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Coronavirus disease 2019

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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
COVID-19 symptoms
Symptoms of COVID-19
Pronunciation
Specialty Infectious diseases
Symptoms Fever, cough, shortness of breath[4]
Complications Pneumoniaviral sepsisacute respiratory distress syndromekidney 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 testingCT scan
Prevention Hand washingquarantinephysical distancing
Treatment Symptomatic and supportive
Frequency 755,591[5] confirmed cases
Deaths 36,873[5] (4.6% of confirmed cases)

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 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 fevercough, and shortness of breath.[9] Other symptoms may include muscle painsputum production, diarrheasore throatloss of smell, and abdominal pain.[4][10][11] While the majority of cases result in mild symptoms, some progress to pneumonia and multi-organ failure.[7][12] As of March 28, 2020, the overall rate of deaths per number of diagnosed cases is 4.6 percent; ranging from 0.2 percent to 15 percent according to age group and other health problems.[13]

The virus is mainly spread during close contact and via respiratory droplets produced when people cough or sneeze.[14][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 washingsocial 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 by some national health authorities for those who suspect they have the virus and their caregivers, but not for the general public, although simple cloth masks may be used by those who desire them.[24][25] There is no vaccine or specific antiviral treatment for COVID-19. Management involves treatment of symptomssupportive careisolation, and experimental measures.[26]

The World Health Organization (WHO) declared the 2019–20 coronavirus outbreak a Public Health Emergency of International Concern (PHEIC) on 30 January 2020[27][28] and a pandemic on 11 March 2020.[8] Local transmission of the disease has been recorded in many countries across all six WHO regions.[29]

Signs and symptoms

Symptom[30] %
Fever 87.9
Dry cough 67.7
Fatigue 38.1
Sputum production 33.4
Loss of smell 15[31] to 30[11][32]
Shortness of breath 18.6
Muscle or joint pain 14.8
Sore throat 13.9
Headache 13.6
Chills 11.4
Nausea or vomiting 5.0
Nasal congestion 4.8
Diarrhoea 3.7 to 31[33]
Haemoptysis 0.9
Conjunctival congestion 0.8

Those infected with the virus may be asymptomatic or develop flu-like symptoms, including fever, cough, fatigue, and shortness of breath.[4][34][35] 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.[36] Less commonly, upper respiratory symptoms, such as sneezingrunny nose, or sore throat may be seen. Symptoms such as nauseavomiting, and diarrhea have been observed in varying percentages.[33][37][38] Some cases in China initially presented only with chest tightness and palpitations.[39] 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][32] although not as common as initially reported.[31] In some, the disease may progress to pneumoniamulti-organ failure, and death.[7][12] In those who develop severe symptoms, time from symptom onset to needing mechanical ventilation is typically eight days.[40]

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.[41][42] 97.5% of people who develop symptoms will do so within 11.5 days of infection.[43]

Cause

The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[44] It is primarily spread between people during close contact and via respiratory droplets from coughs and sneezes.[45] A study investigating the rate of decay of the virus found no viable viruses after four hours on copper, 24 hours on cardboard, 72 hours on stainless steel, and 72 hours on plastic. However, detection rates did not reach 100% and varied between surface type (limit of detection was 3.33×100.5 TCID50 per liter of air for aerosols, 100.5 TCID50 per milliliter of medium for plastic, steel, and cardboard, and 101.5 TCID50 per milliliter of medium for copper). Estimation of the rate of decay with a Bayesian regression model suggests that viruses may remain viable up to 18 hours on copper, 55 hours on cardboard, 90 hours on stainless steel, and over 100 hours on plastic. The virus remained viable in aerosols throughout the time of the experiment (three hours).[46] The virus has also been found in faeces, and transmission through faeces is being researched.[47][48]

The disease spreads faster where people are close together or travel between areas. Travel restrictions can reduce the basic reproduction number from 2.35 to 1.05, allowing the epidemic to be more manageable.[49]

An observational study of nine people found no vertical transmission from mother to the newborn.[50]

The virus has been found in the faeces of as many as 53%[47] of hospitalised people and more anal swab positives have been found than oral swab positives in the later stages of infection.[51] The virus was found in faeces from one to twelve days, and seventeen percent of patients continued to present the virus in faeces after no longer presenting them in respiratory samples, indicating that the viral gastrointestinal infection and the potential fecal-oral transmission can last even after viral clearance in the respiratory tract.[47] Reoccurrence of the virus has also been detected through anal swabs suggesting a shift from more oral positive during the early stages of the disease to more anal positive during later periods.[51]

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.[52] 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,[53][54] though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective and that these hypotheses need to be tested.[55] As the alveolar disease progresses, respiratory failure might develop and death may follow.[54]

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastricduodenal and rectal epithelium[47] as well as endothelial cells and enterocytes of the small intestine.[56]

Diagnosis

CDC rRT-PCR test kit for COVID-19[57]

The WHO has published several testing protocols for the disease.[58] The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR).[59] 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][60] Results are generally available within a few hours to two days.[61][62] Blood tests can be used, but these require two blood samples taken two weeks apart and the results have little immediate value.[63] Chinese scientists were able to isolate a strain of the coronavirus and publish the genetic sequence so that laboratories across the world could independently develop polymerase chain reaction (PCR) tests to detect infection by the virus.[7][64][65] As of 19 March 2020,[66] there were no antibody tests though efforts to develop them are ongoing.[67] The FDA approved the first point-of-care test on 21 March 2020 for use at the end of that month.[68]

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 Xrays are of little value in early stages, whereas CT scans of the chest are useful even before symptom occur.[69] Typical features on CT include bilateral multilobar ground-glass opacificities with a peripheral, asymmetric and posterior distribution.[69] Subpleural dominancecrazy paving[clarification needed] and consolidation develop as the disease evolves.[70] 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”.[71]

Pathology

Few data are available about microscopic lesions and the pathophysiology of COVID-19.[72][73] The main pathological findings at autopsy are:

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.[75][76][77]

Alternatives to flattening the curve[78][79]

Preventive measures to reduce the chances of infection include staying at home, avoiding crowded places, washing hands with soap and warm water often and for at least 20 seconds, practicing good respiratory hygiene and avoiding touching the eyes, nose, or mouth with unwashed hands.[80][81][82] 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.[80] They also recommend proper hand hygiene after any cough or sneeze.[80] Social distancing strategies aim to reduce contact of infected persons with large groups by closing schools and workplaces, restricting travel, and canceling mass gatherings.[83] Social distancing also includes that people stay at least six feet apart (about 1.80 meters).[84]

Because a vaccine against SARS-CoV-2 is not expected to become available until 2021 at the earliest,[85] 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.[76] 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.[76]

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.[86] Some countries also recommend healthy individuals to wear face masks, particularly China,[87] Hong Kong[88] and Thailand.[89] 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.[90] 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.[91]

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.[92][93] 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 sanitizer with at least 60% alcohol, but only when soap and water are not readily available.[80]

For areas where commercial hand sanitizers are not readily available, WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanolHydrogen 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.[94]

Management

Four steps to putting on personal protective equipment[95]

People are managed with supportive care, which may include fluid, oxygen support, and supporting other affected vital organs.[96][97][98] 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.[99][100]

The WHO and Chinese National Health Commission have published recommendations for taking care of people who are hospitalised with COVID-19.[101][102] Intensivists and pulmonologists in the US have compiled treatment recommendations from various agencies into a free resource, the IBCC.[103][104]

Medications

Some medical professionals recommend paracetamol (acetaminophen) over ibuprofen for first-line use.[105][106][107] The WHO does not oppose the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for symptoms,[108] and the FDA states that currently there is no evidence that NSAIDs worsen COVID-19 symptoms.[109]

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.[110][111][112] Steroids such as methylprednisolone are not recommended unless the disease is complicated by acute respiratory distress syndrome.[113][114]

Personal protective equipment

Precautions must be taken to minimize the risk of virus transmission, especially in healthcare settings when performing procedures that can generate aerosols, such as intubation or hand ventilation.[115]

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

When available, respirators (instead of facemasks) are preferred.[121] N95 respirators are approved for industrial settings but the FDA has authorized 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.[122] When masks are not available the CDC recommends using face shields, or as a last resort homemade masks.[123]

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.[124][125] Some Canadian doctors recommend the use of invasive mechanical ventilation because this technique limits the spread of aerosolized transmission vectors.[124] Severe cases are most common in older adults (those older than 60 years[124] and especially those older than 80 years).[126] 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.[127] 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).[127] One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died.[99] Around 20-30% of the people in hospital with pneumonia from COVID19 needed ICU care for respiratory support.[128] A number of organizations are using 3D printing to produce various needed equipment.[129]

Acute respiratory distress syndrome

Mechanical ventilation becomes more complex as ARDS develops in COVID-19 and oxygenation becomes more difficult.[130] Ventilators capable of pressure control modes and high PEEP[131] (often unavailable on older and transport ventilators) are needed to maximize oxygen delivery while minimizing the risk of ventilator-associated lung injury and pneumothorax.[132]

Options for ARDS[130]
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
Inhaled nitrous oxide 5-20 ppm
Fluid management Goal is a negative balance of 1/2-1L per day
Antibiotics For secondary bacterial infections
Glucocorticoids Not recommended

Experimental treatment

No medications are approved to treat the disease by the WHO although some are recommended by individual national medical authorities.[133] Research into potential treatments started in January 2020,[134] and several antiviral drugs are in clinical trials.[135][136] Although new medications may take until 2021 to develop,[137] several of the medications being tested are already approved for other uses, or are already in advanced testing.[133] Antiviral medication may be tried in people with severe disease.[96] The WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments.[138]

Information technology

In February 2020, China launched a mobile app to deal with the disease outbreak.[139] 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.[140]

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.[141][142] 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.[143] 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.[144] Russia deployed facial recognition technology to detect quarantine breakers.[145] Italian regional health commissioner Giulio Gallera said that he has been informed by mobile phone operators that “40% of people are continuing to move around anyway”.[146] German government conducted a 48 hours weekend hackathon with more than 42.000 participants.[147][148] Also the president of Estonia, Kersti Kaljulaid, made a global call for creative solutions against the spread of coronavirus.[149]

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.[150][151]

Prognosis

The severity of diagnosed cases in China
The severity of diagnosed COVID-19 cases in China[152]
3D Medical Animation Still Shot graph showing Case Fatality rates by age group from SARS-COV-2 in China.
Case fatality rates by age group in China. Data through 11 February 2020.[153]
Case fatality rate depending on other health problems
Case fatality rate in China depending on other health problems. Data through 11 February 2020.[153]
Case fatality rate by country and number of cases
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.[30]

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%.[154][155] 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.[156][157]

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.[158][159] Complications associated with COVID-19 include sepsisabnormal 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.[160] Liver injury as shown by blood markers of liver damage is frequently seen in severe cases.[161]

Some studies have found that the neutrophil to lymphocyte ratio (NLR) may be helpful in early screening for severe illness.[162]

Many of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertensiondiabetes mellitus, and cardiovascular disease.[163] The Istituto Superiore di Sanità (ISS) reported that 88% of overall deaths in Italy had at least one comorbidity.[164] 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.[165] According to the same report, the median time between onset of symptoms and death was nine days, with five being spent hospitalized. However, patients transferred to an ICU had a median time of six days between hospitalization and death.[165] 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.[166] 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%.[167] 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).[30] 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.[39]

Availability of medical resources and the socioeconomics of a region may also affect mortality.[168] Estimates of the mortality from the condition vary because of those regional differences,[169] but also because of methodological difficulties. The under-counting of mild cases can cause the mortality rate to be overestimated.[170] However, the fact that deaths are the result of cases contracted in the past can mean the current mortality rate is underestimated.[171][172]

Reinfection

It is unknown if past infection provides effective and long-term immunity in people who recover from the disease.[173] Immunity is likely, based on the behaviour of other coronaviruses,[174] but cases in which recovery from COVID-19 have been followed by positive tests for coronavirus at a later date have been reported.[175][176] It is 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.[177]

 
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+
China as of 11 February[153] 0.0 0.2 0.2 0.2 0.4 1.3 3.6 8.0 14.8
Italy as of 26 March[164] 0.0 0.0 0.0 0.3 0.7 1.7 5.7 16.9 24.4
Netherlands as of 27 March[178] 0.0 0.0 0.0 0.0 0.0 0.3 3.7 9.3 19.1
South Korea as of 30 March[179] 0.0 0.0 0.0 0.1 0.1 0.6 1.7 7.0 18.3
Spain as of 26 March[180] 0.0 0.3 0.2 0.2 0.4 0.6 2.1 5.7 15.3
 
Case fatality rates (%) by age in the United States
Age 0-19 20-44 45-54 55-64 65-74 75-84 ≥85
United States as of 16 March[181] 0.0 0.1

0.2
0.5

0.8
1.4

2.6
2.7

4.9
4.3

10.5
10.4

27.3
Note: The lower bound includes all cases. The upper bound excludes cases that were missing data.

History

The virus is thought to be natural and have an animal origin,[182][183] through spillover infection.[184] The origin is unknown but by December 2019 the spread of infection was almost entirely driven by human-to-human transmission.[153][185] The earliest known infection occurred on 17 November 2019 in Wuhan, China.[186]

Epidemiology

Several measures are commonly used to quantify mortality.[187] 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.[188]

The death-to-case ratio reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on WHO statistics, the global death-to-case ratio was 4.7% (29,957 / 634,835) as of 29 March.[189] The number varies by region.[190]

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.[191]

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 coronaVI for virus and D for disease, while 19 is for the year that the outbreak was first identified; 31 December 2019.[194] 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.[195][196]

While the disease is named COVID-19, the virus that causes it is named severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2.[197] The virus was initially referred to as the 2019 novel coronavirus or 2019-nCoV.[198] The WHO additionally uses “the COVID-19 virus” and “the virus responsible for COVID-19” in public communications.[197] Coronaviruses were named in 1968 for their appearance in electron micrographs which was reminiscent of the solar coronacorona meaning crown in Latin.[199][200][201]

In February 2020, the World Health Organization advised the public to not refer to Coronavirus as the “Chinese virus” or “Wuhan virus”.[202][203][204][205] 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 ArtsWushu and Kung Fu. Use of these terms (popularized 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 aggressive gift to the world, when actually thousands of Chinese suffered and died from COVID-19, especially in Wuhan.[206][207]

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.[54] Personal hygiene, and a healthy lifestyle and diet have been recommended to improve immunity.[208]

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.[209] 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.[210]

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.[211]

Antivirals

Several existing antiviral medications are being evaluated for treatment of COVID-19 and some have moved into clinical trials.[133] In March 2020, WHO launched a multi-country trial involving 10 countries called “Solidarity” in response to COVID-19 pandemic. Remdesivirchloroquine and hydroxychloroquinelopinavir/ritonavir and lopinavir/ritonavir combined with interferon beta are the experimental treatments currently being researched under Solidarity Trial.[212][213]

There is tentative evidence for remdesivir as of March 2020.[214] Remdesivir inhibits SARS-CoV-2 in vitro.[215] Phase 3 clinical trials are being conducted in the US, in China, and in Italy.[133][216][217]

Chloroquine, previously used to treat malaria, was studied in China in February 2020, with positive preliminary results.[218] However, there are calls for peer review of the research.[219] 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.[220]

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.[221] Korean and Chinese Health Authorities recommend the use of chloroquine.[222][223] 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. As of 20 March 2020, the treatment has not yet been approved by the U.S. Food and Drug Administration.[224]

The Chinese 7th edition guidelines also include interferonribavirin, or umifenovir for use against COVID-19.[223]

In 2020, a trial found that lopinavir/ritonavir was ineffective in the treatment of severe illness.[225] Nitazoxanide has been recommended for further in vivo study after demonstrating low concentration inhibition of SARS-CoV-2.[215]

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.[226][227] 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.[226]

In February 2020, favipiravir was being studied in China for experimental treatment of the emergent COVID-19 disease.[228][229]

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.[230]

Tocilizumab has been included in treatment guidelines by China’s National Health Commission after a small study was completed.[231][232] It is undergoing a phase 2 non randomized test at the national level in Italy after showing positive results in people with severe disease.[221][233][234][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.[235][236][237] 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.[238][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.[239]

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.[240] This strategy was tried for SARS.[240] Viral neutralization is the anticipated mechanism of action by which passive antibody therapy can mediate defense against SARS-CoV-2. Other mechanisms, such as antibody-dependent cellular cytotoxicity and/or phagocytosis, may however be possible.[240] Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development.[240] 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.[241]

See also