A RESEARCH ON CORONA VIRUS DISEASE 2019(COVID -19)
REVIEW – Dayasagar Parajuli 4th April 2020,
Corona virus disease 2019 (COVID -19) is an infectious disease caused by severe acute respiratory syndrome corona virus 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 corona virus pandemic. Common symptoms include fever, cough, and shortness of breath. Other symptoms may include muscle pain, sputum production, diarrhea, sore throat, loss of smell, and abdominal pain. While the majority of cases result in mild symptoms, some progress to viral pneumonia and multi-organ failure. As of 3 April 2020, more than 1,010,000 cases of COVID-19 have been reported in more than two hundred countries and territories, resulting in over 53,000 deaths. More than 211,000 people have recovered.
The virus is mainly spread during close contact, and by small droplets produced when people cough, sneeze, or talk. Respiratory droplets may be produced during breathing but the virus is not generally airborne. People may also contract COVID-19 by touching a contaminated surface and then their face. It is most contagious when people are symptomatic, although spread may be possible before symptoms appear. The virus can survive on surfaces up to 72 hours. Time from exposure to onset of symptoms is generally between two and fourteen days, with an average of five days. The standard method of diagnosis is by reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab. The infection can also be diagnosed from a combination of symptoms, risk factors and a chest CT scan showing features of pneumonia.
Recommended measures to prevent infection include frequent hand washing, social distancing (maintaining physical distance from others, especially from those with symptoms), covering coughs and sneezes with a tissue or inner elbow, and keeping unwashed hands away from the face. 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 many countries across all six WHO regions.
SIGNS AND SYMPTOMS
Those infected with the virus may be asymptomatic or develop flu-like symptoms, including 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. Symptoms such as nausea, vomiting, and diarrhea have been observed in varying percentages. Some cases in China initially presented only with chest tightness and palpitations. 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, although not as common as initially reported. 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.
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, but their role in transmission is unknown. Preliminary evidence suggests asymptomatic cases 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 South Korea’s CDC reporting that 20% of all confirmed cases remained asymptomatic during their hospital stay.
TRANSMISSION
Respiratory droplets may also be produced during 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. It may also spread when one touches a contaminated surface, known as fomite transmission, and then touches their eyes, nose, or mouth. While there are concerns it may spread by feces, this risk is believed to be low.
The virus is most contagious when people are symptomatic; while spread may be possible before symptoms appear, this risk is low. The European Centre for Disease Prevention and Control (ECDC) states that while it is not entirely clear how easily the disease spreads, one person generally infects two to three others.
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 and stainless steel, and for up to four hours on copper. This, however, varies based on the humidity and temperature. Surfaces may be decontaminated with a number of solutions (within one minute of exposure to the disinfectant for a stainless steel surface), including 62–71% ethanol, 50–100% isopropanol, 0.1% sodium hypochlorite, 0.5% hydrogen peroxide, and 0.2–7.5% povidone-iodine. Other solutions, such as benzalkonium chloride and chrohexidine gluconate, are less effective.
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 at most 92% of genetic material shared between pangolin coronavirus and SARS-CoV-2, which is insufficient to prove pangolins to be the intermediate host.
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 19 March 2020. there were no antibody tests though efforts to develop them are ongoing. The FDA 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 March 2020 review concluded that chest X-rays are of little value in early stages, whereas CT scans of the chest are useful even before symptoms occur. Typical features on CT include bilateral multilobar ground-glass opacificities with a peripheral, asymmetric and posterior distribution. Subpleural dominance, crazy paving and consolidation develop as the disease evolves. 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”.
Typical CT imaging findings
CT imaging of rapid progression stage
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:
- mild pneumonia: pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation
- severe pneumonia: diffuse alveolar damage (DAD) with diffuse alveolar exudates. This diffuse DAD is responsible of the acute respiratory distress syndrome (ARDS) and severe hypoxemia observed in this disease.
- healing pneumonia: organization of exudates in alveolar cavities, and pulmonary interstitial fibrosis
- plasmocytosis in BAL
- Blood: disseminated intravascular coagulation (DIC) ; leukoerythroblastic reaction
- Liver: microvesicular steatosis
PREVENTIONS
Preventive measures to reduce the chances of infection include staying at home, avoiding crowded places, washing hands with soap and water often and for at least 20 seconds, practicing good respiratory hygiene and avoiding touching the eyes, nose, or mouth with unwashed hands. 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. They also recommend proper hand hygiene after any cough or sneeze. Social distancing strategies aim to reduce contact of infected persons with large groups by closing schools and workplaces, restricting travel, and canceling mass gatherings. Social distancing also includes that people stay at least six feet apart (1.83 meters).
Because a vaccine against SARS-CoV-2 is not expected to become available until 2021 at the earliest, 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. 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.
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. Some countries also recommend healthy individuals to wear face masks, including China, Hong Kong, Thailand, Czech Republic, and Austria. 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. 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.
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, 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.
Prevention efforts are multiplicative, with effects far beyond that of a single spread. Each avoided case leads to more avoided cases down the line, which in turn can stop the outbreak in its tracks.
HISTORY
The virus is thought to be natural and have an animal origin, through spillover infection. The origin is unknown but by December 2019 the spread of infection was almost entirely driven by human-to-human transmission. The earliest reported infection has been unofficially reported to have occurred on 17 November 2019 in Wuhan, China. 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.
EPIDIMIOLOGY
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 5.2% (53,069/1,016,128) as of 3 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.
Total confirmed cases over time
Total deaths over time
Total confirmed cases of COVID-19 per million people, 20 March 2020
Total confirmed deaths due to COVID-19 per million people, 24 March 2020
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. Personal hygiene, and a healthy lifestyle and diet have been recommended to improve immunity.
v 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. 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.
v Antivirals
Several existing antiviral medications are being evaluated for treatment of COVID-19 and some have moved into clinical trials. In March 2020, WHO launched a multi-country trial involving 10 countries called “Solidarity” in response to COVID-19 pandemic. Remdesivir, chloroquine and hydroxychloroquine, lopinavir/ritonavir, and lopinavir/ritonavir combined with interferon beta are the experimental treatments currently being researched under Solidarity Trial.
There is tentative evidence for remdesivir as of March 2020. Remdesivir inhibits SARS-CoV-2 in vitro. Phase 3 clinical trials are being conducted in the U.S., China, and Italy.
Chloroquine, previously used to treat malaria, was studied in China in February 2020, with positive 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 authorization 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.
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 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.
In February 2020, favipiravir was being studied in China for experimental treatment of the emergent COVID-19 disease.
v 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.
Tocilizumab has been included in treatment guidelines by China’s National Health Commission after .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 for treatment against cytokine release syndrome induced by a different cause, CAR T cell therapy, in 2017.]
The Feinstein Institute of Northwell Health announced in March a study on “a human antibody that may prevent the activity” of IL-6.
v 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. This strategy was tried for SARS. Viral neutralization is the anticipated mechanism of action by which passive antibody therapy can mediate defense against SARS-CoV-2. Other mechanisms however, such as antibody-dependent cellular cytotoxicity and/or phagocytosis, may be possible. 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.
Source :-WHO/WIKIPEDIA
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