences

The impact of the pandemic and its mortality rate are different for men and women.[316] Mortality is higher in men in studies conducted in China and Italy.[1][317][318] The higher risk for men appears in their 50s, and begins to taper off only at 90.[318] In China, the death rate was 2.8 percent for men and 1.7 percent for women.[318] The exact reasons for this sex-difference are not known, but genetic and behavioural factors could be a reason.[316] Sex-based immunological differences, a lower 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.[318] In Europe, of those infected with COVID‑19, 57% were men; of those infected with COVID‑19 who also died, 72% were men.[319] As of April 2020, the U.S. government is not tracking sex-related data of COVID‑19 infections.[320] Research has shown that viral illnesses like Ebola, HIV, influenza, and SARS affect men and women differently.[320] A higher percentage of health workers, particularly nurses, are women, and they have a higher chance of being exposed to the virus.[321] School closures, lockdowns, and reduced access to healthcare following the COVID-19 pandemic may differentially affect the genders and possibly exaggerate existing gender disparity.[316][322]

### Ethnic differences

In the U.S., a greater proportion of deaths due to COVID-19 have occurred among African Americans.[323] Structural factors that prevent African Americans from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as public transit and health care. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death.[324] Similar issues affect Native American and Latino communities.[323] According to a U.S 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.[325] 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.[326] Leaders have called for efforts to research and address the disparities.[327]

## Society and culture

### Name

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus",[328][329][330] with the disease sometimes called "Wuhan pneumonia".[331][332] In the past, many diseases have been named after geographical locations, such as the Spanish flu,[333] Middle East Respiratory Syndrome, and Zika virus.[334]

In January 2020, the World Health Organisation recommended 2019-nCov[335] and 2019-nCoV acute respiratory disease[336] as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species or groups of people in disease and virus names to prevent social stigma.[337][338][339]

The official names COVID‑19 and SARS-CoV-2 were issued by the WHO on 11 February 2020.[340] WHO chief Tedros Adhanom Ghebreyesus explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019).[341] The WHO additionally uses "the COVID‑19 virus" and "the virus responsible for COVID‑19" in public communications.[340] Both the disease and virus are commonly referred to as "coronavirus" in the media and public discourse.

### Misinformation

After the initial outbreak of COVID‑19, conspiracy theorists spread misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease, which rapidly spread online.[342][343][344]

### Decreased emergency room use

In Austria, 39% fewer persons sought help for cardiac symptoms in the month of March. A study estimated that there were 110 incidents of preventable cardiac death as compared to 86 confirmed deaths from Coronavirus as of 29 March.[345]

A preliminary study in the U.S. found 38% under-utilization of cardiac care units as compared to normal.[346] The head of cardiology at the University of Arizona has stated, "My worry is some of these people are dying at home because they're too scared to go to the hospital."[347] There is also concern that persons with symptoms of stroke and appendicitis are delaying seeking help.[347][348]

## Other animals

Humans appear to be capable of spreading the virus to some other animals. A domestic cat in Liège, Belgium, tested positive after it started showing symptoms (diarrhoea, vomiting, shortness of breath) a week later than its owner, who was also positive.[349] Tigers and lions at the Bronx Zoo in New York, United States, tested positive for the virus and showed symptoms of COVID‑19, including a dry cough and loss of appetite.[350] Minks at two farms in the Netherlands also tested positive for COVID-19.[351]

A study on domesticated animals inoculated with the virus found that cats and ferrets appear to be "highly susceptible" to the disease, while dogs appear to be less susceptible, with lower levels of viral replication. The study failed to find evidence of viral replication in pigs, ducks, and chickens.[352]

In March 2020, researchers from the University of Hong Kong have shown that Syrian hamsters could be a model organism for COVID-19 research.[353]

## Research

No medication or vaccine is approved to treat the disease.[188] International research on vaccines and medicines in COVID‑19 is underway by government organisations, academic groups, and industry researchers.[354][355] In March, the World Health Organisation initiated the "Solidarity Trial" to assess the treatment effects of four existing antiviral compounds with the most promise of efficacy.[356] The World Health Organization suspended hydroxychloroquine from its global drug trials for COVID-19 treatments on 26 May 2020 due to safety concerns. It had previously enrolled 3,500 patients from 17 countries in the Solidarity Trial.[357] France, Italy and Belgium also banned the use of hydroxychloroquine as a COVID-19 treatment.[358]

There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand. To minimise the harm from misinformation, medical professionals and the public are advised to expect rapid changes to available information, and to be attentive to retractions and other updates.[359]

### Vaccine

There is no available vaccine, but various agencies are actively developing vaccine candidates. Previous work on SARS-CoV is being used because both SARS-CoV and SARS-CoV-2 use the ACE2 receptor to enter human cells.[360] Three vaccination strategies are being investigated. First, researchers aim to build a whole virus vaccine. The use of such a virus, be it inactive or dead, aims to elicit a prompt immune response of the human body to a new infection with COVID‑19. A second strategy, subunit vaccines, aims to create a vaccine that sensitises the immune system to certain subunits of the virus. In the case of SARS-CoV-2, such research focuses on the S-spike protein that helps the virus intrude the ACE2 enzyme receptor. A third strategy is that of the nucleic acid vaccines (DNA or RNA vaccines, a novel technique for creating a vaccination). Experimental vaccines from any of these strategies would have to be tested for safety and efficacy.[361]

On 16 March 2020, the first clinical trial of a vaccine started with four volunteers in Seattle, Washington, United States. The vaccine contains a harmless genetic code copied from the virus that causes the disease.[362]

Antibody-dependent enhancement has been suggested as a potential challenge for vaccine development for SARS-COV-2, but this is controversial.[363]

### Medications

At least 29 phase II–IV efficacy trials in COVID‑19 were concluded in March 2020, or scheduled to provide results in April from hospitals in China.[364][365] There are more than 300 active clinical trials underway as of April 2020.[131] Seven trials were evaluating already approved treatments, including four studies on hydroxychloroquine or chloroquine.[365] Repurposed antiviral drugs make up most of the Chinese research, with nine phase III trials on remdesivir across several countries due to report by the end of April.[364][365] Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.[365]

The COVID‑19 Clinical Research Coalition has goals to 1) facilitate rapid reviews of clinical trial proposals by ethics committees and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data and 4) facilitate sharing of clinical trial outcomes before publication.[366][367]

Several existing medications are being evaluated for the treatment of COVID‑19,[188] including remdesivir, chloroquine, hydroxychloroquine, lopinavir/ritonavir, and lopinavir/ritonavir combined with interferon beta.[356][368] There is tentative evidence for efficacy by remdesivir, as of March 2020.[369][370] Clinical improvement was observed in patients treated with compassionate-use remdesivir.[371] Remdesivir inhibits SARS-CoV-2 in vitro.[372] Phase III clinical trials are underway in the U.S., China, and Italy.[188][364][373]

In 2020, a trial found that lopinavir/ritonavir was ineffective in the treatment of severe illness.[374] Nitazoxanide has been recommended for further in vivo study after demonstrating low concentration inhibition of SARS-CoV-2.[372]

There are mixed results as of 3 April 2020 as to the effectiveness of hydroxychloroquine as a treatment for COVID‑19, with some studies showing little or no improvement.[375][376] One study has shown an association between hydroxychloroquine or chloroquine use with higher death rates along with other side effects.[377][378] The studies of chloroquine and hydroxychloroquine with or without azithromycin have major limitations that have prevented the medical community from embracing these therapies without further study.[131]

Oseltamivir does not inhibit SARS-CoV-2 in vitro and has no known role in COVID‑19 treatment.[131]

### Cytokine storm

A cytokine storm can be a complication in the later stages of severe COVID‑19. There is preliminary evidence that hydroxychloroquine may be useful in controlling cytokine storms in late-phase severe forms of the disease.[379]

Tocilizumab has been included in treatment guidelines by China's National Health Commission after a small study was completed.[380][381] It is undergoing a phase 2 non-randomised trial at the national level in Italy after showing positive results in people with severe disease.[382][383] 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.[384][385][386] The interleukin-6 receptor antagonist was approved by the FDA to undergo a phase III clinical trial assessing the 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.[387] To date, 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.[388]

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.[389]

The Feinstein Institute of Northwell Health announced in March a study on "a human antibody that may prevent the activity" of IL-6.[390]

### Passive antibodies

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.[391] This strategy was tried for SARS with inconclusive results.[391] Viral neutralisation is the anticipated mechanism of action by which passive antibody therapy can mediate defence against SARS-CoV-2.[392] The spike protein of SARS-CoV-2 is the primary target for neutralizing antibodies.[392] Other mechanisms, however, such as antibody-dependent cellular cytotoxicity and/or phagocytosis, may be possible.[391] Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development.[391] Production of convalescent serum, which consists of the liquid portion of the blood from recovered patients and contains antibodies specific to this virus, could be increased for quicker deployment.[393]

## Notes

1. ^ Close contact is defined as one metre (~3.3 feet) by the WHO[7] and ~1.8 metres (six feet) by the CDC.[20]
2. ^ An uncovered cough can travel up to 8.2 metres (27 feet).[21]

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