Coronavirus disease 2019 – Wikipedia

Viral respiratory disease first detected in 2019

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[10] The disease was first identified in 2019 in Wuhan, China, and has spread globally, resulting in the 201920 coronavirus pandemic.[11][12] Common symptoms include fever, cough and shortness of breath. Muscle pain, sputum production and sore throat are less common symptoms.[6][13] While the majority of cases result in mild symptoms,[14] some progress to pneumonia and multi-organ failure.[11][15] The deaths per number of diagnosed cases is estimated at between 1% and 5% but varies by age and other health conditions.[16][17]

The infection is spread from one person to others via respiratory droplets, often produced during coughing and sneezing.[18][19] Time from exposure to onset of symptoms is generally between 2 and 14 days, with an average of 5 days.[20][21] The standard method of diagnosis is by reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab or throat swab. The infection can also be diagnosed from a combination of symptoms, risk factors and a chest CT scan showing features of pneumonia.[22][23]

Recommended measures to prevent the disease include frequent hand washing, maintaining distance from other people and not touching one's face.[24] The use of masks is recommended for those who suspect they have the virus and their caregivers, but not the general public.[25][26] There is no vaccine or specific antiviral treatment for COVID-19; management involves treatment of symptoms, supportive care, isolation and experimental measures.[27]

The World Health Organization (WHO) declared the 201920 coronavirus outbreak a pandemic[12] and a Public Health Emergency of International Concern (PHEIC).[28][29] Evidence of local transmission of the disease has been found in many countries across all six WHO regions.[30]

Those infected with the virus may either be asymptomatic or develop flu-like symptoms that include fever, cough and shortness of breath.[6][32][33]Diarrhoea and upper respiratory symptoms such as sneezing, runny nose, or sore throat are less common.[34] Cases can progress to pneumonia, multi-organ failure and death in the most vulnerable.[11][15]

The incubation period ranges from two to 14 days, with an estimated median incubation period of five to six days, according to the World Health Organization (WHO).[35][36] The median time from onset to clinical recovery for mild cases is approximately 2 weeks and is 3-6 weeks for people with severe or critical disease. Preliminary data suggests that the time period from onset to the development of severe disease, including hypoxia, is 1 week. Among people who have died, the time from symptom onset to outcome ranges from 2-8 weeks.[37]

One study in China found that CT scans showed ground-glass opacities in 56%, but 18% had no radiological findings. 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation and 1.4% died.[38] Bilateral and peripheral ground glass opacities are the most typical CT findings.[39]Consolidation, linear opacities and reverse halo sign are other radiological findings.[39] Initially, the lesions are confined to one lung, but as the disease progresses, indications manifest in both lungs in 88% of so-called "late patients" in the study group (the subset for whom time between onset of symptoms and chest CT was 612 days).[39]

It has been noted that children seem to have milder symptoms than adults.[40]

The disease is caused by the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously referred to as the 2019 novel coronavirus (2019-nCoV).[41] It is primarily spread between people via respiratory droplets from coughs and sneezes.[19]

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 "spike", to connect to ACE2 and intrude the hosting cell.[42] 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,[43][44] though another view is that increasing ACE2 using Angiotensin II receptor blocker drugs could be protective and that these hypotheses need to be tested.[45] As the alveolar disease progresses respiratory failure might develop and death might ensue.[44] ACE2 might also be the path for the virus to assault the heart causing acute cardiac injury. People with existing cardiovascular conditions have worst prognosis.[46]

The virus is thought to have an animal origin,[47] through spillover infection.[48] It was first transmitted to humans in Wuhan, China, in November or December 2019, and the primary source of infection became human-to-human transmission by early January 2020.[49][50] On 14 March 2020, South China Morning Post reported that a 55-year-old from Hubei province could have been the first person to have contracted the disease on 17 November 2019.[51] As of 14 March 2020, 67,790 cases and 3,075 deaths due to the virus have been reported in Hubei province; a case fatality rate (CFR) of 4.54%.[51]

The WHO has published several testing protocols for the disease.[53] The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR).[54] The test can be done on respiratory samples obtained by various methods, including a nasopharyngeal swab or sputum sample.[55] Results are generally available within a few hours to 2 days.[56][57] Blood tests can be used, but these require two blood samples taken two weeks apart and the results have little immediate value.[58] 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.[11][59][60]

As of 26 February 2020, there were no antibody tests or point-of-care tests though efforts to develop them are ongoing.[61]

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.[22] A study published by a team at the Tongji Hospital in Wuhan on 26 February 2020 showed that a chest CT scan for COVID-19 has more sensitivity (98%) than the polymerase chain reaction (71%).[23] False negative results may occur due to PCR kit failure, or due to either issues with the sample or issues performing the test. False positive results are likely to be rare.[62]

Typical CT imaging findings

CT imaging of rapid progression stage

Because a vaccine against SARS-CoV-2 is not expected to become available until 2021 at the earliest,[68] a key part of managing the COVID-19 pandemic is trying to decrease the epidemic peak, known as flattening the epidemic curve.[64] This helps decrease the risk of health services being overwhelmed and provides more time for a vaccine and treatment to be developed.[64]

Preventive measures to reduce the chances of infection in locations with an outbreak of the disease are similar to those published for other coronaviruses: stay home, avoid travel and public activities, wash hands with soap and hot water often, practice good respiratory hygiene and avoid touching the eyes, nose, or mouth with unwashed hands.[69][70]Social distancing strategies aim to reduce contact of infected persons with large groups by closing schools and workplaces, restricting travel and canceling mass gatherings.

According to the WHO, the use of masks is only recommended if a person is coughing or sneezing or when one is taking care of someone with a suspected infection.[71]

To prevent transmission of the virus, the Centers for Disease Control and Prevention (CDC) in the United States recommends that infected individuals stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask when exposed to an individual or location of a suspected infection, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.[72][73] 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 recommended using an alcohol-based hand sanitizer with at least 60% alcohol, but only when soap and water are not readily available.[69] The WHO advises individuals to avoid touching the eyes, nose, or mouth with unwashed hands.[70] Spitting in public places also should be avoided.[74]

There are no specific antiviral medications. People are managed with supportive care such as fluid and oxygen support.[76][77] The WHO and Chinese National Health Commission have published treatment recommendations for taking care of people who are hospitalised with COVID-19.[78][79]Steroids such as methylprednisolone are not recommended unless the disease is complicated by acute respiratory distress syndrome.[80][81]Intensivists and pulmonologists in the US have compiled treatment recommendations from various agencies into a free resource, the IBCC.[82][83] The CDC recommends that those who suspect they carry the virus wear a simple face-mask.[25]

Management of people infected by the virus includes taking precautions while applying therapeutic manoeuvres, especially when performing procedures like intubation or hand ventilation that can generate aerosols.[84]

The CDC outlines the specific personal protective equipment and the order in which healthcare providers should put it on when dealing with someone who may have COVID-19: 1) gown, 2) mask or respirator [1], 3) goggles or a face shield, 4) gloves.[85][86]

Most cases of COVID-19 are not severe enough to require mechanical ventilation (artificial assistance to support breathing), but a percentage of cases do. This is most common in older adults (those older than 60 years and especially those older than 80 years). This component of treatment is the biggest rate-limiter of health system capacity that drives 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). This is why social distancing is so important to saving the lives of others, not just to preserving one's own. This fact falsifies the argument that a young healthy adult can ignore the need for social distancing, accept a mild flu-like illness, recover, and move on. The burden on the healthcare system will also limit the availability of other types of health care, such as that required after a motor vehicle collision.

Antiviral medication may be tried in people with severe disease.[76] The WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments.[87] There is tentative evidence for remdesivir as of March 2020.[88]Lopinavir/ritonavir is also being studied in China.[89]Chloroquine was being trialled in China in February 2020, with preliminary results that seem positive.[90]Nitazoxanide has been recommended for further in vivo study after demonstrating low concentration inhibition of SARS-CoV-2.[91]

Tocilizumab, an immunosuppressive drug, mainly used for the treatment of rheumatoid arthritis, has been included in treatment guidelines by China's National Health Commission after a completed small study by the University of Science and Technology of China.[92][93] The drug is undergoing testing in five hospitals in Italy after showing positive results in people with severe disease.[94][95] 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 patients.[96][97] 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.[98]

In February 2020, China launched a mobile app to deal with the disease outbreak.[99] 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.[100]

Infected 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.[101][102]

Many of those who die of COVID-19 have preexisting conditions, including hypertension, diabetes and cardiovascular disease.[103] In a study of early cases, the median time from exhibiting initial symptoms to death was 14 days, with a full range of 6 to 41 days.[104] 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%.[105] 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%.[105] No deaths had occurred in people younger than 10 as of 26February2020[update].[105] Availability of medical resources and the socioeconomics of a region may also affect mortality.[106]

Histopathological examinations of post-mortem lung samples showed 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).[107]

It is unknown if past infection provides effective and long-term immunity in people who recover from the disease.[108] Immunity is likely, based on the behaviour of other coronaviruses,[109] but some cases of someone recovering and later testing positive again have been reported in various countries.[110][111] It is unclear if those cases are the result of reinfection, relapse, or testing error; more research is needed about how the SARS-CoV-2 virus interacts with the human immune system.

The severity of diagnosed COVID19 cases in China[115]

Case fatality rates by age group in China. Data through 11 February 2020.[116]

Case fatality rate depending on other health problems

On 12 March, the Hong Kong Hospital Authority announced they had found a drop of 20% to 30% in lung capacity in two to three of around a dozen people who had recovered from the disease. The people who recovered gasp if they walk more quickly. Lung scans of the nine people infected at Princess Margaret Hospital suggested they had sustained organ damage.[117]

The case fatality rate (CFR) depends on the availability of healthcare, the typical age and health problems within the population, and the number of undiagnosed cases.[118][119] Preliminary research has yielded case fatality rate numbers between 2% and 3%;[16] in January 2020 the WHO suggested that the case fatality rate was approximately 3%,[120] and 2% in February 2020 in Hubei.[121] Other CFR numbers, which adjust for differences in time of confirmation, death or cured, are respectively 7%[122] and 33% for people in Wuhan 31 January.[123] An unreviewed preprint of 55 deaths noted that early estimates of mortality may be too high as asymptomatic infections are missed. They estimated a mean infection fatality ratio (IFR, the mortality among infected) ranging from 0.8% - 0.9%.[124] The outbreak in 20192020 has caused at least 174,893edit[7] confirmed infections and 6,705edit[7] deaths.

An observational study of nine people, found no vertical transmission from mother to the newborn.[125] Also, a descriptive study in Wuhan found no evidence of viral transmission through vaginal sex (from female to partner), but authors note that transmission during sex might occur through other routes.[126]

Because of its key role in the transmission and progression of the disease, ACE2 has been the focus of a significant proportion of research and various therapeutic approaches have been suggested.[44]

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 ACE2 enzyme to invade human cells.[127] 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 for 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. A third strategy is 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.[128]

No medication has yet been approved to treat coronavirus infections in humans by the WHO although some are recommended by the Korean and Chinese medical authorities.[129] Trials of many antivirals have been started in COVID-19 including oseltamivir, lopinavir/ritonavir, ganciclovir, favipiravir, baloxavir marboxil, umifenovir, and interferon alfa but currently there are no data to support their use.[130] Korean Health Authorities recommend lopinavir/ritonavir or chloroquine[131] and the Chinese 7th edition guidelines include interferon, lopinavir/ritonavir, ribavirin, chloroquine and/or umifenovir.[132]

Research into potential treatments for the disease was initiated in January 2020, and several antiviral drugs are already in clinical trials.[133][134] Although completely new drugs may take until 2021 to develop,[135] several of the drugs being tested are already approved for other antiviral indications, or are already in advanced testing.[129]

Remdesivir and chloroquine effectively inhibit the coronavirus in vitro.[91] Remdesivir is being trialled in US and in China.[130]

Preliminary results from a multicentric trial, announced in a press conference and described by Gao, Tian and Yang, suggested that chloroquine is effective and safe in treating COVID-19 associated pneumonia, "improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course".[90]

Recent studies have demonstrated that initial spike protein priming by transmembrane protease serine 2 (TMPRSS2) is essential for entry of SARS-CoV-2, SARS-CoV and MERS-CoV via interaction with the ACE2 receptor.[136][137] These findings suggest that the TMPRSS2 inhibitor Camostat approved for clinical use in Japan for inhibiting fibrosis in liver and kidney disease, postoperative reflux esophagitis and pancreatitis might constitute an effective off-label treatment option.[136]

Using blood donations from healthy people who have already recovered from COVID-19 holds promise,[138] a strategy which has also been tried for SARS, an earlier cousin of COVID-19.[138] The mechanism of action is that the antibodies naturally produced in the immune systems of those who have already recovered are transferred to people in need of them via a nonvaccine form of immunization.[138] Such convalescent serum therapy (antiserum therapy) is also analogous to the way that hepatitis B immune globulin (HBIG) is used to prevent hepatitis B or human rabies immune globulin (HRIG) is used to treat rabies.[138] Other forms of passive antibody therapy, such as with manufactured monoclonal antibodies, may come later after biopharmaceutical development,[138] but convalescent serum production could be increased for quicker deployment.[139]

The World Health Organization announced on 11 February 2020 that "COVID-19" would be the official name of the disease. World Health Organization chief Tedros Adhanom Ghebreyesus said "co" stands for "corona", "vi" for "virus" and "d" for "disease", while "19" was for the year, as the outbreak was first identified on 31 December 2019. Tedros said 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.[140][141]

While the disease is named COVID-19, the virus that causes it was named SARS-CoV-2 by the WHO.[142] The virus was initially referred to as the 2019 novel coronavirus or 2019-nCoV.[143] The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.[142]

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