Coronavirus disease 2019

Coronavirus disease 2019 (COVID-19)
Other names	2019-nCoV acute respiratory disease Novel coronavirus pneumonia[1] Wuhan pneumonia[2][3] Wuhan coronavirus "Coronavirus" or other names for SARS-CoV-2
Symptoms of COVID-19
Pronunciation	/kəˈroʊnəˌvaɪrəs dɪˈziːz, ˈkoʊvɪd/
Specialty	Infectious diseases
Symptoms	Fever, cough, shortness of breath[4]
Complications	Pneumonia, viral sepsis, acute respiratory distress syndrome, kidney failure
Usual onset	Incubation period typically 5–6 days (may range between 2–14 days)
Causes	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Risk factors	Travel, viral exposure
Diagnostic method	rRT-PCR testing, CT scan
Prevention	Hand washing, quarantine, physical distancing
Treatment	Symptomatic and supportive
Frequency	1,013,157[5] confirmed cases
Deaths	52,863 (5.2% of confirmed cases)[5]

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).^[6] The disease was first identified in December 2019 in Wuhan, the capital of China's Hubei province, and has since spread globally, resulting in the ongoing 2019–20 coronavirus pandemic.^[7][8] Common symptoms include fever, cough, and shortness of breath.^[9] Other symptoms may include muscle pain, sputum production, diarrhea, sore throat, loss of smell, and abdominal pain.^[4][10][11] While the majority of cases result in mild symptoms, some progress to viral pneumonia and multi-organ failure.^[7][12] As of 2 April 2020, more than 1,010,000^[5] cases of COVID-19 have been reported in more than two hundred countries and territories,^[13] resulting in over 52,800 deaths.^[5] More than 210,000 people have recovered.^[5]

The virus is mainly spread during close contact,^[a] and by small droplets produced when people cough, sneeze, or talk.^[14][16][15] Respiratory droplets may be produced during breathing but the virus is not generally airborne.^[14][16] People may also contract COVID-19 by touching a contaminated surface and then their face.^[14][15] It is most contagious when people are symptomatic, although spread may be possible before symptoms appear.^[15] The virus can survive on surfaces up to 72 hours.^[17] Time from exposure to onset of symptoms is generally between two and fourteen days, with an average of five days.^[9][18] The standard method of diagnosis is by reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab.^[19] The infection can also be diagnosed from a combination of symptoms, risk factors and a chest CT scan showing features of pneumonia.^[20][21]

Recommended measures to prevent infection include frequent hand washing, social distancing (maintaining physical distance from others, especially from those with symptoms), covering coughs and sneezes with a tissue or inner elbow, and keeping unwashed hands away from the face.^[22][23] The use of masks is recommended for those who suspect they have the virus and their caregivers.^[24] Recommendations for mask use by the general public vary, with some authorities recommending against their use, some recommending their use, and others requiring their use.^[25][26][27] Currently, there is no vaccine or specific antiviral treatment for COVID-19. Management involves treatment of symptoms, supportive care, isolation, and experimental measures.^[28]

The World Health Organization (WHO) declared the 2019–20 coronavirus outbreak a Public Health Emergency of International Concern (PHEIC)^[29][30] on 30 January 2020, and a pandemic on 11 March 2020.^[8] Local transmission of the disease has been recorded in many countries across all six WHO regions.^[31]

Signs and symptoms

Those infected with the virus may be asymptomatic or develop flu-like symptoms, including fever, cough, fatigue, and shortness of breath.^[4][36][37] Emergency symptoms include difficulty breathing, persistent chest pain or pressure, confusion, difficulty waking, and bluish face or lips; immediate medical attention is advised if these symptoms are present.^[38] Less commonly, upper respiratory symptoms, such as sneezing, runny nose, or sore throat may be seen. Symptoms such as nausea, vomiting, and diarrhea have been observed in varying percentages.^[35][39][40] Some cases in China initially presented only with chest tightness and palpitations.^[41] In March 2020 there were reports indicating that loss of the sense of smell (anosmia) may be a common symptom among those who have mild disease,^[11][34] although not as common as initially reported.^[33] In some, the disease may progress to pneumonia, multi-organ failure, and death.^[7][12] In those who develop severe symptoms, time from symptom onset to needing mechanical ventilation is typically eight days.^[42]

As is common with infections, there is a delay between the moment when a person is infected with the virus and the time when they develop symptoms. This is called the incubation period. The incubation period for COVID-19 is typically five to six days but may range from two to 14 days.^[43][44] 97.5% of people who develop symptoms will do so within 11.5 days of infection.^[45]

Reports indicate that not all who are infected develop symptoms, but their role in transmission is unknown.^[46] Preliminary evidence suggests asymptomatic cases may contribute to the spread of the disease.^[47][48] The proportion of infected people who do not display symptoms is currently unknown and being studied, with South Korea's CDC reporting that 20% of all confirmed cases remained asymptomatic during their hospital stay.^[48][49]

Cause

Transmission

Respiratory droplets, produced when a man is sneezing

Play media

A video discussing the basic reproduction number and case fatality rate in the context of the pandemic

Some details about how the disease is spread are still being determined.^[16][15] The WHO and CDC state that it is primarily spread during close contact and by small droplets produced when people cough or sneeze;^[14][15] with close contact being within 1–3 m (3 ft 3 in–9 ft 10 in).^[14] A study in Singapore found that an uncovered coughing can lead to droplets travelling up to 4.5 meters (15 feet).^[50][51]

Respiratory droplets may also be produced during breathing out, including when talking. Though the virus is not generally airborne,^[14][52] The National Academy of Science has suggested that bioaerosol transmission may be possible and air collectors positioned in the hallway outside of people's rooms yielded samples positive for viral RNA.^[53] The droplets can land in the mouths or noses of people who are nearby or possibly be inhaled into the lungs.^[54] Some medical procedures such as intubation and cardiopulmonary resuscitation (CPR) may cause respiratory secretions to be aerosolised and thus result in airborne spread.^[52] It may also spread when one touches a contaminated surface, known as fomite transmission, and then touches their eyes, nose, or mouth.^[14] While there are concerns it may spread by feces, this risk is believed to be low.^[14][15]

The virus is most contagious when people are symptomatic; while spread may be possible before symptoms appear, this risk is low.^[15][14] The European Centre for Disease Prevention and Control (ECDC) states that while it is not entirely clear how easily the disease spreads, one person generally infects two to three others.^[16]

The virus survives for hours to days on surfaces.^[16][14] Specifically, the virus was found to be detectable for one day on cardboard, for up to three days on plastic and stainless steel, and for up to four hours on copper.^[55] This, however, varies based on the humidity and temperature.^[56] Surfaces may be decontaminated with a number of solutions (within one minute of exposure to the disinfectant for a stainless steel surface), including 62–71% ethanol, 50–100% isopropanol, 0.1% sodium hypochlorite, 0.5% hydrogen peroxide, and 0.2–7.5% povidone-iodine. Other solutions, such as benzalkonium chloride and chrohexidine gluconate, are less effective.^[57]

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.^[58] All features of the novel SARS-CoV-2 virus occur in related coronaviruses in nature.^[59]

Outside the human body, the virus is killed by household soap, which bursts its protective bubble.^[60]

SARS-CoV-2 is closely related to the original SARS-CoV.^[61] It is thought to have a 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).^[62][63] In February 2020, Chinese researchers found that there is only one amino acid difference in certain parts of the genome sequences between the viruses from pangolins and those from humans, however, whole-genome comparison to date found at most 92% of genetic material shared between pangolin coronavirus and SARS-CoV-2, which is insufficient to prove pangolins to be the intermediate host.^[64]

Pathophysiology

The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme ACE2, which is most abundant in the type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell.^[65] The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and some have suggested that decreasing ACE2 activity might be protective,^[66][67] though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective and that these hypotheses need to be tested.^[68] As the alveolar disease progresses, respiratory failure might develop and death may follow.^[67]

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium^[69] as well as endothelial cells and enterocytes of the small intestine.^[70]

Diagnosis

CDC rRT-PCR test kit for COVID-19^[71]

The WHO has published several testing protocols for the disease.^[72] The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR).^[73] The test is typically done on respiratory samples obtained by a nasopharyngeal swab, however a nasal swab or sputum sample may also be used.^[19][74] Results are generally available within a few hours to two days.^[75][76] Blood tests can be used, but these require two blood samples taken two weeks apart and the results have little immediate value.^[77] 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.^[7][78][79] As of 19 March 2020,^[80] there were no antibody tests though efforts to develop them are ongoing.^[81] The FDA approved the first point-of-care test on 21 March 2020 for use at the end of that month.^[82]

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.^[20]

A March 2020 review concluded that chest X-rays are of little value in early stages, whereas CT scans of the chest are useful even before symptoms occur.^[60] Typical features on CT include bilateral multilobar ground-glass opacificities with a peripheral, asymmetric and posterior distribution.^[60] Subpleural dominance, crazy paving^{[clarification needed]} and consolidation develop as the disease evolves.^[83] As of March 2020, the American College of Radiology recommends that "CT should not be used to screen for or as a first-line test to diagnose COVID-19".^[84]

• 

  Typical CT imaging findings

• 

  CT imaging of rapid progression stage

Pathology

Few data are available about microscopic lesions and the pathophysiology of COVID-19.^[85][86] The main pathological findings at autopsy are:

• Macroscopy: pleurisy, pericarditis, lung consolidation and pulmonary oedema
• Four types of severity of viral pneumonia can be observed:
  • minor pneumonia: minor serous exudation, minor fibrin exudation
  • mild pneumonia: pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation
  • severe pneumonia: diffuse alveolar damage (DAD) with diffuse alveolar exudates. This diffuse DAD is responsible of the acute respiratory distress syndrome (ARDS) and severe hypoxemia observed in this disease.
  • healing pneumonia: organization of exudates in alveolar cavities, and pulmonary interstitial fibrosis
  • plasmocytosis in BAL^[87]
• Blood: disseminated intravascular coagulation (DIC) ^[88]; leukoerythroblastic reaction^[89]
• Liver: microvesicular steatosis

Prevention

An illustration of the effect of spreading out infections over a long period of time, known as flattening the curve; decreasing peaks allows healthcare services to better manage the same volume of patients.^[90][91][92]

Alternatives to flattening the curve^[93][94]

Preventive measures to reduce the chances of infection include staying at home, avoiding crowded places, washing hands with soap and water often and for at least 20 seconds, practicing good respiratory hygiene and avoiding touching the eyes, nose, or mouth with unwashed hands.^[95][96][97] 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.^[95] They also recommend proper hand hygiene after any cough or sneeze.^[95] Social distancing strategies aim to reduce contact of infected persons with large groups by closing schools and workplaces, restricting travel, and canceling mass gatherings.^[98] Social distancing also includes that people stay at least six feet apart (1.83 meters).^[99]

Because a vaccine against SARS-CoV-2 is not expected to become available until 2021 at the earliest,^[100] a key part of managing the COVID-19 pandemic is trying to decrease the epidemic peak, known as "flattening the curve", through various measures seeking to reduce the rate of new infections.^[91] Slowing the infection rate helps decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until therapeutics or a vaccine become available.^[91]

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.^[101] Some countries also recommend healthy individuals to wear face masks, including China,^[102] Hong Kong,^[103] Thailand,^[104] Czech Republic,^[105] and Austria.^[106] In order to meet the need for masks, the WHO estimates that global production will need to increase by 40%. Hoarding and speculation have worsened the problem, with the price of masks increasing sixfold, N95 respirators tripled, and gowns doubled.^[107] Some health experts consider wearing non-medical grade masks and other face coverings like scarves or bandanas a good way to prevent people from touching their mouths and noses, even if non-medical coverings would not protect against a direct sneeze or cough from an infected person.^[108]

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.^[109][110] 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.^[95]

For areas where commercial hand sanitisers are not readily available, 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.^[111]

• 

  Prevention efforts are multiplicative, with effects far beyond that of a single spread. Each avoided case leads to more avoided cases down the line, which in turn can stop the outbreak in its tracks.

• Play media

  Handwashing instructions

Management

Four steps to putting on personal protective equipment^[112]

People are managed with supportive care, which may include fluid, oxygen support, and supporting other affected vital organs.^{[113][114][115]} The CDC recommends that those who suspect they carry the virus wear a simple face mask.^[24] Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.^[116][117]

The WHO and Chinese National Health Commission have published recommendations for taking care of people who are hospitalised with COVID-19.^[118][119] Intensivists and pulmonologists in the U.S. have compiled treatment recommendations from various agencies into a free resource, the IBCC.^[120][121]

Medications

Some medical professionals recommend paracetamol (acetaminophen) over ibuprofen for first-line use.^{[122][123][124]} The WHO does not oppose the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for symptoms,^[125] and the FDA says currently there is no evidence that NSAIDs worsen COVID-19 symptoms.^[126]

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.^{[127][128][129]} Steroids such as methylprednisolone are not recommended unless the disease is complicated by acute respiratory distress syndrome.^[130][131]

Personal protective equipment

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.^[132] For healthcare professionals caring for people with COVID19, the CDC recommends placing the person in an Airborne Infection Isolation Room (AIIR) in addition to using standard precautions, contact precautions, and airborne precautions.^[133]

CDC outlines the specific guidelines for the use of personal protective equipment (PPE) during the pandemic. The recommended gear includes:

• respirator or facemask^[134][135]
• gown^{[citation needed]}
• medical gloves^[136][137]
• eye protection^[138]

When available, respirators (instead of facemasks) are preferred.^[139] 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.^[140] When masks are not available the CDC recommends using face shields, or as a last resort homemade masks.^[141]

Mechanical ventilation

Most cases of COVID-19 are not severe enough to require mechanical ventilation (artificial assistance to support breathing), but a percentage of cases do.^[142][143] Some Canadian doctors recommend the use of invasive mechanical ventilation because this technique limits the spread of aerosolised transmission vectors.^[142] Severe cases are most common in older adults (those older than 60 years^[142] and especially those older than 80 years).^[144] 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 hospitalization.^[145] This limited capacity is a significant driver of the need to flatten the curve (to keep the speed at which new cases occur and thus the number of people sick at one point in time lower).^[145] One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died.^[116] Around 20–30% of the people in hospital with pneumonia from COVID19 needed ICU care for respiratory support.^[146] A number of organisations are using 3D printing to produce various needed equipment.^[147]

Acute respiratory distress syndrome

Mechanical ventilation becomes more complex as ARDS develops in COVID-19 and oxygenation becomes increasingly difficult.^[148] Ventilators capable of pressure control modes and high PEEP^[149] are needed to maximise oxygen delivery while minimizing the risk of ventilator-associated lung injury and pneumothorax.^[150] High PEEP may not be available on older ventilators.

Experimental treatment

No medications are approved to treat the disease by the WHO although some are recommended by individual national medical authorities.^[151] Research into potential treatments started in January 2020,^[152] and several antiviral drugs are in clinical trials.^[153][154] Although new medications may take until 2021 to develop,^[155] several of the medications being tested are already approved for other uses, or are already in advanced testing.^[151] Antiviral medication may be tried in people with severe disease.^[113] The WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments.^[156]

Information technology

In February 2020, China launched a mobile app to deal with the disease outbreak.^[157] Users are asked to enter their name and ID number. The app is able to 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.^[158]

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.^[159][160] In March 2020, the Israeli government enabled security agencies to track mobile phone data of people supposed to have coronavirus. The measure was taken to enforce quarantine and protect those who may come into contact with infected citizens.^[161] Also in March 2020, Deutsche Telekom shared aggregated phone location data with the German federal government agency, Robert Koch Institute, in order to research and prevent the spread of the virus.^[162] Russia deployed facial recognition technology to detect quarantine breakers.^[163] 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".^[164] German government conducted a 48 hours weekend hackathon with more than 42.000 participants.^[165][166] Also the president of Estonia, Kersti Kaljulaid, made a global call for creative solutions against the spread of coronavirus.^[167]

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.^[168][169]

Prognosis

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The severity of diagnosed COVID-19 cases in China^[170]

Case fatality rates by age group in China. Data through 11 February 2020.^[171]

Case fatality rate in China depending on other health problems. Data through 11 February 2020.^[171]

The number of deaths vs total cases by country and approximate case fatality rate

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.^[32]

Children are susceptible to the disease, but 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%.^[172][173] Pregnant women may be at higher risk for severe infection with COVID-19 based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.^[174][175]

In some people, COVID-19 may affect the lungs causing pneumonia. In those most severely affected, COVID-19 may rapidly progress to acute respiratory distress syndrome (ARDS) causing respiratory failure, septic shock, or multi-organ failure.^[176][177] Complications associated with COVID-19 include sepsis, abnormal clotting, and damage to the heart, kidneys, and liver. Clotting abnormalities, specifically an increase in prothrombin time, have been described in 6% of those admitted to hospital with COVID-19, while abnormal kidney function is seen in 4% of this group.^[178] Liver injury as shown by blood markers of liver damage is frequently seen in severe cases.^[179]

Some studies have found that the neutrophil to lymphocyte ratio (NLR) may be helpful in early screening for severe illness.^[180]

Many of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease.^[181] The Istituto Superiore di Sanità (ISS) reported that 88% of overall deaths in Italy had at least one comorbidity.^[182] An additional report by the ISS reported that out of 10.4% of deaths where medical charts were available for review, there were at least one comorbidity in 97.9% of sampled patients with the average patient having 2.7 diseases.^[183] According to the same report, the median time between onset of symptoms and death was nine days, with five being spent hospitalised. However, patients transferred to an ICU had a median time of six days between hospitalization and death.^[183] 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.^[184] 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%.^[185] 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).^[32] 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.^[41]

Availability of medical resources and the socioeconomics of a region may also affect mortality.^[186] Estimates of the mortality from the condition vary because of those regional differences,^[187] but also because of methodological difficulties. The under-counting of mild cases can cause the mortality rate to be overestimated.^[188] However, the fact that deaths are the result of cases contracted in the past can mean the current mortality rate is underestimated.^[189][190]

Reinfection

As of March 2020, it was unknown if past infection provides effective and long-term immunity in people who recover from the disease.^[191] Immunity is seen as likely, based on the behaviour of other coronaviruses,^[192] but cases in which recovery from COVID-19 have been followed by positive tests for coronavirus at a later date have been reported.^[193][194] It is^[when?] unclear if these cases are the result of reinfection, relapse, or testing error.^{[citation needed]}

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.^[195]

History

The virus is thought to be natural and have an animal origin,^[200][201] through spillover infection.^[202] The origin is unknown but by December 2019 the spread of infection was almost entirely driven by human-to-human transmission.^[171][203] The earliest reported infection has been unofficially reported to have occurred on 17 November 2019 in Wuhan, China.^[204] 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.^{[205][206][207]} Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019.^[204]

Epidemiology

Several measures are commonly used to quantify mortality.^[208] These numbers vary by region and over time, and are influenced by the volume of testing, healthcare system quality, treatment options, time since initial outbreak, and population characteristics such as age, sex, and overall health.^[209] In late 2019, WHO assigned the 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.^[210]

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 5.2% (52,863/1,013,157) as of 2 April 2020.^[5] The number varies by region.^[211]

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. A number of academics have attempted to calculate these numbers for specific populations.^[212]

• 

  Total confirmed cases over time

• 

  Total deaths over time

• 

  Total confirmed cases of COVID-19 per million people, 20 March 2020^[213]

• 

  Total confirmed deaths due to COVID-19 per million people, 24 March 2020^[214]

Society and culture

Terminology

The World Health Organization announced in February 2020 that COVID-19 is the official name of the disease. World Health Organization chief Tedros Adhanom Ghebreyesus explained that CO stands for corona, VI for virus and D for disease, while 19 is for when the outbreak was first identified: 31 December 2019.^[215] The name had been chosen to avoid references to a specific geographical location (i.e. China), animal species, or group of people, in line with international recommendations for naming aimed at preventing stigmatisation.^[216][217]

While the disease is named COVID-19, the virus that causes it is named severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2.^[218] The virus was initially referred to as the 2019 novel coronavirus or 2019-nCoV.^[219] The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.^[218] Coronaviruses were named in 1968 for their appearance in electron micrographs which was reminiscent of the solar corona, corona meaning crown in Latin.^{[220][221][222]}

In February 2020, the World Health Organization advised the public to not refer to coronavirus as the "Chinese virus" or "Wuhan virus".^{[223][224][225][226]} Even more controversial terms, such as "Wuflu" and "Kung Flu", also emerged in the United States during this period (outside the community of medical professionals) as offensive ways of describing COVID-19. These terms are linked to Wuhan, where the virus was first detected, or China in general, via portmanteau with terms from traditional Chinese Martial Arts, Wushu and Kung Fu. Use of these terms (popularised in social media and alt-right sources) not only downplays the seriousness of the deadly disease but also misinforms by suggesting it is a strain of influenza (when it is not a flu), while simultaneously mocking Chinese culture. It also implies that the pandemic is China's fault, when actually thousands of Chinese suffered and died from COVID-19, especially in Wuhan.^[227][228]

Misinformation

The disease does not spread by shop items that have the name of "Corona" on them and products from China are not necessarily at risk of giving the disease either.^[229][230]

Research

Because of its key role in the transmission and progression of SARS-CoV-2, ACE2 has been the focus of a significant proportion of research and various therapeutic approaches have been suggested.^[67] Personal hygiene, and a healthy lifestyle and diet have been recommended to improve immunity.^[231]

Vaccine

There is no available vaccine, but research into developing a vaccine has been undertaken by various agencies. Previous work on SARS-CoV is being utilised because SARS-CoV-2 and SARS-CoV both use the ACE2 receptor to enter human cells.^[232] There are three vaccination strategies 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.^[233]

On 16 March 2020, the first clinical trial of a vaccine started with four volunteers in Seattle. The vaccine contains a harmless genetic code copied from the virus that causes the disease.^[234]

Antivirals

Several existing antiviral medications are being evaluated for treatment of COVID-19 and some have moved into clinical trials.^[151] In March 2020, WHO launched a multi-country trial involving 10 countries called "Solidarity" in response to COVID-19 pandemic. Remdesivir, chloroquine and hydroxychloroquine, lopinavir/ritonavir, and lopinavir/ritonavir combined with interferon beta are the experimental treatments currently being researched under Solidarity Trial.^[235][236]

There is tentative evidence for remdesivir as of March 2020.^[237] Remdesivir inhibits SARS-CoV-2 in vitro.^[238] Phase 3 clinical trials are being conducted in the U.S., China, and Italy.^{[151][239][240]}

Chloroquine, previously used to treat malaria, was studied in China in February 2020, with positive preliminary results.^[241] However, there are calls for peer review of the research.^[242] The Guangdong Provincial Department of Science and Technology and the Guangdong Provincial Health and Health Commission issued a report stating that chloroquine phosphate "improves the success rate of treatment and shortens the length of person's hospital stay" and recommended it for people diagnosed with mild, moderate and severe cases of novel coronavirus pneumonia.^[243]

On 17 March, the Italian Pharmaceutical Agency included chloroquine and hydroxychloroquine in the list of drugs with positive preliminary results for treatment of COVID-19.^[244] Korean and Chinese Health Authorities recommend the use of chloroquine.^[245][246] However, the Wuhan Institute of Virology, while recommending a daily dose of one gram, notes that twice that dose is highly dangerous and could be lethal. On 28 March 2020, the FDA issued an emergency use authorization for hydroxychloroquine and chloroquine at the discretion of physicians treating people with COVID-19.^[247][248]

The Chinese 7th edition guidelines also include interferon, ribavirin, or umifenovir for use against COVID-19.^[246]

In 2020, a trial found that lopinavir/ritonavir was ineffective in the treatment of severe illness.^[249] Nitazoxanide has been recommended for further in vivo study after demonstrating low concentration inhibition of SARS-CoV-2.^[238]

Studies have demonstrated that initial spike protein priming by transmembrane protease serine 2 (TMPRSS2) is essential for entry of SARS-CoV-2 via interaction with the ACE2 receptor.^[250][251] These findings suggest that the TMPRSS2 inhibitor camostat approved for use in Japan for inhibiting fibrosis in liver and kidney disease might constitute an effective off-label treatment.^[250]

In February 2020, favipiravir was being studied in China for experimental treatment of the emergent COVID-19 disease.^[252][253]

Anti-cytokine storm

Cytokine storm, a life-threatening medical condition, can be a complication in the later stages of severe COVID-19. There is evidence that hydroxychloroquine has anti-cytokine storm properties.^[254]

Tocilizumab has been included in treatment guidelines by China's National Health Commission after a small study was completed.^[255][256] It is undergoing a phase 2 non randomised test at the national level in Italy after showing positive results in people with severe disease.^{[244][257][258][unreliable medical source?]} Combined with a serum ferritin blood test to identify cytokine storms, it is meant to counter such developments, which are thought to be the cause of death in some affected people.^{[259][260][261]} The interleukin-6 receptor antagonist was approved by the FDA for treatment against cytokine release syndrome induced by a different cause, CAR T cell therapy, in 2017.^{[262][unreliable medical source?]}

The Feinstein Institute of Northwell Health announced in March a study on "a human antibody that may prevent the activity" of IL-6.^[263]

Passive antibody therapy

Transferring donated blood containing 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 immunisation.^[264] This strategy was tried for SARS.^[264] Viral neutralization is the anticipated mechanism of action by which passive antibody therapy can mediate defense against SARS-CoV-2. Other mechanisms however, such as antibody-dependent cellular cytotoxicity and/or phagocytosis, may be possible.^[264] Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development.^[264] 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.^[265]

See also

• Coronavirus diseases, a group of closely related syndromes
• Li Wenliang, a doctor at Central Hospital of Wuhan, who later contracted and died of COVID-19 after raising awareness of the spread of the virus.
• Disease X, a World Health Organisation term

References

Further reading

• Guo YR, Cao QD, Hong ZS, et al. (March 2020). "The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status". Mil Med Res. 7 (1): 11. doi:10.1186/s40779-020-00240-0. PMC 7068984. PMID 32169119.

External links

Scholia has a topic profile for Coronavirus disease 2019.

Health agencies:

• Coronavirus disease (COVID-19) by the World Health Organization
• Coronavirus 2019 (COVID-19) by the U.S. Centers for Disease Control and Prevention

Directories:

• COVID-19 at Curlie
• COVID-19 Resource Directory on OpenMD

Medical journals:

• Coronavirus Disease 2019 (COVID-19) by JAMA
• Coronavirus: News and Resources by the BMJ Publishing Group
• Novel Coronavirus Information Center by Elsevier
• COVID-19 Resource Centre by The Lancet
• SARS-CoV-2 and COVID-19 by Nature
• Coronavirus (Covid-19) by the New England Journal of Medicine
• Covid-19: Novel Coronavirus by Wiley Publishing

Other:

• Epidemiology simulator

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