Abstract

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 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. Common symptoms include fever, cough, and shortness of breath. Other symptoms may include fatigue, muscle pain, diarrhea, sore throat, loss of smell, and abdominal pain. The time from exposure to onset of symptoms is typically around five days but may range from two to fourteen days. While the majority of cases result in mild symptoms, some progress to viral pneumonia and multi-organ failure. As of 17 April 2020, more than 2.23 million cases have been reported across 210 countries and territories, resulting in more than 153,000 deaths. More than 567,000 people have recovered.

The virus is primarily spread between people during close contact, often via small droplets produced by coughing, sneezing, or talking. While these droplets are produced when breathing out, they usually fall to the ground or onto surfaces rather than being infectious over long distances. People may also become infected by touching a contaminated surface and then touching their eyes, nose, or mouth. The virus can survive on surfaces up to 72 hours. It is most contagious during the first three days after the onset of symptoms, although spread may be possible before symptoms appear and in later stages of the disease.

The standard method of diagnosis is by real-time reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab. Chest CT imaging may also be helpful for diagnosis in individuals where there is a high suspicion of infection based on symptoms and risk factors; however, it is not recommended for routine screening.

Recommended measures to prevent infection include frequent hand washing, 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. The use of masks is recommended for those who suspect they have the virus and their caregivers. 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. Currently, there is no vaccine or specific antiviral treatment for COVID-19. Management involves treatment of symptoms, supportive care, isolation, and experimental measures.

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

Signs and symptoms

Those infected with the virus may be asymptomatic or develop flu-like symptoms such as fever, cough, fatigue, and shortness of breath. 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. Less commonly, upper respiratory symptoms such as sneezing, runny nose or sore throat may be seen. Gastrointestinal symptoms such as nausea, vomiting and diarrhoea have been observed in varying percentages. Some cases in China initially presented only with chest tightness and palpitations. In some, the disease may progress to pneumonia, multi-organ failure, and death. In those who develop severe symptoms, time from symptom onset to needing mechanical ventilation is typically eight days.

Loss of smell was identified as a common early symptom of COVID-19 in March 2020, although not as common as initially reported.

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. 97.5% of people who develop symptoms will do so within 11.5 days of infection.

Reports indicate that not all who are infected develop symptoms. The role of these asymptomatic carriers in transmission is not yet fully known; however, preliminary evidence suggests that they may contribute to the spread of the disease. The proportion of infected people who do not display symptoms is currently unknown and being studied, with the Korea Centers for Disease Control and Prevention (KCDC) reporting that 20% of all confirmed cases remained asymptomatic during their hospital stay. China's National Health Commission began including asymptomatic cases in its daily cases on 1 April; of the 166 infections on that day, 130 (78%) were asymptomatic at the time of testing.

Cause | Transmission

Some details about how the disease is spread are still being determined. The WHO and the U.S. Centers for Disease Control and Prevention (CDC) say it is primarily spread during close contact and by small droplets produced when people cough, sneeze or talk; with close contact being within approximately 1–3 m (3–10 ft). Both sputum and saliva can carry large viral loads. Loud talking releases more droplets than normal talking. A study in Singapore found that an uncovered cough can lead to droplets travelling up to 4.5 meters (15 feet). An article published in March 2020 argued that advice on droplet distance might be based on 1930s research which ignored the effects of warm moist outbreath surrounding the droplets and that an uncovered cough or sneeze can travel up to 8.2 metres (27 feet).

Respiratory droplets may also be produced while breathing out, including when talking. Though the virus is not generally airborne, 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. The droplets can land in the mouths or noses of people who are nearby or possibly be inhaled into the lungs. Some medical procedures such as intubation and cardiopulmonary resuscitation (CPR) may cause respiratory secretions to be aerosolised and thus result in airborne spread. Initial studies suggested a doubling time of the number of infected persons of 6–7 days and a basic reproduction number (R0) of 2.2–2.7, but a study to be published on April 07, 2020 calculated a much higher median R0 value of 5.7.

It may also spread when one touches a contaminated surface, known as fomite transmission, and then touches one's eyes, nose or mouth. While there are concerns it may spread via feces, this risk is believed to be low.

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

The virus survives for hours to days on surfaces. Specifically, the virus was found to be detectable for one day on cardboard, for up to three days on plastic (polypropylene) and stainless steel (AISI 304), and for up to four hours on 99% copper. This, however, varies depending on the humidity and temperature. Surfaces may be decontaminated with a number of solutions (with one minute of exposure to the product achieving a 4 or more log reduction (99.99% reduction)), including 78–95% ethanol (alcohol used in spirits), 70–100% 2-propanol (isopropyl alcohol), the combination of 45% 2-propanol with 30% 1-propanol, 0.21% sodium hypochlorite (bleach), 0.5% hydrogen peroxide, or 0.23–7.5% povidone-iodine. Soap and detergent are also effective if correctly used; soap products degrade the virus' fatty protective layer, deactivating it, as well as freeing them from skin and other surfaces. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate (a surgical disinfectant), are less effective.

In a Hong Kong study, saliva samples were taken a median of two days after the start of hospitalization. In five of six patients, the first sample showed the highest viral load, and the sixth patient showed the highest viral load on the second day tested.

Cause | Virology

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. All features of the novel SARS-CoV-2 virus occur in related coronaviruses in nature. Outside the human body, the virus is killed by household soap, which bursts its protective bubble.

SARS-CoV-2 is closely related to the original SARS-CoV. 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). 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 that at most 92% of genetic material was shared between pangolin coronavirus and SARS-CoV-2, which is insufficient to prove pangolins to be the intermediate host.

Pathophysiology

The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in 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. 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, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective and these hypotheses need to be tested. As the alveolar disease progresses, respiratory failure might develop and death may follow.

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

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. Acute cardiac injury was found in 12% of infected people admitted in hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms is high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injury may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis (31%) and venous thromboembolism (25%) have been found in ICU patients with COVID-19 infections and may be related to poor prognosis.

Autopsies of people who died of COVID-19 have found diffuse alveolar damage (DAD), and lymphocyte-containing inflammatory infiltrates within the lung.

Pathophysiology | Immunopathology

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

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in COVID-19 patients. Lymphocytic infiltrates have also been reported at autopsy.

Diagnosis

The WHO has published several testing protocols for the disease. The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR). The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within a few hours to two days. Blood tests can be used, but these require two blood samples taken two weeks apart and the results have little immediate value. 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. As of 4 April 2020, antibody tests (which may detect active infections and whether a person had been infected in the past) were in development, but not yet widely used. The Chinese experience with testing has shown the accuracy is only 60 to 70%. The FDA in the United States approved the first point-of-care test on 21 March 2020 for use at the end of that month.

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.

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

Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but is not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses.

Diagnosis | Pathology

Few data are available about microscopic lesions and the pathophysiology of COVID-19. 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. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

- healing pneumonia: organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

- plasmocytosis in BAL

- Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

- Liver: microvesicular steatosis

Prevention

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, practising good respiratory hygiene and avoiding touching the eyes, nose or mouth with unwashed hands. The CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. The CDC has recommended the use of cloth face coverings in public settings, in part to limit transmission by asymptomatic individuals.

Social distancing strategies aim to reduce contact of infected persons with large groups by closing schools and workplaces, restricting travel and cancelling large public gatherings. Distancing guidelines also include that people stay at least 6 feet (1.8 m) apart. There is no medication known to be effective at preventing COVID-19.

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

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. A number of countries have recommended that healthy individuals wear face masks or cloth face coverings like scarves or bandanas in public, including China, Hong Kong, and the United States.

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. 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.

For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

Management

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

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

Management | Medications

As of April 2020, there is no specific treatment for COVID-19. Research is, however, ongoing. For symptoms, some medical professionals recommend paracetamol (acetaminophen) over ibuprofen for first-line use. The WHO does not oppose the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for symptoms, and the FDA says currently there is no evidence that NSAIDs worsen COVID-19 symptoms.

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

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

Management | 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. For healthcare professionals caring for people with COVID-19, the CDC recommends placing the person in an Airborne Infection Isolation Room (AIIR) in addition to using standard precautions, contact precautions and airborne precautions.

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

When available, respirators (instead of facemasks) are preferred. N95 respirators are approved for industrial settings but the FDA has authorised the masks for use under an Emergency Use Authorisation (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. When masks are not available, the CDC recommends using face shields or, as a last resort, homemade masks.

Management | Mechanical ventilation

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

Severe cases are most common in older adults (those older than 60 years, and especially those older than 80 years). Many developed countries do not have enough hospital beds per capita, which limits a health system's capacity to handle a sudden spike in the number of COVID-19 cases severe enough to require hospitalisation. This limited capacity is a significant driver behind calls to "flatten the curve"—to lower the speed at which new cases occur and thus keep the number of persons sick at any one time lower. One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died. In China, approximately 30% of people in hospital with COVID-19 are eventually admitted to ICU.

Management | Acute respiratory distress syndrome

Main article: Acute respiratory distress syndrome

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

Management | Experimental treatment

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

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

Management | Information technology

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

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. 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. 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. Russia deployed facial recognition technology to detect quarantine breakers. 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". German government conducted a 48 hours weekend hackathon with more than 42.000 participants. Also the president of Estonia, Kersti Kaljulaid, made a global call for creative solutions against the spread of coronavirus.

Management | 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.

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

Prognosis

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.

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%. 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.

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. 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. Approximately 20-30% of people who present with COVID-19 demonstrate elevated liver enzymes (transaminases). Liver injury as shown by blood markers of liver damage is frequently seen in severe cases.

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

Many of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus and cardiovascular disease. The Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available for review, 97.2% of sampled patients had at least one comorbidity with the average patient having 2.7 diseases. According to the same report, the median time between onset of symptoms and death was ten days, with five being spent hospitalised. However, patients transferred to an ICU had a median time of seven days between hospitalisation and death. 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. 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%. 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). 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. According to March data from the United States, 89% of those hospitalised had preexisting conditions.

Availability of medical resources and the socioeconomics of a region may also affect mortality. Estimates of the mortality from the condition vary because of those regional differences, but also because of methodological difficulties. The under-counting of mild cases can cause the mortality rate to be overestimated. However, the fact that deaths are the result of cases contracted in the past can mean the current mortality rate is underestimated. Smokers were 1.4 times more likely to have severe symptoms of COVID-19 and approximately 2.4 times more likely to require intensive care or die compared to non-smokers.

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. This may also lead to post-intensive care syndrome following recovery.

Total infection fatality rate is estimated to be 0.66% (0.39–1.3). Infection fatality rate is fatality per all infected individuals, regardless of whether they were diagnosed or had any symptoms. Numbers in parentheses are 95% credible intervals for the estimates.

Prognosis | Reinfection

As of March 2020, it was unknown if past infection provides effective and long-term immunity in people who recover from the disease. Immunity is seen as likely, based on the behaviour of other coronaviruses, but cases in which recovery from COVID-19 have been followed by positive tests for coronavirus at a later date have been reported. These cases are believed to be worsening of a lingering infection rather than re-infection.

History

The virus is thought to be natural and have an animal origin, through spillover infection. The actual origin is unknown, but by December 2019 the spread of infection was almost entirely driven by human-to-human transmission. 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. Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019.

Epidemiology

Several measures are commonly used to quantify mortality. 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. 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.

The death-to-case ratio reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 6.9% (153,379/2,234,109) as of 17 April 2020. The number varies by region.

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.

Epidemiology | Antibody tests

While not all infected people develop antibodies, the presence of antibodies may provide information about how many people have been infected.

In the epicentre of the outbreak in Italy, Castiglione d'Adda, a small village of 4600, 80 (1.7%) are already dead. Out of 60 people in the village who were tested 40 appear to have developed antibodies and possible immunity, most did so without being diagnosed, and many did not have symptoms.

In the German region of Gangelt, where 0.06% of the population has died, 14% have antibodies (15% have been infected and 2% were currently infectious). In Gangelt, the disease was spread by Carnival festivals, and spread to younger people, causing a relatively lower mortality, and not all COVID-19 deaths may have been formally classified as such. Furthermore, the German health system has not been overwhelmed.

In the Netherlands, about 3% may have antibodies, as assessed from blood donors. There, the confirmed deaths from the disease is 0.018% of the population, however the excess deaths with respect to normal circumstances is about twice as high as not all COVID-19 deaths are recorded as such.

In Santa Clara county, 45 out of 3,000 individuals (1.5%) had antibodies (following adjusting the researchers claim 2.8% people had the infection). 69 (0.004% of the population) have been confirmed to have died from COVID-19.

Epidemiology | Sex differences

The impact of the pandemic and its mortality rate are different for men and women. Mortality is higher in men in studies conducted in China and Italy. The highest risk for men is in their 50s, with the gap between men and women closing only at 90. In China, the death rate was 2.8 percent for men and 1.7 percent for women. The exact reasons for this sex-difference is not known, but genetic and behavioural factors could be a reason. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected individuals were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently. A higher percentage of health workers, particularly nurses, are women, and they have a higher chance of being exposed to the virus. School closures, lockdowns and reduced access to healthcare following the 2019–20 coronavirus pandemic may deferentially affect the genders and possibly exaggerate existing gender disparity.

Society and culture | Nomenclature

The World Health Organization announced on 11 February 2020 that the official name of the disease would be "COVID-19". WHO chief Tedros Adhanom Ghebreyesus explained that CO stands for corona, VI for virus, D for disease, and 19 for when the outbreak was first identified: 31 December 2019. The name had been chosen to avoid references to a specific geographical location (e.g. China), animal species or group of people, in line with international recommendations for naming aimed at preventing stigmatisation.

The virus that causes COVID-19 is named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications. Coronaviruses were named in 1968 for their appearance in electron micrographs which was reminiscent of the solar corona, corōna meaning crown in Latin. Both the disease and virus are commonly referred to as "coronavirus".

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus". In January 2020, WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease in accordance with 2015 guidance against using locations in disease and virus names. The official names COVID-19 and SARS-CoV-2 were issued on 11 February 2020.

Society and culture | Manufacturing

It has been suggested that this article be merged into 2019–20 coronavirus pandemic#Management. (Discuss) Proposed since April 2020.

Due to capacity limitations in the standard supply chains, some digital manufacturers are printing healthcare material such as nasal swabs and ventilator parts. In one example, when an Italian hospital urgently required a ventilator valve, and the supplier was unable to deliver in the timescale required, a local startup reverse-engineered and printed the required 100 valves overnight.

Society and culture | Misinformation

Main article: Misinformation related to the 2019–20 coronavirus pandemic

After the initial outbreak of COVID-19, conspiracy theories, misinformation and disinformation emerged regarding the origin, scale, prevention, treatment and other aspects of the disease and rapidly spread online.

Society and culture | Other animals

Humans appear to be capable of spreading the virus to some other animals. A domestic cat in Liège tested positive after it started showing symptoms (diarrhoea, vomiting, shortness of breath) a week later than its owner, who was also positive. Tigers at the Bronx Zoo tested positive for the virus and showed symptoms of COVID-19, including a dry cough and loss of appetite.

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

Research

No medications or vaccine is approved to treat the disease. International research on vaccines and medicines in COVID-19 are underway by government organisations, academic groups and industry researchers. In March, the World Health Organization initiated the "SOLIDARITY Trial" to assess treatment effects of four existing antiviral compounds with the most promise of efficacy.

Research | Vaccine

There is no available vaccine, but various agencies are actively developing vaccine candidates. Previous work on SARS-CoV is being utilised because SARS-CoV and SARS-CoV-2 both use the ACE2 receptor to enter human cells. 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.

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.

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

Research | Medications

Main article: COVID-19 drug repurposing research

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

The COVID-19 Clinical Research Coalition has goals to 1) facilitate rapid reviews of clinical trial proposals by ethics committees and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data and 4) facilitate sharing of clinical trial outcomes before publication. A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April 2020.

Several existing antiviral medications are being evaluated for treatment of COVID-19, including remdesivir, chloroquine and hydroxychloroquine, lopinavir/ritonavir and lopinavir/ritonavir combined with interferon beta. There is tentative evidence for efficacy by remdesivir, as of March 2020. Clinical improvement was observed in patients treated with compassionate-use remdesivir. Remdesivir inhibits SARS-CoV-2 in vitro. Phase III clinical trials are being conducted in the US, China and Italy.

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

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. Korean and Chinese Health Authorities recommend the use of chloroquine. 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 authorisation for hydroxychloroquine and chloroquine at the discretion of physicians treating people with COVID-19.

The Chinese 7th edition guidelines also include interferon, ribavirin or umifenovir for use against COVID-19. Preliminary data indicate that high doses of ribavirin are necessary to inhibit SARS-CoV-2 in vitro. Since studies have been inconsistent with respect to ribavirin's efficacy against other novel coronaviruses (e.g., SARS, MERS) and its significant toxicity, this suggests its role in treating COVID-19 is limited and its best chance of being effective is being a part of combination therapy.

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

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. These findings suggest the TMPRSS2 inhibitor camostat approved for use in Japan for inhibiting fibrosis in liver and kidney disease might constitute an effective off-label treatment.

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

In April 2020 ivermectin is being studied in Australia for a possible treatment for COVID-19 and has been shown to stop viral growth within 48 hours in vitro.

There are mixed results as of 3 April 2020 as to the effectiveness of hydroxychloroquine as a treatment for COVID-19, with some studies showing little or no improvement. The studies of chloroquine and hydroxychloroquine with or without azithromycin have major limitations that have prevented the medical community from embracing these therapies without further study.

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

Research | Anti-cytokine storm

Cytokine storm can be a complication in the later stages of severe COVID-19. There is evidence that hydroxychloroquine may have anti-cytokine storm properties.

Tocilizumab has been included in treatment guidelines by China's National Health Commission after a small study was completed. It is undergoing a phase 2 non randomised test at the national level in Italy after showing positive results in people with severe disease. 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. The interleukin-6 receptor antagonist was approved by the FDA based on retrospective case studies for treatment of steroid refractory cytokine release syndrome induced by a different cause, CAR T cell therapy, in 2017. To date, there is no randomised, controlled evidence that tocilizumab is an efficacious treatment for CRS. Prophylactic tocilizumab has been shown to increase serum IL-6 levels by saturating the IL-6R, driving IL-6 across the blood brain barrier and exacerbating neurotoxicity while having no impact on incidence of CRS.

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

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

Research | Passive antibodies

Transferring purified and concentrated antibodies produced by the immune systems of those who have recovered from COVID-19 to people who need them is being investigated as a non-vaccine method of passive immunisation. This strategy was tried for SARS with inconclusive results. Viral neutralisation is the anticipated mechanism of action by which passive antibody therapy can mediate defence against SARS-CoV-2. Other mechanisms however, such as antibody-dependent cellular cytotoxicity and/or phagocytosis, may be possible. Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development. 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.