covid 19 introduction research paper

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An Introduction to COVID-19

Simon james fong.

4 Department of Computer and Information Science, University of Macau, Taipa, Macau, China

Nilanjan Dey

5 Department of Information Technology, Techno International New Town, Kolkata, West Bengal India

Jyotismita Chaki

6 School of Information Technology and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu India

A novel coronavirus (CoV) named ‘2019-nCoV’ or ‘2019 novel coronavirus’ or ‘COVID-19’ by the World Health Organization (WHO) is in charge of the current outbreak of pneumonia that began at the beginning of December 2019 near in Wuhan City, Hubei Province, China [1–4]. COVID-19 is a pathogenic virus. From the phylogenetic analysis carried out with obtainable full genome sequences, bats occur to be the COVID-19 virus reservoir, but the intermediate host(s) has not been detected till now.

A Brief History of the Coronavirus Outbreak

A novel coronavirus (CoV) named ‘2019-nCoV’ or ‘2019 novel coronavirus’ or ‘COVID-19’ by the World Health Organization (WHO) is in charge of the current outbreak of pneumonia that began at the beginning of December 2019 near in Wuhan City, Hubei Province, China [ 1 – 4 ]. COVID-19 is a pathogenic virus. From the phylogenetic analysis carried out with obtainable full genome sequences, bats occur to be the COVID-19 virus reservoir, but the intermediate host(s) has not been detected till now. Though three major areas of work already are ongoing in China to advise our awareness of the pathogenic origin of the outbreak. These include early inquiries of cases with symptoms occurring near in Wuhan during December 2019, ecological sampling from the Huanan Wholesale Seafood Market as well as other area markets, and the collection of detailed reports of the point of origin and type of wildlife species marketed on the Huanan market and the destination of those animals after the market has been closed [ 5 – 8 ].

Coronaviruses mostly cause gastrointestinal and respiratory tract infections and are inherently categorized into four major types: Gammacoronavirus, Deltacoronavirus, Betacoronavirus and Alphacoronavirus [ 9 – 11 ]. The first two types mainly infect birds, while the last two mostly infect mammals. Six types of human CoVs have been formally recognized. These comprise HCoVHKU1, HCoV-OC43, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) which is the type of the Betacoronavirus, HCoV229E and HCoV-NL63, which are the member of the Alphacoronavirus. Coronaviruses did not draw global concern until the 2003 SARS pandemic [ 12 – 14 ], preceded by the 2012 MERS [ 15 – 17 ] and most recently by the COVID-19 outbreaks. SARS-CoV and MERS-CoV are known to be extremely pathogenic and spread from bats to palm civets or dromedary camels and eventually to humans.

COVID-19 is spread by dust particles and fomites while close unsafe touch between the infector and the infected individual. Airborne distribution has not been recorded for COVID-19 and is not known to be a significant transmission engine based on empirical evidence; although it can be imagined if such aerosol-generating practices are carried out in medical facilities. Faecal spreading has been seen in certain patients, and the active virus has been reported in a small number of clinical studies [ 18 – 20 ]. Furthermore, the faecal-oral route does not seem to be a COVID-19 transmission engine; its function and relevance for COVID-19 need to be identified.

For about 18,738,58 laboratory-confirmed cases recorded as of 2nd week of April 2020, the maximum number of cases (77.8%) was between 30 and 69 years of age. Among the recorded cases, 21.6% are farmers or employees by profession, 51.1% are male and 77.0% are Hubei.

However, there are already many concerns regarding the latest coronavirus. Although it seems to be transferred to humans by animals, it is important to recognize individual animals and other sources, the path of transmission, the incubation cycle, and the features of the susceptible community and the survival rate. Nonetheless, very little clinical knowledge on COVID-19 disease is currently accessible and details on age span, the animal origin of the virus, incubation time, outbreak curve, viral spectroscopy, dissemination pathogenesis, autopsy observations, and any clinical responses to antivirals are lacking among the serious cases.

How Different and Deadly COVID-19 is Compared to Plagues in History

COVID-19 has reached to more than 150 nations, including China, and has caused WHO to call the disease a worldwide pandemic. By the time of 2nd week of April 2020, this COVID-19 cases exceeded 18,738,58, although more than 1,160,45 deaths were recorded worldwide and United States of America became the global epicentre of coronavirus. More than one-third of the COVID-19 instances are outside of China. Past pandemics that have existed in the past decade or so, like bird flu, swine flu, and SARS, it is hard to find out the comparison between those pandemics and this coronavirus. Following is a guide to compare coronavirus with such diseases and recent pandemics that have reformed the world community.

Coronavirus Versus Seasonal Influenza

Influenza, or seasonal flu, occurs globally every year–usually between December and February. It is impossible to determine the number of reports per year because it is not a reportable infection (so no need to be recorded to municipality), so often patients with minor symptoms do not go to a physician. Recent figures placed the Rate of Case Fatality at 0.1% [ 21 – 23 ].

There are approximately 3–5 million reports of serious influenza a year, and about 250,000–500,000 deaths globally. In most developed nations, the majority of deaths arise in persons over 65 years of age. Moreover, it is unsafe for pregnant mothers, children under 59 months of age and individuals with serious illnesses.

The annual vaccination eliminates infection and severe risks in most developing countries but is nevertheless a recognized yet uncomfortable aspect of the season.

In contrast to the seasonal influenza, coronavirus is not so common, has led to fewer cases till now, has a higher rate of case fatality and has no antidote.

Coronavirus Versus Bird Flu (H5N1 and H7N9)

Several cases of bird flu have existed over the years, with the most severe in 2013 and 2016. This is usually from two separate strains—H5N1 and H7N9 [ 24 – 26 ].

The H7N9 outbreak in 2016 accounted for one-third of all confirmed human cases but remained confined relative to both coronavirus and other pandemics/outbreak cases. After the first outbreak, about 1,233 laboratory-confirmed reports of bird flu have occurred. The disease has a Rate of Case Fatality of 20–40%.

Although the percentage is very high, the blowout from individual to individual is restricted, which, in effect, has minimized the number of related deaths. It is also impossible to monitor as birds do not necessarily expire from sickness.

In contrast to the bird flu, coronavirus becomes more common, travels more quickly through human to human interaction, has an inferior cardiothoracic ratio, resulting in further total fatalities and spread from the initial source.

Coronavirus Versus Ebola Epidemic

The Ebola epidemic of 2013 was primarily centred in 10 nations, including Sierra Leone, Guinea and Liberia have the greatest effects, but the extremely high Case Fatality Rate of 40% has created this as a significant problem for health professionals nationwide [ 27 – 29 ].

Around 2013 and 2016, there were about 28,646 suspicious incidents and about 11,323 fatalities, although these are expected to be overlooked. Those who survived from the original epidemic may still become sick months or even years later, because the infection may stay inactive for prolonged periods. Thankfully, a vaccination was launched in December 2016 and is perceived to be effective.

In contrast to the Ebola, coronavirus is more common globally, has caused in fewer fatalities, has a lesser case fatality rate, has no reported problems during treatment and after recovery, does not have an appropriate vaccination.

Coronavirus Versus Camel Flu (MERS)

Camel flu is a misnomer–though camels have MERS antibodies and may have been included in the transmission of the disease; it was originally transmitted to humans through bats [ 30 – 32 ]. Like Ebola, it infected only a limited number of nations, i.e. about 27, but about 858 fatalities from about 2,494 laboratory-confirmed reports suggested that it was a significant threat if no steps were taken in place to control it.

In contrast to the camel flu, coronavirus is more common globally, has occurred more fatalities, has a lesser case fatality rate, and spreads more easily among humans.

Coronavirus Versus Swine Flu (H1N1)

Swine flu is the same form of influenza that wiped 1.7% of the world population in 1918. This was deemed a pandemic again in June 2009 an approximately-21% of the global population infected by this [ 33 – 35 ].

Thankfully, the case fatality rate is substantially lower than in the last pandemic, with 0.1%–0.5% of events ending in death. About 18,500 of these fatalities have been laboratory-confirmed, but statistics range as high as 151,700–575,400 worldwide. 50–80% of severe occurrences have been reported in individuals with chronic illnesses like asthma, obesity, cardiovascular diseases and diabetes.

In contrast to the swine flu, coronavirus is not so common, has caused fewer fatalities, has more case fatality rate, has a longer growth time and less impact on young people.

Coronavirus Versus Severe Acute Respiratory Syndrome (SARS)

SARS was discovered in 2003 as it spread from bats to humans resulted in about 774 fatalities. By May there were eventually about 8,100 reports across 17 countries, with a 15% case fatality rate. The number is estimated to be closer to 9.6% as confirmed cases are counted, with 0.9% cardiothoracic ratio for people aged 20–29, rising to 28% for people aged 70–79. Similar to coronavirus, SARS had bad results for males than females in all age categories [ 36 – 38 ].

Coronavirus is more common relative to SARS, which ended in more overall fatalities, lower case fatality rate, the even higher case fatality rate in older ages, and poorer results for males.

Coronavirus Versus Hong Kong Flu (H3N2)

The Hong Kong flu pandemic erupted on 13 July 1968, with 1–4 million deaths globally by 1969. It was one of the greatest flu pandemics of the twentieth century, but thankfully the case fatality rate was smaller than the epidemic of 1918, resulting in fewer fatalities overall. That may have been attributed to the fact that citizens had generated immunity owing to a previous epidemic in 1957 and to better medical treatment [ 39 ].

In contrast to the Hong Kong flu, coronavirus is not so common, has caused in fewer fatalities and has a higher case fatality rate.

Coronavirus Versus Spanish Flu (H1N1)

The 1918 Spanish flu pandemic was one of the greatest occurrences of recorded history. During the first year of the pandemic, lifespan in the US dropped by 12 years, with more civilians killed than HIV/AIDS in 24 h [ 40 – 42 ].

Regardless of the name, the epidemic did not necessarily arise in Spain; wartime censors in Germany, the United States, the United Kingdom and France blocked news of the disease, but Spain did not, creating the misleading perception that more cases and fatalities had occurred relative to its neighbours

This strain of H1N1 eventually affected more than 500 million men, or 27% of the world’s population at the moment, and had deaths of between 40 and 50 million. At the end of 1920, 1.7% of the world’s people had expired of this illness, including an exceptionally high death rate for young adults aged between 20 and 40 years.

In contrast to the Spanish flu, coronavirus is not so common, has caused in fewer fatalities, has a higher case fatality rate, is more harmful to older ages and is less risky for individuals aged 20–40 years.

Coronavirus Versus Common Cold (Typically Rhinovirus)

Common cold is the most common illness impacting people—Typically, a person suffers from 2–3 colds each year and the average kid will catch 6–8 during the similar time span. Although there are more than 200 cold-associated virus types, infections are uncommon and fatalities are very rare and typically arise mainly in extremely old, extremely young or immunosuppressed cases [ 43 , 44 ].

In contrast to the common cold, coronavirus is not so prevalent, causes more fatalities, has more case fatality rate, is less infectious and is less likely to impact small children.

Reviews of Online Portals and Social Media for Epidemic Information Dissemination

As COVID-19 started to propagate across the globe, the outbreak contributed to a significant change in the broad technology platforms. Where they once declined to engage in the affairs of their systems, except though the possible danger to public safety became obvious, the advent of a novel coronavirus placed them in a different interventionist way of thought. Big tech firms and social media are taking concrete steps to guide users to relevant, credible details on the virus [ 45 – 48 ]. And some of the measures they’re doing proactively. Below are a few of them.

Facebook started adding a box in the news feed that led users to the Centers for Disease Control website regarding COVID-19. It reflects a significant departure from the company’s normal strategy of placing items in the News Feed. The purpose of the update, after all, is personalization—Facebook tries to give the posts you’re going to care about, whether it is because you’re connected with a person or like a post. In the virus package, Facebook has placed a remarkable algorithmic thumb on the scale, potentially pushing millions of people to accurate, authenticated knowledge from a reputable source.

Similar initiatives have been adopted by Twitter. Searching for COVID-19 will carry you to a page highlighting the latest reports from public health groups and credible national news outlets. The search also allows for common misspellings. Twitter has stated that although Russian-style initiatives to cause discontent by large-scale intelligence operations have not yet been observed, a zero-tolerance approach to network exploitation and all other attempts to exploit their service at this crucial juncture will be expected. The problem has the attention of the organization. It also offers promotional support to public service agencies and other non-profit groups.

Google has made a step in making it better for those who choose to operate or research from home, offering specialized streaming services to all paying G Suite customers. Google also confirmed that free access to ‘advanced’ Hangouts Meet apps will be rolled out to both G Suite and G Suite for Education clients worldwide through 1st July. It ensures that companies can hold meetings of up to 250 people, broadcast live to up to about 100,000 users within a single network, and archive and export meetings to Google Drive. Usually, Google pays an additional $13 per person per month for these services in comparison to G Suite’s ‘enterprise’ membership, which adds up to a total of about $25 per client each month.

Microsoft took a similar move, introducing the software ‘Chat Device’ to help public health and protection in the coronavirus epidemic, which enables collaborative collaboration via video and text messaging. There’s an aspect of self-interest in this. Tech firms are offering out their goods free of charge during periods of emergency for the same purpose as newspapers are reducing their paywalls: it’s nice to draw more paying consumers.

Pinterest, which has introduced much of the anti-misinformation strategies that Facebook and Twitter are already embracing, is now restricting the search results for ‘coronavirus’, ‘COVID-19’ and similar words for ‘internationally recognized health organizations’.

Google-owned YouTube, traditionally the most conspiratorial website, has recently introduced a connection to the World Health Organization virus epidemic page to the top of the search results. In the early days of the epidemic, BuzzFeed found famous coronavirus conspiratorial videos on YouTube—especially in India, where one ‘explain’ with a false interpretation of the sources of the disease racketeered 13 million views before YouTube deleted it. Yet in the United States, conspiratorial posts regarding the illness have failed to gain only 1 million views.

That’s not to suggest that misinformation doesn’t propagate on digital platforms—just as it travels through the broader Internet, even though interaction with friends and relatives. When there’s a site that appears to be under-performing in the global epidemic, it’s Facebook-owned WhatsApp, where the Washington Post reported ‘a torrent of disinformation’ in places like Nigeria, Indonesia, Peru, Pakistan and Ireland. Given the encrypted existence of the app, it is difficult to measure the severity of the problem. Misinformation is also spread in WhatsApp communities, where participation is restricted to about 250 individuals. Knowledge of one category may be readily exchanged with another; however, there is a considerable amount of complexity of rotating several groups to peddle affected healing remedies or propagate false rumours.

Preventative Measures and Policies Enforced by the World Health Organization (WHO) and Different Countries

Coronavirus is already an ongoing epidemic, so it is necessary to take precautions to minimize both the risk of being sick and the transmission of the disease.

WHO Advice [ 49 ]

• Wash hands regularly with alcohol-based hand wash or soap and water.
• Preserve contact space (at least 1 m/3 feet between you and someone who sneezes or coughs).
• Don’t touch your nose, head and ears.
• Cover your nose and mouth as you sneeze or cough, preferably with your bent elbow or tissue.
• Try to find early medical attention if you have fatigue, cough and trouble breathing.
• Take preventive precautions if you are in or have recently go to places where coronavirus spreads.

The first person believed to have become sick because of the latest virus was near in Wuhan on 1 December 2019. A formal warning of the epidemic was released on 31 December. The World Health Organization was informed of the epidemic on the same day. Through 7 January, the Chinese Government addressed the avoidance and regulation of COVID-19. A curfew was declared on 23 January to prohibit flying in and out of Wuhan. Private usage of cars has been banned in the region. Chinese New Year (25 January) festivities have been cancelled in many locations [ 50 ].

On 26 January, the Communist Party and the Government adopted more steps to contain the COVID-19 epidemic, including safety warnings for travellers and improvements to national holidays. The leading party has agreed to prolong the Spring Festival holiday to control the outbreak. Universities and schools across the world have already been locked down. Many steps have been taken by the Hong Kong and Macau governments, in particular concerning schools and colleges. Remote job initiatives have been placed in effect in many regions of China. Several immigration limits have been enforced.

Certain counties and cities outside Hubei also implemented travel limits. Public transit has been changed and museums in China have been partially removed. Some experts challenged the quality of the number of cases announced by the Chinese Government, which constantly modified the way coronavirus cases were recorded.

Italy, a member state of the European Union and a popular tourist attraction, entered the list of coronavirus-affected nations on 30 January, when two positive cases in COVID-19 were identified among Chinese tourists. Italy has the largest number of coronavirus infections both in Europe and outside of China [ 51 ].

Infections, originally limited to northern Italy, gradually spread to all other areas. Many other nations in Asia, Europe and the Americas have tracked their local cases to Italy. Several Italian travellers were even infected with coronavirus-positive in foreign nations.

Late in Italy, the most impacted coronavirus cities and counties are Lombardia, accompanied by Veneto, Emilia-Romagna, Marche and Piedmonte. Milan, the second most populated city in Italy, is situated in Lombardy. Other regions in Italy with coronavirus comprised Campania, Toscana, Liguria, Lazio, Sicilia, Friuli Venezia Giulia, Umbria, Puglia, Trento, Abruzzo, Calabria, Molise, Valle d’Aosta, Sardegna, Bolzano and Basilicata.

Italy ranks 19th of the top 30 nations getting high-risk coronavirus airline passengers in China, as per WorldPop’s provisional study of the spread of COVID-19.

The Italian State has taken steps like the inspection and termination of large cultural activities during the early days of the coronavirus epidemic and has gradually declared the closing of educational establishments and airport hygiene/disinfection initiatives.

The Italian National Institute of Health suggested social distancing and agreed that the broader community of the country’s elderly is a problem. In the meantime, several other nations, including the US, have recommended that travel to Italy should be avoided temporarily, unless necessary.

The Italian government has declared the closing (quarantine) of the impacted areas in the northern region of the nation so as not to spread to the rest of the world. Italy has declared the immediate suspension of all to-and-fro air travel with China following coronavirus discovery by a Chinese tourist to Italy. Italian airlines, like Ryan Air, have begun introducing protective steps and have begun calling for the declaration forms to be submitted by passengers flying to Poland, Slovakia and Lithuania.

The Italian government first declined to permit fans to compete in sporting activities until early April to prevent the potential transmission of coronavirus. The step ensured players of health and stopped event cancellations because of coronavirus fears. Two days of the declaration, the government cancelled all athletic activities owing to the emergence of the outbreak asking for an emergency. Sports activities in Veneto, Lombardy and Emilia-Romagna, which recorded coronavirus-positive infections, were confirmed to be temporarily suspended. Schools and colleges in Italy have also been forced to shut down.

Iran announced the first recorded cases of SARS-CoV-2 infection on 19 February when, as per the Medical Education and Ministry of Health, two persons died later that day. The Ministry of Islamic Culture and Guidance has declared the cancellation of all concerts and other cultural activities for one week. The Medical Education and Ministry of Health has also declared the closing of universities, higher education colleges and schools in many cities and regions. The Department of Sports and Culture has taken action to suspend athletic activities, including football matches [ 52 ].

On 2 March 2020, the government revealed plans to train about 300,000 troops and volunteers to fight the outbreak of the epidemic, and also send robots and water cannons to clean the cities. The State also developed an initiative and a webpage to counter the epidemic. On 9 March 2020, nearly 70,000 inmates were immediately released from jail owing to the epidemic, presumably to prevent the further dissemination of the disease inside jails. The Revolutionary Guards declared a campaign on 13 March 2020 to clear highways, stores and public areas in Iran. President Hassan Rouhani stated on 26 February 2020 that there were no arrangements to quarantine areas impacted by the epidemic and only persons should be quarantined. The temples of Shia in Qom stayed open to pilgrims.

South Korea

On 20 January, South Korea announced its first occurrence. There was a large rise in cases on 20 February, possibly due to the meeting in Daegu of a progressive faith community recognized as the Shincheonji Church of Christ. Any citizens believed that the hospital was propagating the disease. As of 22 February, 1,261 of the 9,336 members of the church registered symptoms. A petition was distributed calling for the abolition of the church. More than 2,000 verified cases were registered on 28 February, increasing to 3,150 on 29 February [ 53 ].

Several educational establishments have been partially closing down, including hundreds of kindergartens in Daegu and many primary schools in Seoul. As of 18 February, several South Korean colleges had confirmed intentions to delay the launch of the spring semester. That included 155 institutions deciding to postpone the start of the semester by two weeks until 16 March, and 22 institutions deciding to delay the start of the semester by one week until 9 March. Also, on 23 February 2020, all primary schools, kindergartens, middle schools and secondary schools were declared to postpone the start of the semester from 2 March to 9 March.

South Korea’s economy is expected to expand by 1.9%, down from 2.1%. The State has given 136.7 billion won funding to local councils. The State has also coordinated the purchase of masks and other sanitary supplies. Entertainment Company SM Entertainment is confirmed to have contributed five hundred million won in attempts to fight the disease.

In the kpop industry, the widespread dissemination of coronavirus within South Korea has contributed to the cancellation or postponement of concerts and other programmes for kpop activities inside and outside South Korea. For instance, circumstances such as the cancellation of the remaining Asian dates and the European leg for the Seventeen’s Ode To You Tour on 9 February 2020 and the cancellation of all Seoul dates for the BTS Soul Tour Map. As of 15 March, a maximum of 136 countries and regions provided entry restrictions and/or expired visas for passengers from South Korea.

The overall reported cases of coronavirus rose significantly in France on 12 March. The areas with reported cases include Paris, Amiens, Bordeaux and Eastern Haute-Savoie. The first coronaviral death happened in France on 15 February, marking it the first death in Europe. The second death of a 60-year-old French national in Paris was announced on 26 February [ 54 ].

On February 28, fashion designer Agnès B. (not to be mistaken with Agnès Buzyn) cancelled fashion shows at the Paris Fashion Week, expected to continue until 3 March. On a subsequent day, the Paris half-marathon, planned for Sunday 1 March with 44,000 entrants, was postponed as one of a series of steps declared by Health Minister Olivier Véran.

On 13 March, the Ligue de Football Professional disbanded Ligue 1 and Ligue 2 (France’s tier two professional divisions) permanently due to safety threats.

Germany has a popular Regional Pandemic Strategy detailing the roles and activities of the health care system participants in the case of a significant outbreak. Epidemic surveillance is carried out by the federal government, like the Robert Koch Center, and by the German governments. The German States have their preparations for an outbreak. The regional strategy for the treatment of the current coronavirus epidemic was expanded by March 2020. Four primary goals are contained in this plan: (1) to minimize mortality and morbidity; (2) to guarantee the safety of sick persons; (3) to protect vital health services and (4) to offer concise and reliable reports to decision-makers, the media and the public [ 55 ].

The programme has three phases that may potentially overlap: (1) isolation (situation of individual cases and clusters), (2) safety (situation of further dissemination of pathogens and suspected causes of infection), (3) prevention (situation of widespread infection). So far, Germany has not set up border controls or common health condition tests at airports. Instead, while at the isolation stage-health officials are concentrating on recognizing contact individuals that are subject to specific quarantine and are tracked and checked. Specific quarantine is regulated by municipal health authorities. By doing so, the officials are seeking to hold the chains of infection small, contributing to decreased clusters. At the safety stage, the policy should shift to prevent susceptible individuals from being harmed by direct action. By the end of the day, the prevention process should aim to prevent cycles of acute treatment to retain emergency facilities.

United States

The very first case of coronavirus in the United States was identified in Washington on 21 January 2020 by an individual who flew to Wuhan and returned to the United States. The second case was recorded in Illinois by another individual who had travelled to Wuhan. Some of the regions with reported novel coronavirus infections in the US are California, Arizona, Connecticut, Illinois, Texas, Wisconsin and Washington [ 56 ].

As the epidemic increased, requests for domestic air travel decreased dramatically. By 4 March, U.S. carriers, like United Airlines and JetBlue Airways, started growing their domestic flight schedules, providing generous unpaid leave to workers and suspending recruits.

A significant number of universities and colleges cancelled classes and reopened dormitories in response to the epidemic, like Cornell University, Harvard University and the University of South Carolina.

On 3 March 2020, the Federal Reserve reduced its goal interest rate from 1.75% to 1.25%, the biggest emergency rate cut following the 2008 global financial crash, in combat the effect of the recession on the American economy. In February 2020, US businesses, including Apple Inc. and Microsoft, started to reduce sales projections due to supply chain delays in China caused by the COVID-19.

The pandemic, together with the subsequent financial market collapse, also contributed to greater criticism of the crisis in the United States. Researchers disagree about when a recession is likely to take effect, with others suggesting that it is not unavoidable, while some claim that the world might already be in recession. On 3 March, Federal Reserve Chairman Jerome Powell reported a 0.5% (50 basis point) interest rate cut from the coronavirus in the context of the evolving threats to economic growth.

When ‘social distance’ penetrated the national lexicon, disaster response officials promoted the cancellation of broad events to slow down the risk of infection. Technical conferences like E3 2020, Apple Inc.’s Worldwide Developers Conference (WWDC), Google I/O, Facebook F8, and Cloud Next and Microsoft’s MVP Conference have been either having replaced or cancelled in-person events with internet streaming events.

On February 29, the American Physical Society postponed its annual March gathering, planned for March 2–6 in Denver, Colorado, even though most of the more than 11,000 physicist attendees already had arrived and engaged in the pre-conference day activities. On March 6, the annual South to Southwest (SXSW) seminar and festival planned to take place from March 13–22 in Austin, Texas, was postponed after the city council announced a local disaster and forced conferences to be shut down for the first time in 34 years.

Four of North America’s major professional sports leagues—the National Hockey League (NHL), National Basketball Association (NBA), Major League Soccer (MLS) and Major League Baseball (MLB) —jointly declared on March 9 that they would all limit the media access to player accommodations (such as locker rooms) to control probable exposure.

Emergency Funding to Fight the COVID-19

COVID-19 pandemic has become a common international concern. Different countries are donating funds to fight against it [ 57 – 60 ]. Some of them are mentioned here.

China has allocated about 110.48 billion yuan ($15.93 billion) in coronavirus-related funding.

Foreign Minister Mohammad Javad Zarif said that Iran has requested the International Monetary Fund (IMF) of about $5 billion in emergency funding to help to tackle the coronavirus epidemic that has struck the Islamic Republic hard.

President Donald Trump approved the Emergency Supplementary Budget Bill to support the US response to a novel coronavirus epidemic. The budget plan would include about $8.3 billion in discretionary funding to local health authorities to promote vaccine research for production. Trump originally requested just about $2 billion to combat the epidemic, but Congress quadrupled the number in its version of the bill. Mr. Trump formally announced a national emergency that he claimed it will give states and territories access to up to about $50 billion in federal funding to tackle the spread of the coronavirus outbreak.

California politicians approved a plan to donate about $1 billion on the state’s emergency medical responses as it readies hospitals to fight an expected attack of patients because of the COVID-19 pandemic. The plans, drawn up rapidly in reaction to the dramatic rise in reported cases of the virus, would include the requisite funds to establish two new hospitals in California, with the assumption that the state may not have the resources to take care of the rise in patients. The bill calls for an immediate response of about $500 million from the State General Fund, with an additional about $500 million possible if requested.

India committed about $10 million to the COVID-19 Emergency Fund and said it was setting up a rapid response team of physicians for the South Asian Association for Regional Cooperation (Saarc) countries.

South Korea unveiled an economic stimulus package of about 11.7 trillion won ($9.8 billion) to soften the effects of the biggest coronavirus epidemic outside China as attempts to curb the disease exacerbate supply shortages and drain demand. Of the 11,7 trillion won expected, about 3.2 trillion won would cover up the budget shortfall, while an additional fiscal infusion of about 8.5 trillion won. An estimated 10.3 trillion won in government bonds will be sold this year to fund the extra expenditure. About 2.3 trillion won will be distributed to medical establishments and would support quarantine operations, with another 3.0 trillion won heading to small and medium-sized companies unable to pay salaries to their employees and child care supports.

The Swedish Parliament announced a set of initiatives costing more than 300 billion Swedish crowns ($30.94 billion) to help the economy in the view of the coronavirus pandemic. The plan contained steps like the central government paying the entire expense of the company’s sick leave during April and May, and also the high cost of compulsory redundancies owing to the crisis.

In consideration of the developing scenario, an updating of this strategy is planned to take place before the end of March and will recognize considerably greater funding demands for the country response, R&D and WHO itself.

Artificial Intelligence, Data Science and Technological Solutions Against COVID-19

These days, Artificial Intelligence (AI) takes a major role in health care. Throughout a worldwide pandemic such as the COVID-19, technology, artificial intelligence and data analytics have been crucial in helping communities cope successfully with the epidemic [ 61 – 65 ]. Through the aid of data mining and analytical modelling, medical practitioners are willing to learn more about several diseases.

Public Health Surveillance

The biggest risk of coronavirus is the level of spreading. That’s why policymakers are introducing steps like quarantines around the world because they can’t adequately monitor local outbreaks. One of the simplest measures to identify ill patients through the study of CCTV images that are still around us and to locate and separate individuals that have serious signs of the disease and who have touched and disinfected the related surfaces. Smartphone applications are often used to keep a watch on people’s activities and to assess whether or not they have come in touch with an infected human.

Remote Biosignal Measurement

Many of the signs such as temperature or heartbeat are very essential to overlook and rely entirely on the visual image that may be misleading. However, of course, we can’t prevent someone from checking their blood pressure, heart or temperature. Also, several advances in computer vision can predict pulse and blood pressure based on facial skin examination. Besides, there are several advances in computer vision that can predict pulse and blood pressure based on facial skin examination.

Access to public records has contributed to the development of dashboards that constantly track the virus. Several companies are designing large data dashboards. Face recognition and infrared temperature monitoring technologies have been mounted in all major cities. Chinese AI companies including Hanwang Technology and SenseTime have reported having established a special facial recognition system that can correctly identify people even though they are covered.

IoT and Wearables

Measurements like pulse are much more natural and easier to obtain from tracking gadgets like activity trackers and smartwatches that nearly everybody has already. Some work suggests that the study of cardiac activity and its variations from the standard will reveal early signs of influenza and, in this case, coronavirus.

Chatbots and Communication

Apart from public screening, people’s knowledge and self-assessment may also be used to track their health. If you can check your temperature and pulse every day and monitor your coughs time-to-time, you can even submit that to your record. If the symptoms are too serious, either an algorithm or a doctor remotely may prescribe a person to stay home, take several other preventive measures, or recommend a visit from the doctor.

Al Jazeera announced that China Mobile had sent text messages to state media departments, telling them about the citizens who had been affected. The communications contained all the specifics of the person’s travel history.

Tencent runs WeChat, and via it, citizens can use free online health consultation services. Chatbots have already become important connectivity platforms for transport and tourism service providers to keep passengers up-to-date with the current transport protocols and disturbances.

Social Media and Open Data

There are several people who post their health diary with total strangers via Facebook or Twitter. Such data becomes helpful for more general research about how far the epidemic has progressed. For consumer knowledge, we may even evaluate the social network group to attempt to predict what specific networks are at risk of being viral.

Canadian company BlueDot analyses far more than just social network data: for instance, global activities of more than four billion passengers on international flights per year; animal, human and insect population data; satellite environment data and relevant knowledge from health professionals and journalists, across 100,000 news posts per day covering 65 languages. This strategy was so successful that the corporation was able to alert clients about coronavirus until the World Health Organization and the Centers for Disease Control and Prevention notified the public.

Automated Diagnostics

COVID-19 has brought up another healthcare issue today: it will not scale when the number of patients increases exponentially (actually stressed doctors are always doing worse) and the rate of false-negative diagnosis remains very high. Machine learning therapies don’t get bored and scale simply by growing computing forces.

Baidu, the Chinese Internet company, has made the Lineatrfold algorithm accessible to the outbreak-fighting teams, according to the MIT Technology Review. Unlike HIV, Ebola and Influenza, COVID-19 has just one strand of RNA and it can mutate easily. The algorithm is also simpler than other algorithms that help to determine the nature of the virus. Baidu has also developed software to efficiently track large populations. It has also developed an Ai-powered infrared device that can detect a difference in the body temperature of a human. This is currently being used in Beijing’s Qinghe Railway Station to classify possibly contaminated travellers where up to 200 individuals may be checked in one minute without affecting traffic movement, reports the MIT Review.

Singapore-based Veredus Laboratories, a supplier of revolutionary molecular diagnostic tools, has currently announced the launch of the VereCoV detector package, a compact Lab-on-Chip device able to detect MERS-CoV, SARS-CoV and COVID-19, i.e. Wuhan Coronavirus, in a single study.

The VereCoV identification package is focused on VereChip technology, a Lab-on-Chip device that incorporates two important molecular biological systems, Polymerase Chain Reaction (PCR) and a microarray, which will be able to classify and distinguish within 2 h MERS-CoV, SARS-CoV and COVID-19 with high precision and responsiveness.

This is not just the medical activities of healthcare facilities that are being charged, but also the corporate and financial departments when they cope with the increase in patients. Ant Financials’ blockchain technology helps speed-up the collection of reports and decreases the number of face-to-face encounters with patients and medical personnel.

Companies like the Israeli company Sonovia are aiming to provide healthcare systems and others with face masks manufactured from their anti-pathogenic, anti-bacterial cloth that depends on metal-oxide nanoparticles.

Drug Development Research

Aside from identifying and stopping the transmission of pathogens, the need to develop vaccinations on a scale is also needed. One of the crucial things to make that possible is to consider the origin and essence of the virus. Google’s DeepMind, with their expertise in protein folding research, has rendered a jump in identifying the protein structure of the virus and making it open-source.

BenevolentAI uses AI technologies to develop medicines that will combat the most dangerous diseases in the world and is also working to promote attempts to cure coronavirus, the first time the organization has based its product on infectious diseases. Within weeks of the epidemic, it used its analytical capability to recommend new medicines that might be beneficial.

Robots are not vulnerable to the infection, and they are used to conduct other activities, like cooking meals in hospitals, doubling up as waiters in hotels, spraying disinfectants and washing, selling rice and hand sanitizers, robots are on the front lines all over to deter coronavirus spread. Robots also conduct diagnostics and thermal imaging in several hospitals. Shenzhen-based firm Multicopter uses robotics to move surgical samples. UVD robots from Blue Ocean Robotics use ultraviolet light to destroy viruses and bacteria separately. In China, Pudu Technology has introduced its robots, which are usually used in the cooking industry, to more than 40 hospitals throughout the region. According to the Reuters article, a tiny robot named Little Peanut is distributing food to passengers who have been on a flight from Singapore to Hangzhou, China, and are presently being quarantined in a hotel.

Colour Coding

Using its advanced and vast public service monitoring network, the Chinese government has collaborated with software companies Alibaba and Tencent to establish a colour-coded health ranking scheme that monitors millions of citizens every day. The mobile device was first introduced in Hangzhou with the cooperation of Alibaba. This applies three colours to people—red, green or yellow—based on their transportation and medical records. Tencent also developed related applications in the manufacturing centre of Shenzhen.

The decision of whether an individual will be quarantined or permitted in public spaces is dependent on the colour code. Citizens will sign into the system using pay wallet systems such as Alibaba’s Alipay and Ant’s wallet. Just those citizens who have been issued a green colour code will be permitted to use the QR code in public spaces at metro stations, workplaces, and other public areas. Checkpoints are in most public areas where the body temperature and the code of individual are tested. This programme is being used by more than 200 Chinese communities and will eventually be expanded nationwide.

In some of the seriously infected regions where people remain at risk of contracting the infection, drones are used to rescue. One of the easiest and quickest ways to bring emergency supplies where they need to go while on an epidemic of disease is by drone transportation. Drones carry all surgical instruments and patient samples. This saves time, improves the pace of distribution and reduces the chance of contamination of medical samples. Drones often operate QR code placards that can be checked to record health records. There are also agricultural drones distributing disinfectants in the farmland. Drones, operated by facial recognition, are often used to warn people not to leave their homes and to chide them for not using face masks. Terra Drone uses its unmanned drones to move patient samples and vaccination content at reduced risk between the Xinchang County Disease Control Center and the People’s Hospital. Drones are often used to monitor public areas, document non-compliance with quarantine laws and thermal imaging.

Autonomous Vehicles

At a period of considerable uncertainty to medical professionals and the danger to people-to-people communication, automated vehicles are proving to be of tremendous benefit in the transport of vital products, such as medications and foodstuffs. Apollo, the Baidu Autonomous Vehicle Project, has joined hands with the Neolix self-driving company to distribute food and supplies to a big hospital in Beijing. Baidu Apollo has also provided its micro-car packages and automated cloud driving systems accessible free of charge to virus-fighting organizations.

Idriverplus, a Chinese self-driving organization that runs electrical street cleaning vehicles, is also part of the project. The company’s signature trucks are used to clean hospitals.

This chapter provides an introduction to the coronavirus outbreak (COVID-19). A brief history of this virus along with the symptoms are reported in this chapter. Then the comparison between COVID-19 and other plagues like seasonal influenza, bird flu (H5N1 and H7N9), Ebola epidemic, camel flu (MERS), swine flu (H1N1), severe acute respiratory syndrome, Hong Kong flu (H3N2), Spanish flu and the common cold are included in this chapter. Reviews of online portal and social media like Facebook, Twitter, Google, Microsoft, Pinterest, YouTube and WhatsApp concerning COVID-19 are reported in this chapter. Also, the preventive measures and policies enforced by WHO and different countries such as China, Italy, Iran, South Korea, France, Germany and the United States for COVID-19 are included in this chapter. Emergency funding provided by different countries to fight the COVID-19 is mentioned in this chapter. Lastly, artificial intelligence, data science and technological solutions like public health surveillance, remote biosignal measurement, IoT and wearables, chatbots and communication, social media and open data, automated diagnostics, drug development research, robotics, colour coding, drones and autonomous vehicles are included in this chapter.

• Research article
• Open access
• Published: 04 June 2021

Coronavirus disease (COVID-19) pandemic: an overview of systematic reviews

• Israel Júnior Borges do Nascimento 1 , 2 ,
• Dónal P. O’Mathúna 3 , 4 ,
• Thilo Caspar von Groote 5 ,
• Hebatullah Mohamed Abdulazeem 6 ,
• Ishanka Weerasekara 7 , 8 ,
• Ana Marusic 9 ,
• Livia Puljak   ORCID: orcid.org/0000-0002-8467-6061 10 ,
• Vinicius Tassoni Civile 11 ,
• Irena Zakarija-Grkovic 9 ,
• Tina Poklepovic Pericic 9 ,
• Alvaro Nagib Atallah 11 ,
• Santino Filoso 12 ,
• Nicola Luigi Bragazzi 13 &
• Milena Soriano Marcolino 1

On behalf of the International Network of Coronavirus Disease 2019 (InterNetCOVID-19)

BMC Infectious Diseases volume  21 , Article number:  525 ( 2021 ) Cite this article

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Navigating the rapidly growing body of scientific literature on the SARS-CoV-2 pandemic is challenging, and ongoing critical appraisal of this output is essential. We aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic.

Nine databases (Medline, EMBASE, Cochrane Library, CINAHL, Web of Sciences, PDQ-Evidence, WHO’s Global Research, LILACS, and Epistemonikos) were searched from December 1, 2019, to March 24, 2020. Systematic reviews analyzing primary studies of COVID-19 were included. Two authors independently undertook screening, selection, extraction (data on clinical symptoms, prevalence, pharmacological and non-pharmacological interventions, diagnostic test assessment, laboratory, and radiological findings), and quality assessment (AMSTAR 2). A meta-analysis was performed of the prevalence of clinical outcomes.

Eighteen systematic reviews were included; one was empty (did not identify any relevant study). Using AMSTAR 2, confidence in the results of all 18 reviews was rated as “critically low”. Identified symptoms of COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%) and gastrointestinal complaints (5–9%). Severe symptoms were more common in men. Elevated C-reactive protein and lactate dehydrogenase, and slightly elevated aspartate and alanine aminotransferase, were commonly described. Thrombocytopenia and elevated levels of procalcitonin and cardiac troponin I were associated with severe disease. A frequent finding on chest imaging was uni- or bilateral multilobar ground-glass opacity. A single review investigated the impact of medication (chloroquine) but found no verifiable clinical data. All-cause mortality ranged from 0.3 to 13.9%.

Conclusions

In this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic were of questionable usefulness. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards.

Peer Review reports

The spread of the “Severe Acute Respiratory Coronavirus 2” (SARS-CoV-2), the causal agent of COVID-19, was characterized as a pandemic by the World Health Organization (WHO) in March 2020 and has triggered an international public health emergency [ 1 ]. The numbers of confirmed cases and deaths due to COVID-19 are rapidly escalating, counting in millions [ 2 ], causing massive economic strain, and escalating healthcare and public health expenses [ 3 , 4 ].

The research community has responded by publishing an impressive number of scientific reports related to COVID-19. The world was alerted to the new disease at the beginning of 2020 [ 1 ], and by mid-March 2020, more than 2000 articles had been published on COVID-19 in scholarly journals, with 25% of them containing original data [ 5 ]. The living map of COVID-19 evidence, curated by the Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre), contained more than 40,000 records by February 2021 [ 6 ]. More than 100,000 records on PubMed were labeled as “SARS-CoV-2 literature, sequence, and clinical content” by February 2021 [ 7 ].

Due to publication speed, the research community has voiced concerns regarding the quality and reproducibility of evidence produced during the COVID-19 pandemic, warning of the potential damaging approach of “publish first, retract later” [ 8 ]. It appears that these concerns are not unfounded, as it has been reported that COVID-19 articles were overrepresented in the pool of retracted articles in 2020 [ 9 ]. These concerns about inadequate evidence are of major importance because they can lead to poor clinical practice and inappropriate policies [ 10 ].

Systematic reviews are a cornerstone of today’s evidence-informed decision-making. By synthesizing all relevant evidence regarding a particular topic, systematic reviews reflect the current scientific knowledge. Systematic reviews are considered to be at the highest level in the hierarchy of evidence and should be used to make informed decisions. However, with high numbers of systematic reviews of different scope and methodological quality being published, overviews of multiple systematic reviews that assess their methodological quality are essential [ 11 , 12 , 13 ]. An overview of systematic reviews helps identify and organize the literature and highlights areas of priority in decision-making.

In this overview of systematic reviews, we aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic.

Methodology

Research question.

This overview’s primary objective was to summarize and critically appraise systematic reviews that assessed any type of primary clinical data from patients infected with SARS-CoV-2. Our research question was purposefully broad because we wanted to analyze as many systematic reviews as possible that were available early following the COVID-19 outbreak.

Study design

We conducted an overview of systematic reviews. The idea for this overview originated in a protocol for a systematic review submitted to PROSPERO (CRD42020170623), which indicated a plan to conduct an overview.

Overviews of systematic reviews use explicit and systematic methods for searching and identifying multiple systematic reviews addressing related research questions in the same field to extract and analyze evidence across important outcomes. Overviews of systematic reviews are in principle similar to systematic reviews of interventions, but the unit of analysis is a systematic review [ 14 , 15 , 16 ].

We used the overview methodology instead of other evidence synthesis methods to allow us to collate and appraise multiple systematic reviews on this topic, and to extract and analyze their results across relevant topics [ 17 ]. The overview and meta-analysis of systematic reviews allowed us to investigate the methodological quality of included studies, summarize results, and identify specific areas of available or limited evidence, thereby strengthening the current understanding of this novel disease and guiding future research [ 13 ].

A reporting guideline for overviews of reviews is currently under development, i.e., Preferred Reporting Items for Overviews of Reviews (PRIOR) [ 18 ]. As the PRIOR checklist is still not published, this study was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 statement [ 19 ]. The methodology used in this review was adapted from the Cochrane Handbook for Systematic Reviews of Interventions and also followed established methodological considerations for analyzing existing systematic reviews [ 14 ].

Approval of a research ethics committee was not necessary as the study analyzed only publicly available articles.

Eligibility criteria

Systematic reviews were included if they analyzed primary data from patients infected with SARS-CoV-2 as confirmed by RT-PCR or another pre-specified diagnostic technique. Eligible reviews covered all topics related to COVID-19 including, but not limited to, those that reported clinical symptoms, diagnostic methods, therapeutic interventions, laboratory findings, or radiological results. Both full manuscripts and abbreviated versions, such as letters, were eligible.

No restrictions were imposed on the design of the primary studies included within the systematic reviews, the last search date, whether the review included meta-analyses or language. Reviews related to SARS-CoV-2 and other coronaviruses were eligible, but from those reviews, we analyzed only data related to SARS-CoV-2.

No consensus definition exists for a systematic review [ 20 ], and debates continue about the defining characteristics of a systematic review [ 21 ]. Cochrane’s guidance for overviews of reviews recommends setting pre-established criteria for making decisions around inclusion [ 14 ]. That is supported by a recent scoping review about guidance for overviews of systematic reviews [ 22 ].

Thus, for this study, we defined a systematic review as a research report which searched for primary research studies on a specific topic using an explicit search strategy, had a detailed description of the methods with explicit inclusion criteria provided, and provided a summary of the included studies either in narrative or quantitative format (such as a meta-analysis). Cochrane and non-Cochrane systematic reviews were considered eligible for inclusion, with or without meta-analysis, and regardless of the study design, language restriction and methodology of the included primary studies. To be eligible for inclusion, reviews had to be clearly analyzing data related to SARS-CoV-2 (associated or not with other viruses). We excluded narrative reviews without those characteristics as these are less likely to be replicable and are more prone to bias.

Scoping reviews and rapid reviews were eligible for inclusion in this overview if they met our pre-defined inclusion criteria noted above. We included reviews that addressed SARS-CoV-2 and other coronaviruses if they reported separate data regarding SARS-CoV-2.

Information sources

Nine databases were searched for eligible records published between December 1, 2019, and March 24, 2020: Cochrane Database of Systematic Reviews via Cochrane Library, PubMed, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Web of Sciences, LILACS (Latin American and Caribbean Health Sciences Literature), PDQ-Evidence, WHO’s Global Research on Coronavirus Disease (COVID-19), and Epistemonikos.

The comprehensive search strategy for each database is provided in Additional file 1 and was designed and conducted in collaboration with an information specialist. All retrieved records were primarily processed in EndNote, where duplicates were removed, and records were then imported into the Covidence platform [ 23 ]. In addition to database searches, we screened reference lists of reviews included after screening records retrieved via databases.

Study selection

All searches, screening of titles and abstracts, and record selection, were performed independently by two investigators using the Covidence platform [ 23 ]. Articles deemed potentially eligible were retrieved for full-text screening carried out independently by two investigators. Discrepancies at all stages were resolved by consensus. During the screening, records published in languages other than English were translated by a native/fluent speaker.

Data collection process

We custom designed a data extraction table for this study, which was piloted by two authors independently. Data extraction was performed independently by two authors. Conflicts were resolved by consensus or by consulting a third researcher.

We extracted the following data: article identification data (authors’ name and journal of publication), search period, number of databases searched, population or settings considered, main results and outcomes observed, and number of participants. From Web of Science (Clarivate Analytics, Philadelphia, PA, USA), we extracted journal rank (quartile) and Journal Impact Factor (JIF).

We categorized the following as primary outcomes: all-cause mortality, need for and length of mechanical ventilation, length of hospitalization (in days), admission to intensive care unit (yes/no), and length of stay in the intensive care unit.

The following outcomes were categorized as exploratory: diagnostic methods used for detection of the virus, male to female ratio, clinical symptoms, pharmacological and non-pharmacological interventions, laboratory findings (full blood count, liver enzymes, C-reactive protein, d-dimer, albumin, lipid profile, serum electrolytes, blood vitamin levels, glucose levels, and any other important biomarkers), and radiological findings (using radiography, computed tomography, magnetic resonance imaging or ultrasound).

We also collected data on reporting guidelines and requirements for the publication of systematic reviews and meta-analyses from journal websites where included reviews were published.

Quality assessment in individual reviews

Two researchers independently assessed the reviews’ quality using the “A MeaSurement Tool to Assess Systematic Reviews 2 (AMSTAR 2)”. We acknowledge that the AMSTAR 2 was created as “a critical appraisal tool for systematic reviews that include randomized or non-randomized studies of healthcare interventions, or both” [ 24 ]. However, since AMSTAR 2 was designed for systematic reviews of intervention trials, and we included additional types of systematic reviews, we adjusted some AMSTAR 2 ratings and reported these in Additional file 2 .

Adherence to each item was rated as follows: yes, partial yes, no, or not applicable (such as when a meta-analysis was not conducted). The overall confidence in the results of the review is rated as “critically low”, “low”, “moderate” or “high”, according to the AMSTAR 2 guidance based on seven critical domains, which are items 2, 4, 7, 9, 11, 13, 15 as defined by AMSTAR 2 authors [ 24 ]. We reported our adherence ratings for transparency of our decision with accompanying explanations, for each item, in each included review.

One of the included systematic reviews was conducted by some members of this author team [ 25 ]. This review was initially assessed independently by two authors who were not co-authors of that review to prevent the risk of bias in assessing this study.

Synthesis of results

For data synthesis, we prepared a table summarizing each systematic review. Graphs illustrating the mortality rate and clinical symptoms were created. We then prepared a narrative summary of the methods, findings, study strengths, and limitations.

For analysis of the prevalence of clinical outcomes, we extracted data on the number of events and the total number of patients to perform proportional meta-analysis using RStudio© software, with the “meta” package (version 4.9–6), using the “metaprop” function for reviews that did not perform a meta-analysis, excluding case studies because of the absence of variance. For reviews that did not perform a meta-analysis, we presented pooled results of proportions with their respective confidence intervals (95%) by the inverse variance method with a random-effects model, using the DerSimonian-Laird estimator for τ 2 . We adjusted data using Freeman-Tukey double arcosen transformation. Confidence intervals were calculated using the Clopper-Pearson method for individual studies. We created forest plots using the RStudio© software, with the “metafor” package (version 2.1–0) and “forest” function.

Managing overlapping systematic reviews

Some of the included systematic reviews that address the same or similar research questions may include the same primary studies in overviews. Including such overlapping reviews may introduce bias when outcome data from the same primary study are included in the analyses of an overview multiple times. Thus, in summaries of evidence, multiple-counting of the same outcome data will give data from some primary studies too much influence [ 14 ]. In this overview, we did not exclude overlapping systematic reviews because, according to Cochrane’s guidance, it may be appropriate to include all relevant reviews’ results if the purpose of the overview is to present and describe the current body of evidence on a topic [ 14 ]. To avoid any bias in summary estimates associated with overlapping reviews, we generated forest plots showing data from individual systematic reviews, but the results were not pooled because some primary studies were included in multiple reviews.

Our search retrieved 1063 publications, of which 175 were duplicates. Most publications were excluded after the title and abstract analysis ( n = 860). Among the 28 studies selected for full-text screening, 10 were excluded for the reasons described in Additional file 3 , and 18 were included in the final analysis (Fig. 1 ) [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Reference list screening did not retrieve any additional systematic reviews.

PRISMA flow diagram

Characteristics of included reviews

Summary features of 18 systematic reviews are presented in Table 1 . They were published in 14 different journals. Only four of these journals had specific requirements for systematic reviews (with or without meta-analysis): European Journal of Internal Medicine, Journal of Clinical Medicine, Ultrasound in Obstetrics and Gynecology, and Clinical Research in Cardiology . Two journals reported that they published only invited reviews ( Journal of Medical Virology and Clinica Chimica Acta ). Three systematic reviews in our study were published as letters; one was labeled as a scoping review and another as a rapid review (Table 2 ).

All reviews were published in English, in first quartile (Q1) journals, with JIF ranging from 1.692 to 6.062. One review was empty, meaning that its search did not identify any relevant studies; i.e., no primary studies were included [ 36 ]. The remaining 17 reviews included 269 unique studies; the majority ( N = 211; 78%) were included in only a single review included in our study (range: 1 to 12). Primary studies included in the reviews were published between December 2019 and March 18, 2020, and comprised case reports, case series, cohorts, and other observational studies. We found only one review that included randomized clinical trials [ 38 ]. In the included reviews, systematic literature searches were performed from 2019 (entire year) up to March 9, 2020. Ten systematic reviews included meta-analyses. The list of primary studies found in the included systematic reviews is shown in Additional file 4 , as well as the number of reviews in which each primary study was included.

Population and study designs

Most of the reviews analyzed data from patients with COVID-19 who developed pneumonia, acute respiratory distress syndrome (ARDS), or any other correlated complication. One review aimed to evaluate the effectiveness of using surgical masks on preventing transmission of the virus [ 36 ], one review was focused on pediatric patients [ 34 ], and one review investigated COVID-19 in pregnant women [ 37 ]. Most reviews assessed clinical symptoms, laboratory findings, or radiological results.

Systematic review findings

The summary of findings from individual reviews is shown in Table 2 . Overall, all-cause mortality ranged from 0.3 to 13.9% (Fig. 2 ).

A meta-analysis of the prevalence of mortality

Clinical symptoms

Seven reviews described the main clinical manifestations of COVID-19 [ 26 , 28 , 29 , 34 , 35 , 39 , 41 ]. Three of them provided only a narrative discussion of symptoms [ 26 , 34 , 35 ]. In the reviews that performed a statistical analysis of the incidence of different clinical symptoms, symptoms in patients with COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%), gastrointestinal disorders, such as diarrhea, nausea or vomiting (5.0–9.0%), and others (including, in one study only: dizziness 12.1%) (Figs. 3 , 4 , 5 , 6 , 7 , 8 and 9 ). Three reviews assessed cough with and without sputum together; only one review assessed sputum production itself (28.5%).

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

Three reviews described methodologies, protocols, and tools used for establishing the diagnosis of COVID-19 [ 26 , 34 , 38 ]. The use of respiratory swabs (nasal or pharyngeal) or blood specimens to assess the presence of SARS-CoV-2 nucleic acid using RT-PCR assays was the most commonly used diagnostic method mentioned in the included studies. These diagnostic tests have been widely used, but their precise sensitivity and specificity remain unknown. One review included a Chinese study with clinical diagnosis with no confirmation of SARS-CoV-2 infection (patients were diagnosed with COVID-19 if they presented with at least two symptoms suggestive of COVID-19, together with laboratory and chest radiography abnormalities) [ 34 ].

Therapeutic possibilities

Pharmacological and non-pharmacological interventions (supportive therapies) used in treating patients with COVID-19 were reported in five reviews [ 25 , 27 , 34 , 35 , 38 ]. Antivirals used empirically for COVID-19 treatment were reported in seven reviews [ 25 , 27 , 34 , 35 , 37 , 38 , 41 ]; most commonly used were protease inhibitors (lopinavir, ritonavir, darunavir), nucleoside reverse transcriptase inhibitor (tenofovir), nucleotide analogs (remdesivir, galidesivir, ganciclovir), and neuraminidase inhibitors (oseltamivir). Umifenovir, a membrane fusion inhibitor, was investigated in two studies [ 25 , 35 ]. Possible supportive interventions analyzed were different types of oxygen supplementation and breathing support (invasive or non-invasive ventilation) [ 25 ]. The use of antibiotics, both empirically and to treat secondary pneumonia, was reported in six studies [ 25 , 26 , 27 , 34 , 35 , 38 ]. One review specifically assessed evidence on the efficacy and safety of the anti-malaria drug chloroquine [ 27 ]. It identified 23 ongoing trials investigating the potential of chloroquine as a therapeutic option for COVID-19, but no verifiable clinical outcomes data. The use of mesenchymal stem cells, antifungals, and glucocorticoids were described in four reviews [ 25 , 34 , 35 , 38 ].

Laboratory and radiological findings

Of the 18 reviews included in this overview, eight analyzed laboratory parameters in patients with COVID-19 [ 25 , 29 , 30 , 32 , 33 , 34 , 35 , 39 ]; elevated C-reactive protein levels, associated with lymphocytopenia, elevated lactate dehydrogenase, as well as slightly elevated aspartate and alanine aminotransferase (AST, ALT) were commonly described in those eight reviews. Lippi et al. assessed cardiac troponin I (cTnI) [ 25 ], procalcitonin [ 32 ], and platelet count [ 33 ] in COVID-19 patients. Elevated levels of procalcitonin [ 32 ] and cTnI [ 30 ] were more likely to be associated with a severe disease course (requiring intensive care unit admission and intubation). Furthermore, thrombocytopenia was frequently observed in patients with complicated COVID-19 infections [ 33 ].

Chest imaging (chest radiography and/or computed tomography) features were assessed in six reviews, all of which described a frequent pattern of local or bilateral multilobar ground-glass opacity [ 25 , 34 , 35 , 39 , 40 , 41 ]. Those six reviews showed that septal thickening, bronchiectasis, pleural and cardiac effusions, halo signs, and pneumothorax were observed in patients suffering from COVID-19.

Quality of evidence in individual systematic reviews

Table 3 shows the detailed results of the quality assessment of 18 systematic reviews, including the assessment of individual items and summary assessment. A detailed explanation for each decision in each review is available in Additional file 5 .

Using AMSTAR 2 criteria, confidence in the results of all 18 reviews was rated as “critically low” (Table 3 ). Common methodological drawbacks were: omission of prospective protocol submission or publication; use of inappropriate search strategy: lack of independent and dual literature screening and data-extraction (or methodology unclear); absence of an explanation for heterogeneity among the studies included; lack of reasons for study exclusion (or rationale unclear).

Risk of bias assessment, based on a reported methodological tool, and quality of evidence appraisal, in line with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method, were reported only in one review [ 25 ]. Five reviews presented a table summarizing bias, using various risk of bias tools [ 25 , 29 , 39 , 40 , 41 ]. One review analyzed “study quality” [ 37 ]. One review mentioned the risk of bias assessment in the methodology but did not provide any related analysis [ 28 ].

This overview of systematic reviews analyzed the first 18 systematic reviews published after the onset of the COVID-19 pandemic, up to March 24, 2020, with primary studies involving more than 60,000 patients. Using AMSTAR-2, we judged that our confidence in all those reviews was “critically low”. Ten reviews included meta-analyses. The reviews presented data on clinical manifestations, laboratory and radiological findings, and interventions. We found no systematic reviews on the utility of diagnostic tests.

Symptoms were reported in seven reviews; most of the patients had a fever, cough, dyspnea, myalgia or muscle fatigue, and gastrointestinal disorders such as diarrhea, nausea, or vomiting. Olfactory dysfunction (anosmia or dysosmia) has been described in patients infected with COVID-19 [ 43 ]; however, this was not reported in any of the reviews included in this overview. During the SARS outbreak in 2002, there were reports of impairment of the sense of smell associated with the disease [ 44 , 45 ].

The reported mortality rates ranged from 0.3 to 14% in the included reviews. Mortality estimates are influenced by the transmissibility rate (basic reproduction number), availability of diagnostic tools, notification policies, asymptomatic presentations of the disease, resources for disease prevention and control, and treatment facilities; variability in the mortality rate fits the pattern of emerging infectious diseases [ 46 ]. Furthermore, the reported cases did not consider asymptomatic cases, mild cases where individuals have not sought medical treatment, and the fact that many countries had limited access to diagnostic tests or have implemented testing policies later than the others. Considering the lack of reviews assessing diagnostic testing (sensitivity, specificity, and predictive values of RT-PCT or immunoglobulin tests), and the preponderance of studies that assessed only symptomatic individuals, considerable imprecision around the calculated mortality rates existed in the early stage of the COVID-19 pandemic.

Few reviews included treatment data. Those reviews described studies considered to be at a very low level of evidence: usually small, retrospective studies with very heterogeneous populations. Seven reviews analyzed laboratory parameters; those reviews could have been useful for clinicians who attend patients suspected of COVID-19 in emergency services worldwide, such as assessing which patients need to be reassessed more frequently.

All systematic reviews scored poorly on the AMSTAR 2 critical appraisal tool for systematic reviews. Most of the original studies included in the reviews were case series and case reports, impacting the quality of evidence. Such evidence has major implications for clinical practice and the use of these reviews in evidence-based practice and policy. Clinicians, patients, and policymakers can only have the highest confidence in systematic review findings if high-quality systematic review methodologies are employed. The urgent need for information during a pandemic does not justify poor quality reporting.

We acknowledge that there are numerous challenges associated with analyzing COVID-19 data during a pandemic [ 47 ]. High-quality evidence syntheses are needed for decision-making, but each type of evidence syntheses is associated with its inherent challenges.

The creation of classic systematic reviews requires considerable time and effort; with massive research output, they quickly become outdated, and preparing updated versions also requires considerable time. A recent study showed that updates of non-Cochrane systematic reviews are published a median of 5 years after the publication of the previous version [ 48 ].

Authors may register a review and then abandon it [ 49 ], but the existence of a public record that is not updated may lead other authors to believe that the review is still ongoing. A quarter of Cochrane review protocols remains unpublished as completed systematic reviews 8 years after protocol publication [ 50 ].

Rapid reviews can be used to summarize the evidence, but they involve methodological sacrifices and simplifications to produce information promptly, with inconsistent methodological approaches [ 51 ]. However, rapid reviews are justified in times of public health emergencies, and even Cochrane has resorted to publishing rapid reviews in response to the COVID-19 crisis [ 52 ]. Rapid reviews were eligible for inclusion in this overview, but only one of the 18 reviews included in this study was labeled as a rapid review.

Ideally, COVID-19 evidence would be continually summarized in a series of high-quality living systematic reviews, types of evidence synthesis defined as “ a systematic review which is continually updated, incorporating relevant new evidence as it becomes available ” [ 53 ]. However, conducting living systematic reviews requires considerable resources, calling into question the sustainability of such evidence synthesis over long periods [ 54 ].

Research reports about COVID-19 will contribute to research waste if they are poorly designed, poorly reported, or simply not necessary. In principle, systematic reviews should help reduce research waste as they usually provide recommendations for further research that is needed or may advise that sufficient evidence exists on a particular topic [ 55 ]. However, systematic reviews can also contribute to growing research waste when they are not needed, or poorly conducted and reported. Our present study clearly shows that most of the systematic reviews that were published early on in the COVID-19 pandemic could be categorized as research waste, as our confidence in their results is critically low.

Our study has some limitations. One is that for AMSTAR 2 assessment we relied on information available in publications; we did not attempt to contact study authors for clarifications or additional data. In three reviews, the methodological quality appraisal was challenging because they were published as letters, or labeled as rapid communications. As a result, various details about their review process were not included, leading to AMSTAR 2 questions being answered as “not reported”, resulting in low confidence scores. Full manuscripts might have provided additional information that could have led to higher confidence in the results. In other words, low scores could reflect incomplete reporting, not necessarily low-quality review methods. To make their review available more rapidly and more concisely, the authors may have omitted methodological details. A general issue during a crisis is that speed and completeness must be balanced. However, maintaining high standards requires proper resourcing and commitment to ensure that the users of systematic reviews can have high confidence in the results.

Furthermore, we used adjusted AMSTAR 2 scoring, as the tool was designed for critical appraisal of reviews of interventions. Some reviews may have received lower scores than actually warranted in spite of these adjustments.

Another limitation of our study may be the inclusion of multiple overlapping reviews, as some included reviews included the same primary studies. According to the Cochrane Handbook, including overlapping reviews may be appropriate when the review’s aim is “ to present and describe the current body of systematic review evidence on a topic ” [ 12 ], which was our aim. To avoid bias with summarizing evidence from overlapping reviews, we presented the forest plots without summary estimates. The forest plots serve to inform readers about the effect sizes for outcomes that were reported in each review.

Several authors from this study have contributed to one of the reviews identified [ 25 ]. To reduce the risk of any bias, two authors who did not co-author the review in question initially assessed its quality and limitations.

Finally, we note that the systematic reviews included in our overview may have had issues that our analysis did not identify because we did not analyze their primary studies to verify the accuracy of the data and information they presented. We give two examples to substantiate this possibility. Lovato et al. wrote a commentary on the review of Sun et al. [ 41 ], in which they criticized the authors’ conclusion that sore throat is rare in COVID-19 patients [ 56 ]. Lovato et al. highlighted that multiple studies included in Sun et al. did not accurately describe participants’ clinical presentations, warning that only three studies clearly reported data on sore throat [ 56 ].

In another example, Leung [ 57 ] warned about the review of Li, L.Q. et al. [ 29 ]: “ it is possible that this statistic was computed using overlapped samples, therefore some patients were double counted ”. Li et al. responded to Leung that it is uncertain whether the data overlapped, as they used data from published articles and did not have access to the original data; they also reported that they requested original data and that they plan to re-do their analyses once they receive them; they also urged readers to treat the data with caution [ 58 ]. This points to the evolving nature of evidence during a crisis.

Our study’s strength is that this overview adds to the current knowledge by providing a comprehensive summary of all the evidence synthesis about COVID-19 available early after the onset of the pandemic. This overview followed strict methodological criteria, including a comprehensive and sensitive search strategy and a standard tool for methodological appraisal of systematic reviews.

In conclusion, in this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all the reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic could be categorized as research waste. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards to provide patients, clinicians, and decision-makers trustworthy evidence.

Availability of data and materials

All data collected and analyzed within this study are available from the corresponding author on reasonable request.

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Acknowledgments

We thank Catherine Henderson DPhil from Swanscoe Communications for pro bono medical writing and editing support. We acknowledge support from the Covidence Team, specifically Anneliese Arno. We thank the whole International Network of Coronavirus Disease 2019 (InterNetCOVID-19) for their commitment and involvement. Members of the InterNetCOVID-19 are listed in Additional file 6 . We thank Pavel Cerny and Roger Crosthwaite for guiding the team supervisor (IJBN) on human resources management.

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

Helene Fuld Health Trust National Institute for Evidence-based Practice in Nursing and Healthcare, College of Nursing, The Ohio State University, Columbus, OH, USA

Dónal P. O’Mathúna

School of Nursing, Psychotherapy and Community Health, Dublin City University, Dublin, Ireland

Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

Thilo Caspar von Groote

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Hebatullah Mohamed Abdulazeem

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Livia Puljak

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IJBN conceived the research idea and worked as a project coordinator. DPOM, TCVG, HMA, IW, AM, LP, VTC, IZG, TPP, ANA, SF, NLB and MSM were involved in data curation, formal analysis, investigation, methodology, and initial draft writing. All authors revised the manuscript critically for the content. The author(s) read and approved the final manuscript.

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Supplementary Information

Additional file 1: appendix 1..

Search strategies used in the study.

Additional file 2: Appendix 2.

Adjusted scoring of AMSTAR 2 used in this study for systematic reviews of studies that did not analyze interventions.

Additional file 3: Appendix 3.

List of excluded studies, with reasons.

Additional file 4: Appendix 4.

Table of overlapping studies, containing the list of primary studies included, their visual overlap in individual systematic reviews, and the number in how many reviews each primary study was included.

Additional file 5: Appendix 5.

A detailed explanation of AMSTAR scoring for each item in each review.

Additional file 6: Appendix 6.

List of members and affiliates of International Network of Coronavirus Disease 2019 (InterNetCOVID-19).

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Borges do Nascimento, I.J., O’Mathúna, D.P., von Groote, T.C. et al. Coronavirus disease (COVID-19) pandemic: an overview of systematic reviews. BMC Infect Dis 21 , 525 (2021). https://doi.org/10.1186/s12879-021-06214-4

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Covid-19: emergence, spread, possible treatments, and global burden.

• 1 Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
• 2 Department of Health Sciences, School of Education and Health, Cape Breton University, Sydney, NS, Canada

The Coronavirus (CoV) is a large family of viruses known to cause illnesses ranging from the common cold to acute respiratory tract infection. The severity of the infection may be visible as pneumonia, acute respiratory syndrome, and even death. Until the outbreak of SARS, this group of viruses was greatly overlooked. However, since the SARS and MERS outbreaks, these viruses have been studied in greater detail, propelling the vaccine research. On December 31, 2019, mysterious cases of pneumonia were detected in the city of Wuhan in China's Hubei Province. On January 7, 2020, the causative agent was identified as a new coronavirus (2019-nCoV), and the disease was later named as COVID-19 by the WHO. The virus spread extensively in the Wuhan region of China and has gained entry to over 210 countries and territories. Though experts suspected that the virus is transmitted from animals to humans, there are mixed reports on the origin of the virus. There are no treatment options available for the virus as such, limited to the use of anti-HIV drugs and/or other antivirals such as Remdesivir and Galidesivir. For the containment of the virus, it is recommended to quarantine the infected and to follow good hygiene practices. The virus has had a significant socio-economic impact globally. Economically, China is likely to experience a greater setback than other countries from the pandemic due to added trade war pressure, which have been discussed in this paper.

Introduction

Coronaviridae is a family of viruses with a positive-sense RNA that possess an outer viral coat. When looked at with the help of an electron microscope, there appears to be a unique corona around it. This family of viruses mainly cause respiratory diseases in humans, in the forms of common cold or pneumonia as well as respiratory infections. These viruses can infect animals as well ( 1 , 2 ). Up until the year 2003, coronavirus (CoV) had attracted limited interest from researchers. However, after the SARS (severe acute respiratory syndrome) outbreak caused by the SARS-CoV, the coronavirus was looked at with renewed interest ( 3 , 4 ). This also happened to be the first epidemic of the 21st century originating in the Guangdong province of China. Almost 10 years later, there was a MERS (Middle East respiratory syndrome) outbreak in 2012, which was caused by the MERS-CoV ( 5 , 6 ). Both SARS and MERS have a zoonotic origin and originated from bats. A unique feature of these viruses is the ability to mutate rapidly and adapt to a new host. The zoonotic origin of these viruses allows them to jump from host to host. Coronaviruses are known to use the angiotensin-converting enzyme-2 (ACE-2) receptor or the dipeptidyl peptidase IV (DPP-4) protein to gain entry into cells for replication ( 7 – 10 ).

In December 2019, almost seven years after the MERS 2012 outbreak, a novel Coronavirus (2019-nCoV) surfaced in Wuhan in the Hubei region of China. The outbreak rapidly grew and spread to neighboring countries. However, rapid communication of information and the increasing scale of events led to quick quarantine and screening of travelers, thus containing the spread of the infection. The major part of the infection was restricted to China, and a second cluster was found on a cruise ship called the Diamond Princess docked in Japan ( 11 , 12 ).

The new virus was identified to be a novel Coronavirus and was thus initially named 2019-nCoV; later, it was renamed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ( 13 ), and the disease it causes is now referred to as Coronavirus Disease-2019 (COVID-19) by the WHO. The virus was suspected to have begun its spread in the Huanan seafood wholesale market in the Wuhan region. It is possible that an animal that was carrying the virus was brought into or sold in the market, causing the spread of the virus in the crowded marketplace. One of the first claims made was in an article published in the Journal of Medical Virology ( 14 ), which identified snakes as the possible host. A second possibility was that pangolins could be the wild host of SARS-CoV-2 ( 15 ), though the most likely possibility is that the virus originated from bats ( 13 , 16 – 19 ). Increasing evidence and experts are now collectively concluding the virus had a natural origin in bats, as with previous such respiratory viruses ( 2 , 20 – 24 ).

Similarly, SARS and MERS were also suspected to originate from bats. In the case of MERS, the dromedary camel is an intermediate host ( 5 , 10 ). Bats have been known to harbor coronaviruses for quite some time now. Just as in the case of avian flu, SARS, MERS, and possibly even HIV, with increasing selection and ecological pressure due to human activities, the virus made the jump from animal to man. Humans have been encroaching increasingly into forests, and this is true over much of China, as in Africa. Combined with additional ecological pressure due to climate change, such zoonotic spillovers are now more common than ever. It is likely that the next disease X will also have such an origin ( 25 ). We have learned the importance of identification of the source organism due to the Ebola virus pandemic. Viruses are unstable organisms genetically, constantly mutating by genetic shift or drift. It is not possible to predict when a cross-species jump may occur and when a seemingly harmless variant form of the virus may turn into a deadly strain. Such an incident occurred in Reston, USA, with the Reston virus ( 26 ), an alarming reminder of this possibility. The identification of the original host helps us to contain future spreads as well as to learn about the mechanism of transmission of viruses. Until the virus is isolated from a wild animal host, in this case, mostly bats, the zoonotic origin will remain hypothetical, though likely. It should further be noted that the virus has acquired several mutations, as noted by a group in China, indicating that there are more than two strains of the virus, which may have had an impact on its pathogenicity. However, this claim remains unproven, and many experts have argued otherwise; data proving this are not yet available ( 27 ). A similar finding was reported from Italy and India independently, where they found two strains ( 28 , 29 ). These findings need to be further cross-verified by similar analyses globally. If true, this finding could effectively explain why some nations are more affected than others.

Transmission

When the spread of COVID-19 began ( Figure 1 ), the virus appeared to be contained within China and the cruise ship “Diamond Princess,” which formed the major clusters of the virus. However, as of April 2020, over 210 countries and territories are affected by the virus, with Europe, the USA, and Iran forming the new cluster of the virus. The USA ( Figure 2 ) has the highest number of confirmed COVID-19 cases, whereas India and China, despite being among the most population-dense countries in the world, have managed to constrain the infection rate by the implementation of a complete lockdown with arrangements in place to manage the confirmed cases. Similarly, the UK has also managed to maintain a low curve of the graph by implementing similar measures, though it was not strictly enforced. Reports have indicated that the presence of different strains or strands of the virus may have had an effect on the management of the infection rate of the virus ( 27 – 29 ). The disease is spread by droplet transmission. As of April 2020, the total number of infected individuals stands at around 3 million, with ~200,000 deaths and more than 1 million recoveries globally ( 30 , 34 ). The virus thus has a fatality rate of around 2% and an R 0 of 3 based on current data. However, a more recent report from the CDC, Atlanta, USA, claims that the R 0 could be as high as 5.7 ( 35 ). It has also been observed from data available from China and India that individuals likely to be infected by the virus from both these countries belong to the age groups of 20–50 years ( 36 , 37 ). In both of these countries, the working class mostly belongs to this age group, making exposure more likely. Germany and Singapore are great examples of countries with a high number of cases but low fatalities as compared to their immediate neighbors. Singapore is one of the few countries that had developed a detailed plan of action after the previous SARS outbreak to deal with a similar situation in the future, and this worked in their favor during this outbreak. Both countries took swift action after the outbreak began, with Singapore banning Chinese travelers and implementing screening and quarantine measures at a time when the WHO recommended none. They ordered the elderly and the vulnerable to strictly stay at home, and they ensured that lifesaving equipment and large-scale testing facilities were available immediately ( 38 , 39 ). Germany took similar measures by ramping up testing capacity quite early and by ensuring that all individuals had equal opportunity to get tested. This meant that young, old, and at-risk people all got tested, thus ensuring positive results early during disease progression and that most cases were mild like in Singapore, thus maintaining a lower death percentage ( 40 ). It allowed infected individuals to be identified and quarantined before they even had symptoms. Testing was carried out at multiple labs, reducing the load and providing massive scale, something which countries such as the USA did quite late and India restricted to select government and private labs. The German government also banned large gatherings and advocated social distancing to further reduce the spread, though unlike India and the USA, this was done quite late. South Korea is another example of how a nation has managed to contain the spread and transmission of the infection. South Korea and the USA both reported their first COVID-19 cases on the same day; however, the US administration downplayed the risks of the disease, unlike South Korean officials, who constantly informed their citizens about the developments of the disease using the media and a centralized messaging system. They also employed the Trace, Test, and Treat protocol to identify and isolate patients fast, whereas the USA restricted this to patients with severe infection and only later broadened this criterion, like many European countries as well as India. Unlike the USA, South Korea also has universal healthcare, ensuring free diagnostic testing.

Figure 1 . Timeline of COVID-19 progression ( 30 – 32 ).

Figure 2 . Total confirmed COVID 19 cases as of May 2020 ( 33 ).

The main mode of transmission of 2019-nCoV is human to human. As of now, animal-to-human transfer has not yet been confirmed. Asymptomatic carriers of the virus are at major risk of being superinfectors with this disease, as all those infected may not develop the disease ( 41 ). This is a concern that has been raised by nations globally, with the Indian government raising concerns on how to identify and contain asymptomatic carriers, who could account for 80% of those infected ( 42 ). Since current resources are directed towards understanding the hospitalized individuals showing symptoms, there is still a vast amount of information about asymptomatic individuals that has yet to be studied. For example, some questions that need to be answered include: Do asymptomatic individuals develop the disease at any point in time at all? Do they eventually develop antibodies? How long do they shed the virus for? Can any tissue of these individuals store the virus in a dormant state? Asymptomatic transmission is a gray area that encompasses major unknowns in COVID-19.

The main route of human-to-human transmission is by droplets, which are generated during coughing, talking, or sneezing and are then inhaled by a healthy individual. They can also be indirectly transmitted to a person when they land on surfaces that are touched by a healthy individual who may then touch their nose, mouth, or eyes, allowing the virus entry into the body. Fomites are also a common issue in such diseases ( 43 ).

Aerosol-based transmission of the virus has not yet been confirmed ( 43 ). Stool-based transmission via the fecal-oral route may also be possible since the SARS-CoV-2 has been found in patient feces ( 44 , 45 ). Some patients with COVID-19 tend to develop diarrhea, which can become a major route of transmission if proper sanitation and personal hygiene needs are not met. There is no evidence currently available to suggest intrauterine vertical transmission of the disease in pregnant women ( 46 ).

More investigation is necessary of whether climate has played any role in the containment of the infection in countries such as India, Singapore, China, and Israel, as these are significantly warmer countries as compared with the UK, the USA, and Canada ( Figure 2 ). Ideally, a warm climate should prevent the virus from surviving for longer periods of time on surfaces, reducing transmissibility.

Pathophysiology

On gaining entry via any of the mucus membranes, the single-stranded RNA-based virus enters the host cell using type 2 transmembrane serine protease (TMPRSS2) and ACE2 receptor protein, leading to fusion and endocytosis with the host cell ( 47 – 49 ). The uncoated RNA is then translated, and viral proteins are synthesized. With the help of RNA-dependant RNA polymerase, new RNA is produced for the new virions. The cell then undergoes lysis, releasing a load of new virions into the patients' body. The resultant infection causes a massive release of pro-inflammatory cytokines that causes a cytokine storm.

Clinical Presentation

The clinical presentation of the disease resembles beta coronavirus infections. The virus has an incubation time of 2–14 days, which is the reason why most patients suspected to have the illness or contact with an individual having the illness remain in quarantine for the said amount of time. Infection with SARS-CoV-2 causes severe pneumonia, intermittent fever, and cough ( 50 , 51 ). Symptoms of rhinorrhoea, pharyngitis, and sneezing have been less commonly seen. Patients often develop acute respiratory distress syndrome within 2 days of hospital admission, requiring ventilatory support. It has been observed that during this phase, the mortality tends to be high. Chest CT will show indicators of pneumonia and ground-glass opacity, a feature that has helped to improve the preliminary diagnosis ( 51 ). The primary method of diagnosis for SARS-CoV-2 is with the help of PCR. For the PCR testing, the US CDC recommends testing for the N gene, whereas the Chinese CDC recommends the use of ORF lab and N gene of the viral genome for testing. Some also rely on the radiological findings for preliminary screening ( 52 ). Additionally, immunodiagnostic tests based on the presence of antibodies can also play a role in testing. While the WHO recommends the use of these tests for research use, many countries have pre-emptively deployed the use of these tests in the hope of ramping up the rate and speed of testing ( 52 – 54 ). Later, they noticed variations among the results, causing them to stop the use of such kits; there was also debate among the experts about the sensitivity and specificity of the tests. For immunological tests, it is beneficial to test for antibodies against the virus produced by the body rather than to test for the presence of the viral proteins, since the antibodies can be present in larger titers for a longer span of time. However, the cross-reactivity of these tests with other coronavirus antibodies is something that needs verification. Biochemical parameters such as D-dimer, C-reactive protein, and variations in neutrophil and lymphocyte counts are some other parameters that can be used to make a preliminary diagnosis; however, these parameters vary in a number of diseases and thus cannot be relied upon conclusively ( 51 ). Patients with pre-existing diseases such as asthma or similar lung disorder are at higher risk, requiring life support, as are those with other diseases such as diabetes, hypertension, or obesity. Those above the age of 60 have displayed the highest mortality rate in China, a finding that is mirrored in other nations as well ( Figure 3 ) ( 55 ). If we cross-verify these findings with the population share that is above the age of 70, we find that Italy, the United Kingdom, Canada, and the USA have one of the highest elderly populations as compared to countries such as India and China ( Figure 4 ), and this also reflects the case fatality rates accordingly ( Figure 5 ) ( 33 ). This is a clear indicator that aside from comorbidities, age is also an independent risk factor for death in those infected by COVID-19. Also, in the US, it was seen that the rates of African American deaths were higher. This is probably due to the fact that the prevalence of hypertension and obesity in this community is higher than in Caucasians ( 56 , 57 ). In late April 2020, there are also claims in the US media that young patients in the US with COVID-19 may be at increased risk of stroke; however, this is yet to be proven. We know that coagulopathy is a feature of COVID-19, and thus stroke is likely in this condition ( 58 , 59 ). The main cause of death in COVID-19 patients was acute respiratory distress due to the inflammation in the linings of the lungs caused by the cytokine storm, which is seen in all non-survival cases and in respiratory failure. The resultant inflammation in the lungs, served as an entry point of further infection, associated with coagulopathy end-organ failure, septic shock, and secondary infections leading to death ( 60 – 63 ).

Figure 3 . Case fatality rate by age in selected countries as of April 2020 ( 33 ).

Figure 4 . Case fatality rate in selected countries ( 33 ).

Figure 5 . Population share above 70 years of age ( 33 ).

For COVID-19, there is no specific treatment available. The WHO announced the organization of a trial dubbed the “Solidarity” clinical trial for COVID-19 treatments ( 64 ). This is an international collaborative study that investigates the use of a few prime candidate drugs for use against COVID-19, which are discussed below. The study is designed to reduce the time taken for an RCT by over 80%. There are over 1087 studies ( Supplementary Data 1 ) for COVID-19 registered at clinicaltrials.gov , of which 657 are interventional studies ( Supplementary Data 2 ) ( 65 ). The primary focus of the interventional studies for COVID-19 has been on antimalarial drugs and antiviral agents ( Table 1 ), while over 200 studies deal with the use of different forms of oxygen therapy. Most trials focus on improvement of clinical status, reduction of viral load, time to improvement, and reduction of mortality rates. These studies cover both severe and mild cases.

Table 1 . List of therapeutic drugs under study for COVID-19 as per clinical trials registered under clinicaltrials.gov .

Use of Antimalarial Drugs Against SARS-CoV-2

The use of chloroquine for the treatment of corona virus-based infection has shown some benefit in the prevention of viral replication in the cases of SARS and MERS. However, it was not validated on a large scale in the form of a randomized control trial ( 50 , 66 – 68 ). The drugs of choice among antimalarials are Chloroquine (CQ) and Hydroxychloroquine (HCQ). The use of CQ for COVID-19 was brought to light by the Chinese, especially by the publication of a letter to the editor of Bioscience Trends by Gao et al. ( 69 ). The letter claimed that several studies found CQ to be effective against COVID-19; however, the letter did not provide many details. Immediately, over a short span of time, interest in these two agents grew globally. Early in vitro data have revealed that chloroquine can inhibit the viral replication ( 70 , 71 ).

HCQ and CQ work by raising the pH of the lysosome, the cellular organelle that is responsible for phagocytic degradation. Its function is to combine with cell contents that have been phagocytosed and break them down eventually, in some immune cells, as a downstream process to display some of the broken proteins as antigens, thus further enhancing the immune recruitment against an antigen/pathogen. The drug was to be administered alone or with azithromycin. The use of azithromycin may be advocated by the fact that it has been seen previously to have some immunomodulatory role in airway-related disease. It appears to reduce the release of pro-inflammatory cytokines in respiratory illnesses ( 72 ). However, HCQ and azithromycin are known to have a major drug interaction when co-administered, which increases the risk of QT interval prolongation ( 73 ). Quinine-based drugs are known to have adverse effects such as QT prolongation, retinal damage, hypoglycemia, and hemolysis of blood in patients with G-6-PD deficiency ( 66 ). Several preprints, including, a metanalysis now indicate that HCQ may have no benefit for severe or critically ill patients who have COVID-19 where the outcome is need for ventilation or death ( 74 , 75 ). As of April 21, 2020, after having pre-emptively recommended their use for SARS-CoV-2 infection, the US now advocates against the use of these two drugs based on the new data that has become available.

Use of Antiviral Drugs Against SARS-CoV-2

The antiviral agents are mainly those used in the case of HIV/AIDS, these being Lopinavir and Ritonavir. Other agents such as nucleoside analogs like Favipiravir, Ribavirin, Remdesivir, and Galidesivir have been tested for possible activity in the prevention of viral RNA synthesis ( 76 ). Among these drugs, Lopinavir, Ritonavir, and Remdesivir are listed in the Solidarity trial by the WHO.

Remdesivir is a nucleotide analog for adenosine that gets incorporated into the viral RNA, hindering its replication and causing chain termination. This agent was originally developed for Ebola Virus Disease ( 77 ). A study was conducted with rhesus macaques infected with SARS-CoV-2 ( 78 ). In that study, after 12 h of infection, the monkeys were treated with either Remdesivir or vehicle. The drug showed good distribution in the lungs, and the animals treated with the drug showed a better clinical score than the vehicle group. The radiological findings of the study also indicated that the animals treated with Remdesivir have less lung damage. There was a reduction in viral replication but not in virus shedding. Furthermore, there were no mutations found in the RNA polymerase sequences. A randomized clinical control study that became available in late April 2020 ( 79 ), having 158 on the Remdesivir arm and 79 on the placebo arm, found that Remdesivir reduced the time to recovery in the Remdesivir-treated arm to 11 days, while the placebo-arm recovery time was 15 days. Though this was not found to be statistically significant, the agent provided a basis for further studies. The 28-days mortality was found to be similar for both groups. This has now provided us with a basis on which to develop future molecules. The study has been supported by the National Institute of Health, USA. The authors of the study advocated for more clinical trials with Remdesivir with a larger population. Such larger studies are already in progress, and their results are awaited. Remdesivir is currently one of the drugs that hold most promise against COVID-19.

An early trial in China with Lopinavir and Ritonavir showed no benefit compared with standard clinical care ( 80 ). More studies with this drug are currently underway, including one in India ( 81 , 82 ).

Use of Convalescent Patient Plasma

Another possible option would be the use of serum from convalescent individuals, as this is known to contain antibodies that can neutralize the virus and aid in its elimination. This has been tried previously for other coronavirus infections ( 83 ). Early emerging case reports in this aspect look promising compared to other therapies that have been tried ( 84 – 87 ). A report from China indicates that five patients treated with plasma recovered and were eventually weaned off ventilators ( 84 ). They exhibited reductions in fever and viral load and improved oxygenation. The virus was not detected in the patients after 12 days of plasma transfusion. The US FDA has provided detailed recommendations for investigational COVID-19 Convalescent Plasma use ( 88 ). One of the benefits of this approach is that it can also be used for post-exposure prophylaxis. This approach is now beginning to be increasingly adopted in other countries, with over 95 trials registered on clinicaltrials.gov alone, of which at least 75 are interventional ( 89 ). The use of convalescent patient plasma, though mostly for research purposes, appears to be the best and, so far, the only successful option for treatment available.

From a future perspective, the use of monoclonal antibodies for the inhibition of the attachment of the virus to the ACE-2 receptor may be the best bet. Aside from this, ACE-2-like molecules could also be utilized to attach and inactivate the viral proteins, since inhibition of the ACE-2 receptor would not be advisable due to its negative repercussions physiologically. In the absence of drug regimens and a vaccine, the treatment is symptomatic and involves the use of non-invasive ventilation or intubation where necessary for respiratory failure patients. Patients that may go into septic shock should be managed as per existing guidelines with hemodynamic support as well as antibiotics where necessary.

The WHO has recommended that simple personal hygiene practices can be sufficient for the prevention of spread and containment of the disease ( 90 ). Practices such as frequent washing of soiled hands or the use of sanitizer for unsoiled hands help reduce transmission. Covering of mouth while sneezing and coughing, and disinfection of surfaces that are frequently touched, such as tabletops, doorknobs, and switches with 70% isopropyl alcohol or other disinfectants are broadly recommended. It is recommended that all individuals afflicted by the disease, as well as those caring for the infected, wear a mask to avoid transmission. Healthcare works are advised to wear a complete set of personal protective equipment as per WHO-provided guidelines. Fumigation of dormitories, quarantine rooms, and washing of clothes and other fomites with detergent and warm water can help get rid of the virus. Parcels and goods are not known to transmit the virus, as per information provided by the WHO, since the virus is not able to survive sufficiently in an open, exposed environment. Quarantine of infected individuals and those who have come into contact with an infected individual is necessary to further prevent transmission of the virus ( 91 ). Quarantine is an age-old archaic practice that continues to hold relevance even today for disease containment. With the quarantine being implemented on such a large scale in some countries, taking the form of a national lockdown, the question arises of its impact on the mental health of all individuals. This topic needs to be addressed, especially in countries such as India and China, where it is still a matter of partial taboo to talk about it openly within the society.

In India, the Ministry of Ayurveda, Yoga, and Naturopathy, Unani, Siddha and Homeopathy (AYUSH), which deals with the alternative forms of medicine, issued a press release that the homeopathic, drug Arsenicum album 30, can be taken on an empty stomach for 3 days to provide protection against the infection ( 92 ). It also provided a list of herbal drugs in the same press release as per Ayurvedic and Unani systems of medicine that can boost the immune system to deal with the virus. However, there is currently no evidence to support the use of these systems of medicine against COVID-19, and they need to be tested.

The prevention of the disease with the use of a vaccine would provide a more viable solution. There are no vaccines available for any of the coronaviruses, which includes SARS and MERS. The development of a vaccine, however, is in progress at a rapid pace, though it could take about a year or two. As of April 2020, no vaccine has completed the development and testing process. A popular approach has been with the use of mRNA-based vaccine ( 93 – 96 ). mRNA vaccines have the advantage over conventional vaccines in terms of production, since they can be manufactured easily and do not have to be cultured, as a virus would need to be. Alternative conventional approaches to making a vaccine against SARS-CoV-2 would include the use of live attenuated virus as well as using the isolated spike proteins of the virus. Both of these approaches are in progress for vaccine development ( 97 ). Governments across the world have poured in resources and made changes in their legislation to ensure rapid development, testing, and deployment of a vaccine.

Barriers to Treatment

Lack of transparency and poor media relations.

The lack of government transparency and poor reporting by the media have hampered the measures that could have been taken by healthcare systems globally to deal with the COVID-19 threat. The CDC, as well as the US administration, downplayed the threat and thus failed to stock up on essential supplies, ventilators, and test kits. An early warning system, if implemented, would have caused borders to be shut and early lockdowns. The WHO also delayed its response in sounding the alarm regarding the severity of the outbreak to allow nations globally to prepare for a pandemic. Singapore is a prime example where, despite the WHO not raising concerns and banning travel to and from China, a country banned travelers and took early measures, thus managing the outbreak quite well. South Korea is another example of how things may have played out had those measures by agencies been taken with transparency. Increased transparency would have allowed the healthcare sector to better prepare and reduced the load of patients they had to deal with, helping flatten the curve. The increased patient load and confusion among citizens arising from not following these practices has proved to be a barrier to providing effective treatments to patients with the disease elsewhere in the world.

Lack of Preparedness and Protocols

Despite the previous SARS outbreak teaching us important lessons and providing us with data on a potential outbreak, many nations did not take the important measures needed for a future outbreak. There was no allocation of sufficient funds for such an event. Many countries experienced severe lack of PPE, and the lockdown precautions hampered the logistics of supply and manufacturing of such essential equipment. Singapore and South Korea had protocols in place and were able to implement them at a moment's notice. The spurt of cases that Korea experienced was managed well, providing evidence to this effect. The lack of preparedness and lack of protocol in other nations has resulted in confusion as to how the treatment may be administered safely to the large volume of patients while dealing with diagnostics. Both of these factors have limited the accessibility to healthcare services due to sheer volume.

Socio-Economic Impact

During the SARS epidemic, China faced an economic setback, and experts were unsure if any recovery would be made. However, the global and domestic situation was then in China's favor, as it had a lower debt, allowing it to make a speedy recovery. This is not the case now. Global experts have a pessimistic outlook on the outcome of this outbreak ( 98 ). The fear of COVID-19 disease, lack of proper understanding of the dangers of the virus, and the misinformation spread on the social media ( 99 ) have caused a breakdown of the economic flow globally ( 100 ). An example of this is Indonesia, where a great amount of fear was expressed in responses to a survey when the nation was still free of COVID-19 ( 101 ). The pandemic has resulted in over 2.6 billion people being put under lockdown. This lockdown and the cancellation of the lunar year celebration has affected business at the local level. Hundreds of flights have been canceled, and tourism globally has been affected. Japan and Indonesia are estimated to lose over 2.44 billion dollars due to this ( 102 , 103 ). Workers are not able to work in factories, transportation in all forms is restricted, and goods are not produced or moved. The transport of finished products and raw materials out of China is low. The Economist has published US stock market details indicating that companies in the US that have Chinese roots fell, on average, 5 points on the stock market as compared to the S&P 500 index ( 104 ). Companies such as Starbucks have had to close over 4,000 outlets due to the outbreak as a precaution. Tech and pharma companies are at higher risk since they rely on China for the supply of raw materials and active pharmaceutical ingredients. Paracetamol, for one, has reported a price increase of over 40% in India ( 104 – 106 ). Mass hysteria in the market has caused selling of shares of these companies, causing a tumble in the Indian stock market. Though long-term investors will not be significantly affected, short-term traders will find themselves in soup. Politically, however, this has further bolstered support for world leaders in countries such as India, Germany, and the UK, who are achieving good approval ratings, with citizens being satisfied with the government's approach. In contrast, the ratings of US President Donald Trump have dropped due to the manner in which the COVID-19 pandemic was handled. These minor impacts may be of temporary significance, and the worst and direct impact will be on China itself ( 107 – 109 ), as the looming trade war with the USA had a negative impact on the Chinese and Asian markets. The longer production of goods continues to remain suspended, the more adversely it will affect the Chinese economy and the global markets dependent on it ( 110 ). If this disease is not contained, more and more lockdowns by multiple nations will severely affect the economy and lead to many social complications.

The appearance of the 2019 Novel Coronavirus has added and will continue to add to our understanding of viruses. The pandemic has once again tested the world's preparedness for dealing with such outbreaks. It has provided an outlook on how a massive-scale biological event can cause a socio-economic disturbance through misinformation and social media. In the coming months and years, we can expect to gain further insights into SARS-CoV-2 and COVID-19.

Author Contributions

KN: conceptualization. RK, AA, JM, and KN: investigation. RK and AA: writing—original draft preparation. KN, PN, and JM: writing—review and editing. KN: supervision.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The authors would like to acknowledge the contributions made by Dr. Piya Paul Mudgal, Assistant Professor, Manipal Institute of Virology, Manipal Academy of Higher Education towards inputs provided by her during the drafting of the manuscript.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh.2020.00216/full#supplementary-material

Supplementary Data 1, 2. List of all studies registered for COVID-19 on clinicaltrials.gov .

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Keywords: 2019-nCoV, COVID-19, SARS-CoV-2, coronavirus, pandemic, SARS

Citation: Keni R, Alexander A, Nayak PG, Mudgal J and Nandakumar K (2020) COVID-19: Emergence, Spread, Possible Treatments, and Global Burden. Front. Public Health 8:216. doi: 10.3389/fpubh.2020.00216

Received: 21 February 2020; Accepted: 11 May 2020; Published: 28 May 2020.

Reviewed by:

Copyright © 2020 Keni, Alexander, Nayak, Mudgal and Nandakumar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Krishnadas Nandakumar, mailnandakumar77@gmail.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Open Access

Peer-reviewed

Research Article

The impact of the COVID-19 pandemic on scientific research in the life sciences

Roles Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Affiliation AXES, IMT School for Advanced Studies Lucca, Lucca, Italy

Roles Conceptualization, Data curation, Formal analysis, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Chair of Systems Design D-MTEC, ETH Zürich, Zurich, Switzerland

• Massimo Riccaboni, 
• Luca Verginer

• Published: February 9, 2022
• https://doi.org/10.1371/journal.pone.0263001
• Reader Comments

The COVID-19 outbreak has posed an unprecedented challenge to humanity and science. On the one side, public and private incentives have been put in place to promptly allocate resources toward research areas strictly related to the COVID-19 emergency. However, research in many fields not directly related to the pandemic has been displaced. In this paper, we assess the impact of COVID-19 on world scientific production in the life sciences and find indications that the usage of medical subject headings (MeSH) has changed following the outbreak. We estimate through a difference-in-differences approach the impact of the start of the COVID-19 pandemic on scientific production using the PubMed database (3.6 Million research papers). We find that COVID-19-related MeSH terms have experienced a 6.5 fold increase in output on average, while publications on unrelated MeSH terms dropped by 10 to 12%. The publication weighted impact has an even more pronounced negative effect (-16% to -19%). Moreover, COVID-19 has displaced clinical trial publications (-24%) and diverted grants from research areas not closely related to COVID-19. Note that since COVID-19 publications may have been fast-tracked, the sudden surge in COVID-19 publications might be driven by editorial policy.

Citation: Riccaboni M, Verginer L (2022) The impact of the COVID-19 pandemic on scientific research in the life sciences. PLoS ONE 17(2): e0263001. https://doi.org/10.1371/journal.pone.0263001

Editor: Florian Naudet, University of Rennes 1, FRANCE

Received: April 28, 2021; Accepted: January 10, 2022; Published: February 9, 2022

Copyright: © 2022 Riccaboni, Verginer. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The processed data, instructions on how to process the raw PubMed dataset as well as all code are available via Zenodo at https://doi.org/10.5281/zenodo.5121216 .

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The COVID-19 pandemic has mobilized the world scientific community in 2020, especially in the life sciences [ 1 , 2 ]. In the first three months after the pandemic, the number of scientific papers about COVID-19 was fivefold the number of articles on H1N1 swine influenza [ 3 ]. Similarly, the number of clinical trials related to COVID-19 prophylaxis and treatments skyrocketed [ 4 ]. Thanks to the rapid mobilization of the world scientific community, COVID-19 vaccines have been developed in record time. Despite this undeniable success, there is a rising concern about the negative consequences of COVID-19 on clinical trial research, with many projects being postponed [ 5 – 7 ]. According to Evaluate Pharma, clinical trials were one of the pandemic’s first casualties, with a record number of 160 studies suspended for reasons related to COVID-19 in April 2020 [ 8 , 9 ] reporting a total of 1,200 trials suspended as of July 2020. As a consequence, clinical researchers have been impaired by reduced access to healthcare research infrastructures. Particularly, the COVID-19 outbreak took a tall on women and early-career scientists [ 10 – 13 ]. On a different ground, Shan and colleagues found that non-COVID-19-related articles decreased as COVID-19-related articles increased in top clinical research journals [ 14 ]. Fraser and coworker found that COVID-19 preprints received more attention and citations than non-COVID-19 preprints [ 1 ]. More recently, Hook and Porter have found some early evidence of ‘covidisation’ of academic research, with research grants and output diverted to COVID-19 research in 2020 [ 15 ]. How much should scientists switch their efforts toward SARS-CoV-2 prevention, treatment, or mitigation? There is a growing consensus that the current level of ‘covidisation’ of research can be wasteful [ 4 , 5 , 16 ].

Against this background, in this paper, we investigate if the COVID-19 pandemic has induced a shift in biomedical publications toward COVID-19-related scientific production. The objective of the study is to show that scientific articles listing covid-related Medical Subject Headings (MeSH) when compared against covid-unrelated MeSH have been partially displaced. Specifically, we look at several indicators of scientific production in the life sciences before and after the start of the COVID-19 pandemic: (1) number of papers published, (2) impact factor weighted number of papers, (3) opens access, (4) number of publications related to clinical trials, (5) number of papers listing grants, (6) number of papers listing grants existing before the pandemic. Through a natural experiment approach, we analyze the impact of the pandemic on scientific production in the life sciences. We consider COVID-19 an unexpected and unprecedented exogenous source of variation with heterogeneous effects across biomedical research fields (i.e., MeSH terms).

Based on the difference in difference results, we document the displacement effect that the pandemic has had on several aspects of scientific publishing. The overall picture that emerges from this analysis is that there has been a profound realignment of priorities and research efforts. This shift has displaced biomedical research in fields not related to COVID-19.

The rest of the paper is structured as follows. First, we describe the data and our measure of relatedness to COVID-19. Next, we illustrate the difference-in-differences specification we rely on to identify the impact of the pandemic on scientific output. In the results section, we present the results of the difference-in-differences and network analyses. We document the sudden shift in publications, grants and trials towards COVID-19-related MeSH terms. Finally, we discuss the findings and highlight several policy implications.

Materials and methods

The present analysis is based primarily on PubMed and the Medical Subject Headings (MeSH) terminology. This data is used to estimate the effect of the start of the COVID 19 pandemic via a difference in difference approach. This section is structured as follows. We first introduce the data and then the econometric methodology. This analysis is not based on a pre-registered protocol.

Selection of biomedical publications.

We rely on PubMed, a repository with more than 34 million biomedical citations, for the analysis. Specifically, we analyze the daily updated files up to 31/06/2021, extracting all publications of type ‘Journal Article’. For the principal analysis, we consider 3,638,584 papers published from January 2019 to December 2020. We also analyze 11,122,017 papers published from 2010 onwards to identify the earliest usage of a grant and infer if it was new in 2020. We use the SCImago journal ranking statistics to compute the impact factor weighted number (IFWN) of papers in a given field of research. To assign the publication date, we use the ‘electronically published’ dates and, if missing, the ‘print published’ dates.

Medical subject headings.

We rely on the Medical Subject Headings (MeSH) terminology to approximate narrowly defined biomedical research fields. This terminology is a curated medical vocabulary, which is manually added to papers in the PubMed corpus. The fact that MeSH terms are manually annotated makes this terminology ideal for classification purposes. However, there is a delay between publication and annotation, on the order of several months. To address this delay and have the most recent classification, we search for all 28 425 MeSH terms using PubMed’s ESearch utility and classify paper by the results. The specific API endpoint is https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi , the relevant scripts are available with the code. For example, we assign the term ‘Ageusia’ (MeSH ID D000370) to all papers listed in the results of the ESearch API. We apply this method to the whole period (January 2019—December 2020) and obtain a mapping from papers to the MeSH terms. For every MeSH term, we keep track of the year they have been established. For instance, COVID-19 terms were established in 2020 (see Table 1 ): in January 2020, the WHO recommended 2019-nCoV and 2019-nCoV acute respiratory disease as provisional names for the virus and disease. The WHO issued the official terms COVID-19 and SARS-CoV-2 at the beginning of February 2020. By manually annotating publications, all publications referring to COVID-19 and SARS-CoV-2 since January 2020 have been labelled with the related MeSH terms. Other MeSH terms related to COVID-19, such as coronavirus, for instance, have been established years before the pandemic (see Table 2 ). We proxy MeSH term usage via search terms using the PubMed EUtilities API; this means that we are not using the hand-labelled MeSH terms but rather the PubMed search results. This means that the accuracy of the MeSH term we assign to a given paper is not perfect. In practice, this means that we have assigned more MeSH terms to a given term than a human annotator would have.

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https://doi.org/10.1371/journal.pone.0263001.t001

The list contains only terms with at least 100 publications in 2020.

https://doi.org/10.1371/journal.pone.0263001.t002

Clinical trials and publication types.

We classify publications using PubMed’s ‘PublicationType’ field in the XML baseline files (There are 187 publication types, see https://www.nlm.nih.gov/mesh/pubtypes.html ). We consider a publication to be related to a clinical trial if it lists any of the following descriptors:

• D016430: Clinical Trial
• D017426: Clinical Trial, Phase I
• D017427: Clinical Trial, Phase II
• D017428: Clinical Trial, Phase III
• D017429: Clinical Trial, Phase IV
• D018848: Controlled Clinical Trial
• D065007: Pragmatic Clinical Trial
• D000076362: Adaptive Clinical Trial
• D000077522: Clinical Trial, Veterinary

In our analysis of the impact of COVID-19 on publications related to clinical trials, we only consider MeSH terms that are associated at least once with a clinical trial publication over the two years. We apply this restriction to filter out MeSH terms that are very unlikely to be relevant for clinical trial types of research.

Open access.

We proxy the availability of a journal article to the public, i.e., open access, if it is available from PubMed Central. PubMed Central archives full-text journal articles and provides free access to the public. Note that the copyright license may vary across participating publishers. However, the text of the paper is for all effects and purposes freely available without requiring subscriptions or special affiliation.

We infer if a publication has been funded by checking if it lists any grants. We classify grants as either ‘old’, i.e. existed before 2019, or ‘new’, i.e. first observed afterwards. To do so, we collect all grant IDs for 11,122,017 papers from 2010 on-wards and record their first appearance. This procedure is an indirect inference of the year the grant has been granted. The basic assumption is that if a grant number has not been listed in any publication since 2010, it is very likely a new grant. Specifically, an old grant is a grant listed since 2019 observed at least once from 2010 to 2018.

Note that this procedure is only approximate and has a few shortcomings. Mistyped grant numbers (e.g. ‘1234-M JPN’ and ‘1234-M-JPN’) could appear as new grants, even though they existed before, or new grants might be classified as old grants if they have a common ID (e.g. ‘Grant 1’). Unfortunately, there is no central repository of grant numbers and the associated metadata; however, there are plans to assign DOI numbers to grants to alleviate this problem (See https://gitlab.com/crossref/open_funder_registry for the project).

Impact factor weighted publication numbers (IFWN).

In our analysis, we consider two measures of scientific output. First, we simply count the number of publications by MeSH term. However, since journals vary considerably in terms of impact factor, we also weigh the number of publications by the impact factor of the venue (e.g., journal) where it was published. Specifically, we use the SCImago journal ranking statistics to weigh a paper by the impact factor of the journal it appears in. We use the ‘citation per document in the past two years’ for 45,230 ISSNs. Note that a journal may and often has more than one ISSN, i.e., one for the printed edition and one for the online edition. SCImago applies the same score for a venue across linked ISSNs.

For the impact factor weighted number (IFWN) of publication per MeSH terms, this means that all publications are replaced by the impact score of the journal they appear in and summed up.

COVID-19-relatedness.

To measure how closely related to COVID-19 is a MeSH term, we introduce an index of relatedness to COVID-19. First, we identify the focal COVID-19 terms, which appeared in the literature in 2020 (see Table 1 ). Next, for all other pre-existing MeSH terms, we measure how closely related to COVID-19 they end up being.

Our aim is to show that MeSH terms that existed before and are related have experienced a sudden increase in the number of (impact factor weighted) papers.

Intuitively we can read this measure as: what is the probability in 2020 that a COVID-19 MeSH term is present given that we chose a paper with MeSH term i ? For example, given that in 2020 we choose a paper dealing with “Ageusia” (i.e., Complete or severe loss of the subjective sense of taste), there is a 96% probability that this paper also lists COVID-19, see Table 1 .

Note that a paper listing a related MeSH term does not imply that that paper is doing COVID-19 research, but it implies that one of the MeSH terms listed is often used in COVID-19 research.

In sum, in our analysis, we use the following variables:

• Papers: Number of papers by MeSH term;
• Impact: Impact factor weighted number of papers by MeSH term;
• PMC: Papers listed in PubMed central by MeSH term, as a measure of Open Access publications;
• Trials: number of publications of type “Clinical Trial” by MeSH term;
• Grants: number of papers with at least one grant by MeSH term;
• Old Grants: number of papers listing a grant that has been observed between 2010 and 2018, by MeSH term;

Difference-in-differences

The difference-in-differences (DiD) method is an econometric technique to imitate an experimental research design from observation data, sometimes referred to as a quasi-experimental setup. In a randomized controlled trial, subjects are randomly assigned either to the treated or the control group. Analogously, in this natural experiment, we assume that medical subject headings (MeSH) have been randomly assigned to be either treated (related) or not treated (unrelated) by the pandemic crisis.

Before the COVID, for a future health crisis, the set of potentially impacted medical knowledge was not predictable since it depended on the specifics of the emergency. For instance, ageusia (loss of taste), a medical concept existing since 1991, became known to be a specific symptom of COVID-19 only after the pandemic.

Specifically, we exploit the COVID-19 as an unpredictable and exogenous shock that has deeply affected the publication priorities for biomedical scientific production, as compared to the situation before the pandemic. In this setting, COVID-19 is the treatment, and the identification of this new human coronavirus is the event. We claim that treated MeSH terms, i.e., MeSH terms related to COVID-19, have experienced a sudden increase in terms of scientific production and attention. In contrast, research on untreated MeSH terms, i.e., MeSH terms not related to COVID-19, has been displaced by COVID-19. Our analysis compares the scientific output of COVID-19 related and unrelated MeSH terms before and after January 2020.

In our case, some of the terms turn out to be related to COVID-19 in 2020, whereas most of the MeSH terms are not closely related to COVID-19.

Thus β 1 identifies the overall effect on the control group after the event, β 2 the difference across treated and control groups before the event (i.e. the first difference in DiD) and finally the effect on the treated group after the event, net of the first difference, β 3 . This last parameter identifies the treatment effect on the treated group netting out the pre-treatment difference.

For the DiD to have a causal interpretation, it must be noted that pre-event, the trends of the two groups should be parallel, i.e., the common trend assumption (CTA) must be satisfied. We will show that the CTA holds in the results section.

To specify the DiD model, we need to define a period before and after the event and assign a treatment status or level of exposure to each term.

Before and after.

The pre-treatment period is defined as January 2019 to December 2019. The post-treatment period is defined as the months from January 2020 to December 2020. We argue that the state of biomedical research was similar in those two years, apart from the effect of the pandemic.

Treatment status and exposure.

The treatment is determined by the COVID-19 relatedness index σ i introduced earlier. Specifically, this number indicates the likelihood that COVID-19 will be a listed MeSH term, given that we observe the focal MeSH term i . To show that the effect becomes even stronger the closer related the subject is, and for ease of interpretation, we also discretize the relatedness value into three levels of treatment. Namely, we group MeSH terms with a σ between, 0% to 20%, 20% to 80% and 80% to 100%. The choice of alternative grouping strategies does not significantly affect our results. Results for alternative thresholds of relatedness can be computed using the available source code. We complement the dichotomized analysis by using the treatment intensity (relatedness measure σ ) to show that the result persists.

Panel regression.

In this work, we estimate a random effects panel regression where the units of analysis are 28 318 biomedical research fields (i.e. MeSH terms) observed over time before and after the COVID-19 pandemic. The time resolution is at the monthly level, meaning that for each MeSH term, we have 24 observations from January 2019 to December 2020.

The outcome variable Y it identifies the outcome at time t (i.e., month), for MeSH term i . As before, P t identifies the period with P t = 0 if the month is before January 2020 and P t = 1 if it is on or after this date. In (3) , the treatment level is measure by the relatedness to COVID-19 ( σ i ), where again the γ 1 identifies pre-trend (constant) differences and δ 1 the overall effect.

In total, we estimate six coefficients. As before, the δ l coefficient identifies the DiD effect.

Verifying the Common Trend Assumption (CTA).

We show that the CTA holds for this model by comparing the pre-event trends of the control group to the treated groups (COVID-19 related MeSH terms). Namely, we show that the pre-event trends of the control group are the same as the pre-event trends of the treated group.

Co-occurrence analysis

To investigate if the pandemic has caused a reconfiguration of research priorities, we look at the MeSH term co-occurrence network. Precisely, we extract the co-occurrence network of all 28,318 MeSH terms as they appear in the 3.3 million papers. We considered the co-occurrence networks of 2018, 2019 and 2020. Each node represents a MeSH term in these networks, and a link between them indicates that they have been observed at least once together. The weight of the edge between the MeSH terms is given by the number of times those terms have been jointly observed in the same publications.

Medical language is hugely complicated, and this simple representation does not capture the intricacies, subtle nuances and, in fact, meaning of the terms. Therefore, we do not claim that we can identify how the actual usage of MeSH terms has changed from this object, but rather that it has. Nevertheless, the co-occurrence graph captures rudimentary relations between concepts. We argue that absent a shock to the system, their basic usage patterns, change in importance (within the network) would essentially be the same from year to year. However, if we find that the importance of terms changes more than expected in 2020, it stands to reason that there have been some significant changes.

To show that that MeSH usage has been affected, we compute for each term in the years 2018, 2019 and 2020 their PageRank centrality [ 17 ]. The PageRank centrality tells us how likely a random walker traversing a network would be found at a given node if she follows the weights of the empirical edges (i.e., co-usage probability). Specifically, for the case of the MeSH co-occurrence network, this number represents how often an annotator at the National Library of Medicine would assign that MeSH term following the observed general usage patterns. It is a simplistic measure to capture the complexities of biomedical research. Nevertheless, it captures far-reaching interdependence across MeSH terms as the measure uses the whole network to determine the centrality of every MeSH term. A sudden change in the rankings and thus the position of MeSH terms in this network suggests that a given research subject has risen as it is used more often with other important MeSH terms (or vice versa).

We then compare the growth for each MeSH i term in g i (2019), i.e. before the the COVID-19 pandemic, with the growth after the event ( g i (2020)).

Publication growth

Changes in output and COVID-19 relatedness

Before we show the regression results, we provide descriptive evidence that publications from 2019 to 2020 have drastically increased. By showing that this growth correlates strongly with a MeSH term’s COVID-19 relatedness ( σ ), we demonstrate that (1) σ captures an essential aspect of the growth dynamics and (2) highlight the meteoric rise of highly related terms.

We look at the year over year growth in the number of the impact weighted number of publications per MeSH term from 2018 to 2019 and 2019 to 2020 as defined in the methods section.

Fig 1 shows the yearly growth of the impact weighted number of publications per MeSH term. By comparing the growth of the number of publications from the years 2018, 2019 and 2020, we find that the impact factor weighted number of publications has increased by up to a factor of 100 compared to the previous year for Betacoronavirus, one of the most closely related to COVID-19 MeSH term.

Each dot represents, a MeSH term. The y axis (growth) is in symmetric log scale. The x axis shows the COVID-19 relatedness, σ . Note that the position of the dots on the x-axis is the same in the two plots. Below: MeSH term importance gain (PageRank) and their COVID-19 relatedness.

https://doi.org/10.1371/journal.pone.0263001.g001

Fig 1 , first row, reveals how strongly correlated the growth in the IFWN of publication is to the term’s COVID-19 relatedness. For instance, we see that the term ‘Betacoronavirus’ skyrocketed from 2019 to 2020, which is expected given that SARS-CoV-2 is a species of the genus. Conversely, the term ‘Alphacoronavirus’ has not experienced any growth given that it is twin a genus of the Coronaviridae family, but SARS-CoV-2 is not one of its species. Note also the fast growth in the number of publications dealing with ‘Quarantine’. Moreover, MeSH terms that grew significantly from 2018 to 2019 and were not closely related to COVID-19, like ‘Vaping’, slowed down in 2020. From the graph, the picture emerges that publication growth is correlated with COVID-19 relatedness σ and that the growth for less related terms slowed down.

To show that the usage pattern of MeSH terms has changed following the pandemic, we compute the PageRank centrality using graph-tool [ 18 ] as discussed in the Methods section.

Fig 1 , second row, shows the change in the PageRank centrality of the MeSH terms after the pandemic (2019 to 2020, right plot) and before (2018 to 2019, left plot). If there were no change in the general usage pattern, we would expect the variance in PageRank changes to be narrow across the two periods, see (left plot). However, PageRank scores changed significantly more from 2019 to 2020 than from 2018 to 2019, suggesting that there has been a reconfiguration of the network.

To further support this argument, we carry out a DiD regression analysis.

Common trends assumption

As discussed in the Methods section, we need to show that the CTA assumption holds for the DiD to be defined appropriately. We do this by estimating for each month the number of publications and comparing it across treatment groups. This exercise also serves the purpose of a placebo test. By assuming that each month could have potentially been the event’s timing (i.e., the outbreak), we show that January 2020 is the most likely timing of the event. The regression table, as noted earlier, contains over 70 estimated coefficients, hence for ease of reading, we will only show the predicted outcome per month by group (see Fig 2 ). The full regression table with all coefficients is available in the S1 Table .

The y axis is in log scale. The dashed vertical line identifies January 2020. The dashed horizontal line shows the publications in January 2019 for the 0–20% group before the event. This line highlights that the drop happens after the event. The bands around the lines indicate the 95% confidence interval of the predicted values. The results are the output of the Stata margins command.

https://doi.org/10.1371/journal.pone.0263001.g002

Fig 2 shows the predicted number per outcome variable obtained from the panel regression model. These predictions correspond to the predicted value per relatedness group using the regression parameters estimated via the linear panel regression. The bands around the curves are the 95% confidence intervals.

All outcome measures depict a similar trend per month. Before the event (i.e., January 2020), there is a common trend across all groups. In contrast, after the event, we observe a sudden rise for the outcomes of the COVID-19 related treated groups (green and red lines) and a decline in the outcomes for the unrelated group (blue line). Therefore, we can conclude that the CTA assumption holds.

Regression results

Table 3 shows the DiD regression results (see Eq (3) ) for the selected outcome measures: number of publications (Papers), impact factor weighted number of publications (Impact), open access (OA) publications, clinical trial related publications, and publications with existing grants.

https://doi.org/10.1371/journal.pone.0263001.t003

Table 3 shows results for the discrete treatment level version of the DiD model (see Eq (4) ).

Note that the outcome variable is in natural log scale; hence to get the effect of the independent variable, we need to exponentiate the coefficient. For values close to 0, the effect is well approximated by the percentage change of that magnitude.

In both specifications we see that the least related group, drops in the number of publications between 10% and 13%, respectively (first row of Tables 3 and 4 , exp(−0.102) ≈ 0.87). In line with our expectations, the increase in the number of papers published by MeSH term is positively affected by the relatedness to COVID-19. In the discrete model (row 2), we note that the number of documents with MeSH terms with a COVID-19 relatedness between 20 and 80% grows by 18% and highly related terms by a factor of approximately 6.6 (exp(1.88)). The same general pattern can be observed for the impact weighted publication number, i.e., Model (2). Note, however, that the drop in the impact factor weighted output is more significant, reaching -19% for COVID-19 unrelated publications, and related publications growing by a factor of 8.7. This difference suggests that there might be a bias to publish papers on COVID-19 related subjects in high impact factor journals.

https://doi.org/10.1371/journal.pone.0263001.t004

By looking at the number of open access publications (PMC), we note that the least related group has not been affected negatively by the pandemic. However, the number of COVID-19 related publications has drastically increased for the most COVID-19 related group by a factor of 6.2. Note that the substantial increase in the number of papers available through open access is in large part due to journal and editorial policies to make preferentially COVID research immediately available to the public.

Regarding the number of clinical trial publications, we note that the least related group has been affected negatively, with the number of publications on clinical trials dropping by a staggering 24%. At the same time, publications on clinical trials for COVID-19-related MeSH have increased by a factor of 2.1. Note, however, that the effect on clinical trials is not significant in the continuous regression. The discrepancy across Tables 3 and 4 highlights that, especially for trials, the effect is not linear, where only the publications on clinical trials closely related to COVID-19 experiencing a boost.

It has been reported [ 19 ] that while the number of clinical trials registered to treat or prevent COVID-19 has surged with 179 new registrations in the second week of April 2020 alone. Only a few of these have led to publishable results in the 12 months since [ 20 ]. On the other hand, we find that clinical trial publications, considering related MeSH (but not COVID-19 directly), have had significant growth from the beginning of the pandemic. These results are not contradictory. Indeed counting the number of clinical trial publications listing the exact COVID-19 MeSH term (D000086382), we find 212 publications. While this might seem like a small number, consider that in 2020 only 8,485 publications were classified as clinical trials; thus, targeted trials still made up 2.5% of all clinical trials in 2020 . So while one might doubt the effectiveness of these research efforts, it is still the case that by sheer number, they represent a significant proportion of all publications on clinical trials in 2020. Moreover, COVID-19 specific Clinical trial publications in 2020, being a delayed signal of the actual trials, are a lower bound estimate on the true number of such clinical trials being conducted. This is because COVID-19 studies could only have commenced in 2020, whereas other studies had a head start. Thus our reported estimates are conservative, meaning that the true effect on actual clinical trials is likely larger, not smaller.

Research funding, as proxied by the number of publications with grants, follows a similar pattern, but notably, COVID-19-related MeSH terms list the same proportion of grants established before 2019 as other unrelated MeSH terms, suggesting that grants which were not designated for COVID-19 research have been used to support COVID-19 related research. Overall, the number of publications listing a grant has dropped. Note that this should be because the number of publications overall in the unrelated group has dropped. However, we note that the drop in publications is 10% while the decline in publications with at least one grant is 15%. This difference suggests that publications listing grants, which should have more funding, are disproportionately COVID-19 related papers. To further investigate this aspect, we look at whether the grant was old (pre-2019) or appeared for the first time in or after 2019. It stands to reason that an old grant (pre-2019) would not have been granted for a project dealing with the pandemic. Hence we would expect that COVID-19 related MeSH terms to have a lower proportion of old grants than the unrelated group. In models (6) in Table 4 we show that the number of old grants for the unrelated group drops by 13%. At the same time, the number of papers listing old grants (i.e., pre-2019) among the most related group increased by a factor of 3.1. Overall, these results suggest that COVID-19 related research has been funded largely by pre-existing grants, even though a specific mandate tied to the grants for this use is unlikely.

The scientific community has swiftly reallocated research efforts to cope with the COVID-19 pandemic, mobilizing knowledge across disciplines to find innovative solutions in record time. We document this both in terms of changing trends in the biomedical scientific output and the usage of MeSH terms by the scientific community. The flip side of this sudden and energetic prioritization of effort to fight COVID-19 has been a sudden contraction of scientific production in other relevant research areas. All in all, we find strong support to the hypotheses that the COVID-19 crisis has induced a sudden increase of research output in COVID-19 related areas of biomedical research. Conversely, research in areas not related to COVID-19 has experienced a significant drop in overall publishing rates and funding.

Our paper contributes to the literature on the impact of COVID-19 on scientific research: we corroborate previous findings about the surge of COVID-19 related publications [ 1 – 3 ], partially displacing research in COVID-19 unrelated fields of research [ 4 , 14 ], particularly research related to clinical trials [ 5 – 7 ]. The drop in trial research might have severe consequences for patients affected by life-threatening diseases since it will delay access to new and better treatments. We also confirm the impact of COVID-19 on open access publication output [ 1 ]; also, this is milder than traditional outlets. On top of this, we provide more robust evidence on the impact weighted effect of COVID-19 and grant financed research, highlighting the strong displacement effect of COVID-19 on the allocation of financial resources [ 15 ]. We document a substantial change in the usage patterns of MeSH terms, suggesting that there has been a reconfiguration in the way research terms are being combined. MeSH terms highly related to COVID-19 were peripheral in the MeSH usage networks before the pandemic but have become central since 2020. We conclude that the usage patterns have changed, with COVID-19 related MeSH terms occupying a much more prominent role in 2020 than they did in the previous years.

We also contribute to the literature by estimating the effect of COVID-19 on biomedical research in a natural experiment framework, isolating the specific effects of the COVID-19 pandemic on the biomedical scientific landscape. This is crucial to identify areas of public intervention to sustain areas of biomedical research which have been neglected during the COVID-19 crisis. Moreover, the exploratory analysis on the changes in usage patterns of MeSH terms, points to an increase in the importance of covid-related topics in the broader biomedical research landscape.

Our results provide compelling evidence that research related to COVID-19 has indeed displaced scientific production in other biomedical fields of research not related to COVID-19, with a significant drop in (impact weighted) scientific output related to non-COVID-19 and a marked reduction of financial support for publications not related to COVID-19 [ 4 , 5 , 16 ]. The displacement effect is persistent to the end of 2020. As vaccination progresses, we highlight the urgent need for science policy to re-balance support for research activity that was put on pause because of the COVID-19 pandemic.

We find that COVID-19 dramatically impacted clinical research. Reactivation of clinical trials activities that have been postponed or suspended for reasons related to COVID-19 is a priority that should be considered in the national vaccination plans. Moreover, since grants have been diverted and financial incentives have been targeted to sustain COVID-19 research leading to an excessive entry in COVID-19-related clinical trials and the ‘covidisation’ of research, there is a need to reorient incentives to basic research and otherwise neglected or temporally abandoned areas of biomedical research. Without dedicated support in the recovery plans for neglected research of the COVID-19 era, there is a risk that more medical needs will be unmet in the future, possibly exacerbating the shortage of scientific research for orphan and neglected diseases, which do not belong to COVID-19-related research areas.

Limitations

Our empirical approach has some limits. First, we proxy MeSH term usage via search terms using the PubMed EUtilities API. This means that the accuracy of the MeSH term we assign to a given paper is not fully validated. More time is needed for the completion of manually annotated MeSH terms. Second, the timing of publication is not the moment the research has been carried out. There is a lead time between inception, analysis, write-up, review, revision, and final publication. This delay varies across disciplines. Nevertheless, given that the surge in publications happens around the alleged event date, January 2020, we are confident that the publication date is a reasonable yet imperfect estimate of the timing of the research. Third, several journals have publicly declared to fast-track COVID-19 research. This discrepancy in the speed of publication of COVID-19 related research and other research could affect our results. Specifically, a surge or displacement could be overestimated due to a lag in the publication of COVID-19 unrelated research. We alleviate this bias by estimating the effect considering a considerable time after the event (January 2020 to December 2020). Forth, on the one hand, clinical Trials may lead to multiple publications. Therefore we might overestimate the impact of COVID-19 on the number of clinical trials. On the other hand, COVID-19 publications on clinical trials lag behind, so the number of papers related COVID-19 trials is likely underestimated. Therefore, we note that the focus of this paper is scientific publications on clinical trials rather than on actual clinical trials. Fifth, regarding grants, unfortunately, there is no unique centralized repository mapping grant numbers to years, so we have to proxy old grants with grants that appeared in publications from 2010 to 2018. Besides, grant numbers are free-form entries, meaning that PubMed has no validation step to disambiguate or verify that the grant number has been entered correctly. This has the effect of classifying a grant as new even though it has appeared under a different name. We mitigate this problem by using a long period to collect grant numbers and catch many spellings of the same grant, thereby reducing the likelihood of miss-identifying a grant as new when it existed before. Still, unless unique identifiers are widely used, there is no way to verify this.

So far, there is no conclusive evidence on whether entry into COVID-19 has been excessive. However, there is a growing consensus that COVID-19 has displaced, at least temporally, scientific research in COVID-19 unrelated biomedical research areas. Even though it is certainly expected that more attention will be devoted to the emergency during a pandemic, the displacement of biomedical research in other fields is concerning. Future research is needed to investigate the long-run structural consequences of the COVID-19 crisis on biomedical research.

Supporting information

S1 table. common trend assumption (cta) regression table..

Full regression table with all controls and interactions.

https://doi.org/10.1371/journal.pone.0263001.s001

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• 17. Page L, Brin S, Motwani R, Winograd T. The PageRank citation ranking: Bringing order to the web. Stanford InfoLab; 1999.

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• Pandemic Data Initiative
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Research Papers

Jhu has stopped collecting data as of.

After three years of around-the-clock tracking of COVID-19 data from...

The Johns Hopkins Coronavirus Resource Center has collected, verified, and published local, regional, national, and international pandemic data since it launched in March 2020. From the beginning, the information has been freely available to all — researchers, institutions, the media, the public, and policymakers. As a result, the CRC and its data have been cited in many published research papers and reports. Here we have gathered publications authored by CRC team members that focus on the CRC or its data.

July 14, 2022

Misaligned Federal and State Covid data limits demographic insights

CDC underreports cases and deaths among African American and Hispanic or Latino individuals.

February 17, 2022

Experts Call for Open Public Health Data

Johns Hopkins team highlighted the urgent need for better COVID data collection.

Unifying Epidemiologists and Economists

Researchers from disparate fields join to chart a new path for formulating policies in response to future pandemics.

Mobility Data Supported Social Distancing

Study found that physical distancing was an effective COVID mitigation strategy.

Johns Hopkins Engineers Build COVID Dashboard

Lancet Infectious Diseases published first paper detailing how the global map was built.

Researchers Identify Disparities in COVID Testing

Johns Hopkins team conducted an analysis of state-published demographic data

Confused about COVID? Here’s how to read a research paper

Senior Lecturer in Evidence-Based Healthcare and University Ethics Advisor, University of Portsmouth

Disclosure statement

Simon Kolstoe does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

University of Portsmouth provides funding as a member of The Conversation UK.

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Scientific evidence can be difficult to understand. Normally we can rely on experts to interpret it for us, or the media to accurately report any interesting new discoveries, but the pandemic has challenged this.

Almost daily we are faced with contradictory views claiming to be “based on the scientific evidence”. But if you’re not an academic, how can you go about checking the evidence for yourself?

Scientific research is communicated in the form of “research papers” published in professional journals. To ensure accuracy, each paper is carefully checked by both editors and outside academic experts in a process called “peer review”. Although peer review is not perfect , it does tend to ensure articles are more reliable compared with those produced in other types of publishing .

Therefore, to judge the scientific evidence for yourself, you need to read and understand peer-reviewed papers. This can be daunting, but if you approach research papers with the right strategy they can be easier to digest.

1. Find the research paper

Following the publication of new research, the results are often summarised by the media. Frustratingly, these summaries seldom provide a link to the original peer-reviewed paper itself.

To find the original paper, one good strategy is to track down the original press release from the university or company releasing the research. You can also use an academic search engine like Google scholar or PubMed to search for recent papers published by the authors, who are normally (although not always) named by journalists.

Historically readers have had to pay to read academic papers, but increasingly research papers are free to readers through “ open access ” arrangements. Unfortunately, if a paper is not open access, there is not much you can do to read it without paying a fee to the publisher.

2. Read the abstract and look at the pictures

Research papers are long and dense with a very different structure compared with articles in the normal media. Media articles start with the most important information in the first few lines and then add background or contextual information as the article progresses.

Research papers start off with an introduction describing the background, then sections describing the methods and results, a discussion (highlighting strengths and weaknesses of the research), and finally the conclusion – often only in the very last few sentences. However, to help speed up reading, a summary or “abstract” is always provided at the beginning.

The abstract is the best place to start (and is almost always available for free). If you are not an expert in the subject area, make sure you look up any words you do not understand, because everything mentioned in the abstract will be key to understanding the paper as a whole.

After reading the abstract you may find you have gathered all the information you need about the research, but if after reading it you still would like to find out more, have a quick look at the pictures, figures and diagrams (if available) to get a better idea of the experiments being reported.

3. Determine how good the journal is and who wrote the paper

After reading the abstract I normally look at who the authors are, what university or company they work for, and how good the journal publishing the paper is.

Academics with a track record of producing high-quality research are a good sign. The first and last authors listed in research papers are often the most important , so look them up to see what else they have produced.

Having the research published in a good journal is also important, because the better journals are able to access more experienced peer reviewers and editors. Here the “impact factor” of a journal is often quoted, which relates to how many other researchers refer to the papers published in it.

However, in recent years impact factors have been strongly criticised as a way of judging journals, even though it’s still true that the best research is published in a fairly small number of journals. One alternative to relying on the impact factor is to simply look up the journal title online to see what researchers say about it. As researchers spend a lot of time discussing which journals are best, this should allow you to find out fairly quickly whether the journal you’re looking at is a reputable one.

4. Read the discussion

If you have got this far you are probably convinced that the research paper is interesting and worth a bit more effort to read. So next, find the part of the paper that discusses the results (often called the discussion) and read through this carefully, flicking back to the methods or results sections if you need to understand in more detail how the experiments were done. Again, look up any terms you do not understand.

5. Read the introduction and check out some of the references

Once you have a good idea of what the paper is reporting, finish off by reading the introduction – this normally provides an overview of why the experiments were conducted in the first place. You should now have a very good idea of what the paper is reporting and some of the wider context.

If you are particularly interested in the topic, look too at some of the key references that the paper quotes. If the paper isn’t brand new, go back to an academic search engine to see whether others have since referenced (or cited) it, and what they are saying about the research.

6. When a paper is not a paper

A word of warning: not every article published in a journal reports new research. Journals also contain news articles, opinion pieces and reviews. These are seldom peer reviewed, and although still written for a professional audience, are not considered primary research.

Another thing to watch out for are versions of research papers that are made available online in advance of being checked by peer reviewers, in a form called “preprints”. Preprints can be very useful for finding out about new results quickly because the peer review and journal publication process can take up to a year. This has been necessary during the pandemic, for example. These preprints are normally clearly labelled, just as a warning that the information in them should not be relied upon in the same way as a full, peer-reviewed research paper.

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Collection  29 March 2022

2021 Top 25 COVID-19 Articles

The 25 most downloaded  Nature Communications  articles* on COVID-19 published in 2021 illustrate the collaborative efforts of the international community to combat the ongoing pandemic. These papers highlight valuable research into the biology of coronavirus infection, its detection, treatment as well as into vaccine development and the epidemiology of the disease.

Browse all Top 25 subject area collections  here .

*Data obtained from SN Insights (based on Digital Science's Dimensions) and normalised to account for articles published later in the year.

Research highlights

Anti-spike antibody response to natural SARS-CoV-2 infection in the general population

Most people who are infected with SARS-CoV-2 seroconvert within a few weeks, but the determinants and duration of the antibody response are not known. Here, the authors characterise these features of the immune response using data from a large representative community sample of the UK population.

• Philippa C. Matthews
• the COVID-19 Infection Survey team

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.

• Cathrine Axfors
• Andreas M. Schmitt
• Lars G. Hemkens

Malignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia

Vaccination is an effective strategy in suppressing COVID-19 pandemic, but rare adverse effects have been reported, including cerebral venous thrombosis. Here the authors report two cases of middle cerebral artery infarct within 9-10 days following ChAdOx1 nCov-19 vaccination that also manifest pulmonary and portal vein thrombosis.

• M. De Michele
• M. Iacobucci

Correlation of SARS-CoV-2-breakthrough infections to time-from-vaccine

The duration of effectiveness of SARS-CoV-2 vaccination is not yet known. Here, the authors present preliminary evidence of BNT162b2 vaccine waning across all age groups above 16, with a higher incidence of infection in people who received their second dose early in 2021 compared to later in the year.

• Barak Mizrahi
• Tal Patalon

COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants

Emerging SARS-CoV-2 variants contain mutations in the spike protein that may affect vaccine efficacy. Here, Jalkanen et al . show, using sera from 180 BNT162b2-vaccinated health care workers, that neutralization of SARS-CoV2 variant B.1.1.7 is not affected, while neutralization of B.1.351 variant is five-fold reduced.

• Pinja Jalkanen
• Pekka Kolehmainen
• Ilkka Julkunen

Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection

T cells compose a critical component of the immune response to coronavirus infection with SARS-CoV-2. Here the authors characterise the T cell response to SARS CoV-2 in patients and their close contacts, and show the presence of SARS-CoV-2 specific T cells in the absence of detectable virus infection.

• Zhongfang Wang
• Xiaoyun Yang

Rapid decline of neutralizing antibodies against SARS-CoV-2 among infected healthcare workers

The humoral immune response to SARS-CoV-2 infection is not yet fully understood. Here, Marot et al. monitor the longitudinal profile and neutralizing activity of IgG, IgA, and IgM among 26 healthcare workers and provide evidence for a short-lasting humoral immune protection due to a decrease of neutralizing antibody titers within 3 months.

• Stéphane Marot
• Isabelle Malet
• Anne-Geneviève Marcelin

Efficacy and tolerability of bevacizumab in patients with severe Covid-19

In this single-arm clinical trial, the authors show that treatment of COVID-19 patients with bevacizumab, an anti-vascular endothelial growth factor drug, can improve PaO 2 /FiO 2 ratios and oxygen-support status. Relative to an external control group, bevacizumab shows clinical efficacy by improving oxygenation.

• Jiaojiao Pang

Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in Southeast Asia

A bat origin for SARS-CoV-2 has been proposed. Here, by sampling wild Rhinolophus acuminatus bats from Thailand, the authors identified a SARS-CoV-2-related coronavirus (SC2r-CoV), designated as RacCS203, with 91.5% genome similarity to SARS-CoV-2, and show that sera obtained from bats and Malayan pangolin neutralize SARS-CoV-2.

• Supaporn Wacharapluesadee
• Chee Wah Tan
• Lin-Fa Wang

SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes

The SARS-CoV-2 gene set remains unresolved, hindering dissection of COVID-19 biology. Comparing 44 Sarbecovirus genomes provides a high-confidence protein-coding gene set. The study characterizes protein-level and nucleotide-level evolutionary constraints, and prioritizes functional mutations from the ongoing COVID-19 pandemic.

• Irwin Jungreis
• Rachel Sealfon
• Manolis Kellis

Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival

Antibody responses are critical for protection from developing severe COVID-19 following SARS-CoV-2 infection. Here the authors show that antibody responses against SARS-CoV-2 spike protein correlate with neutralizing capacity and protection, are not affected by heterologous boosting of influenza or common cold immunity, and can last up to 8 months.

• Stefania Dispinseri
• Massimiliano Secchi
• Gabriella Scarlatti

New-onset IgG autoantibodies in hospitalized patients with COVID-19

Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production. Here the authors characterise the new-onset IgG autoantibody response in hospitalised patients with COVID-19 which they correlate to the magnitude of the SARS-CoV2 response.

• Sarah Esther Chang
• Paul J. Utz

SARS-CoV-2 vaccine breakthrough infections with the alpha variant are asymptomatic or mildly symptomatic among health care workers

Several COVID-19 vaccines have shown good efficacy in clinical trials. Here, the authors provide real world effectiveness data in a group of BNT162b2 vaccinated health care workers and find that breakthrough infections are asymptomatic or mild.

• Francesca Rovida
• Irene Cassaniti
• Fausto Baldanti

Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19)

Duration of infectious SARS-CoV-2 shedding is an important measure for improved disease control. Here, the authors use virus cultures of respiratory tract samples from COVID-19 patients and observe a median shedding duration of 8 days and a drop below 5% after 15,2 days post onset of symptoms.

• Jeroen J. A. van Kampen
• David A. M. C. van de Vijver
• Annemiek A. van der Eijk

A novel SARS-CoV-2 related coronavirus in bats from Cambodia

In this study, Delaune et al., isolate and characterise a SARS-CoV-2-related coronavirus from two bats sampled in Cambodia. Their findings suggest that the geographic distribution of SARS-CoV-2-related viruses is wider than previously reported.

• Deborah Delaune
• Veasna Duong

Neutralizing antibody titres in SARS-CoV-2 infections

Here, the authors perform plaque reduction neutralization (PRNT) assays quantitating SARS-CoV-2 specific neutralizing antibodies from 195 patients in different disease states and find that patients with severe disease exhibit higher peaks of neutralizing antibody titres than patients with mild or asymptomatic infections and that serum neutralizing antibody persists for over 6 months in most people.

• Eric H. Y. Lau
• Owen T. Y. Tsang
• Malik Peiris

SARS-CoV-2 antibody dynamics and transmission from community-wide serological testing in the Italian municipality of Vo’

Vo’, Italy, is a unique setting for studying SARS-CoV-2 antibody dynamics because mass testing was conducted there early in the pandemic. Here, the authors perform two follow-up serological surveys and estimate seroprevalence, the extent of within-household transmission, and the impact of contact tracing.

• Ilaria Dorigatti
• Enrico Lavezzo
• Andrea Crisanti

Discrete SARS-CoV-2 antibody titers track with functional humoral stability

The extent of antibody protection against SARS-CoV-2 remains unclear. Here, using a cohort of 120 seroconverted individuals, the authors longitudinally characterize neutralization, Fc-function, and SARS-CoV-2 specific T cell responses, which they show to be prominent only in those subjects that elicited receptor-binding domain (RBD)-specific antibody titers above a certain threshold, suggesting that development of T cell responses to be related to anti-RBD Ab production.

• Yannic C. Bartsch
• Stephanie Fischinger
• Galit Alter

Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography

Shark antibodies (Variable New Antigen Receptors, VNARs) are the smallest naturally occurring antibody fragments. Here, the authors screen a VNAR phage display library against the SARS-CoV2 receptor binding domain (RBD) and identify VNARs that neutralize the SARSCoV-2 virus and discuss their mechanisms of viral neutralization.

• Obinna C. Ubah
• Eric W. Lake
• Caroline J. Barelle

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand

New Zealand has been relatively successful in controlling COVID-19 due to implementation of strict non-pharmaceutical interventions. Here, the authors demonstrate a striking decline in reports of influenza and other non-influenza respiratory pathogens over winter months in which the interventions have been in place.

• Q. Sue Huang
• Richard J. Webby

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.

• Jiandong Huo
• Halina Mikolajek
• Raymond J. Owens

Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance

Cas13b can be harnessed to target and degrade RNA transcripts inside a cellular environment. Here the authors reprogram Cas13b to target SARSCoV-2 transcripts in infected mammalian cells and reveal its resilience to variants thanks to single mismatch tolerance.

• Mohamed Fareh
• Joseph A. Trapani

SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells

T cells are instrumental to protective immune responses against SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic. Here the authors show that, in convalescent COVID-19 patients, memory T cell responses are detectable up to 317 days post-symptom onset, in which the presence of stem cell-like memory T cells further hints long-lasting immunity.

• Jae Hyung Jung
• Min-Seok Rha
• Eui-Cheol Shin

Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing antibodies to human coronaviruses

Long-term characterisation of SARS-CoV-2 antibody kinetics is needed to understand the protective role of the immune response. Here the authors describe antibody levels and neutralisation activity in healthcare workers over seven months and investigate the role of immunity to endemic human coronaviruses.

• Natalia Ortega
• Marta Ribes
• Carlota Dobaño

Mechanism of SARS-CoV-2 polymerase stalling by remdesivir

Remdesivir is a nucleoside analog that inhibits the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and is used as a drug to treat COVID19 patients. Here, the authors provide insights into the mechanism of remdesivir-induced RdRp stalling by determining the cryo-EM structures of SARS-CoV-2 RdRp with bound RNA molecules that contain remdesivir at defined positions and observe that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation.

• Goran Kokic
• Hauke S. Hillen
• Patrick Cramer

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COVID-19 (2019 Novel Coronavirus) Research Guide

COVID-19 Research Guide Home

• Research Articles Downloadable Database
• COVID-19 Science Updates
• Databases and Journals
• Secondary Data and Statistics

From the CDC’s COVID-19 (2019 Novel Coronavirus) website :

“COVID-19 (coronavirus disease 2019) is a disease caused by a virus named SARS-CoV-2. It can be very contagious and spreads quickly. Over one million people have died from COVID-19 in the United States.

COVID-19 most often causes respiratory symptoms that can feel much like a cold, the flu, or pneumonia. COVID-19 may attack more than your lungs and respiratory system. Other parts of your body may also be affected by the disease. Most people with COVID-19 have mild symptoms, but some people become severely ill.

Some people including those with minor or no symptoms will develop Post-COVID Conditions – also called “Long COVID.”

May 11, 2023, marks the end of the federal COVID-19 PHE declaration . After this date, CDC’s authorizations to collect certain types of public health data will expire.

The latest situation summary updates are available on CDC’s web page for COVID-19 . “

This guide provides resources for researching COVID-19. In this guide you can find the following:

• The CDC Database of COVID-19 Research Articles became a collaboration with the WHO to create the WHO COVID-19 database during the pandemic to make it easier for results to be searched, downloaded, and used by researchers worldwide.
• The last version of the CDC COVID-19 database was archived and remain available on this website.  Please note that it has stopped updating as of October 9, 2020 and all new articles were integrated into the WHO COVID-19 database .  The WHO Covid-19 Research Database was a resource created in response to the Public Health Emergency of International Concern (PHEIC). Its content remains searchable and spans the time period March 2020 to June 2023. Since June 2023, manual updates to the database have been discontinued.
• COVID-19 Science Updates : To help inform CDC’s COVID-19 Response, as well as to help CDC staff stay up to date on the latest COVID-19 research, the Response’s Office of the Chief Medical Officer has collaborated with the CDC Office of Library Science to create a series called COVID-19 Science Update . This series, the first of its kind for a CDC emergency response, provides brief summaries of new COVID-19-related studies on many topics, including epidemiology, clinical treatment and management, laboratory science, and modeling. As of December 18, 2021, CDC has stopped production of the weekly COVID-19 Science Update.
• Selected scholarly literature databases and journals available to help you find research about COVID-19.
• Search alerts notify you when new research is published on COVID-19.
• Search alerts available for Ovid , PubMed , Scopus , and News sources .
• Selected sources for secondary data and statistics on COVID-19.
• Selected websites and organizations where you can find more information on COVID-19.

Some resources within this guide are accessible only to those with a CDC user ID and password. Find a library near you that may be able to help you access similar resources by clicking the following links: https://www.worldcat.org/libraries  OR https://www.usa.gov/libraries .

Materials listed in these guides are selected to provide awareness of quality public health literature and resources. A material’s inclusion does not necessarily represent the views of the U.S. Department of Health and Human Services (HHS), the Public Health Service (PHS), or the Centers for Disease Control and Prevention (CDC), nor does it imply endorsement of the material’s methods or findings. HHS, PHS, and CDC assume no responsibility for the factual accuracy of the items presented. The selection, omission, or content of items does not imply any endorsement or other position taken by HHS, PHS, and CDC. Opinion, findings, and conclusions expressed by the original authors of items included in these materials, or persons quoted therein, are strictly their own and are in no way meant to represent the opinion or views of HHS, PHS, or CDC. References to publications, news sources, and non-CDC Websites are provided solely for informational purposes and do not imply endorsement by HHS, PHS, or CDC.

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• The Centers for Disease Control and Prevention (CDC) cannot attest to the accuracy of a non-federal website.
• Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.
• You will be subject to the destination website's privacy policy when you follow the link.
• CDC is not responsible for Section 508 compliance (accessibility) on other federal or private website.

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• The role of COVID-19 vaccines in preventing post-COVID-19 thromboembolic and cardiovascular complications
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• Núria Mercadé-Besora 1 , 2 , 3 ,
• Xintong Li 1 ,
• Raivo Kolde 4 ,
• Nhung TH Trinh 5 ,
• Maria T Sanchez-Santos 1 ,
• Wai Yi Man 1 ,
• Elena Roel 3 ,
• Carlen Reyes 3 ,
• http://orcid.org/0000-0003-0388-3403 Antonella Delmestri 1 ,
• Hedvig M E Nordeng 6 , 7 ,
• http://orcid.org/0000-0002-4036-3856 Anneli Uusküla 8 ,
• http://orcid.org/0000-0002-8274-0357 Talita Duarte-Salles 3 , 9 ,
• Clara Prats 2 ,
• http://orcid.org/0000-0002-3950-6346 Daniel Prieto-Alhambra 1 , 9 ,
• http://orcid.org/0000-0002-0000-0110 Annika M Jödicke 1 ,
• Martí Català 1
• 1 Pharmaco- and Device Epidemiology Group, Health Data Sciences, Botnar Research Centre, NDORMS , University of Oxford , Oxford , UK
• 2 Department of Physics , Universitat Politècnica de Catalunya , Barcelona , Spain
• 3 Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol) , IDIAP Jordi Gol , Barcelona , Catalunya , Spain
• 4 Institute of Computer Science , University of Tartu , Tartu , Estonia
• 5 Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences , University of Oslo , Oslo , Norway
• 6 School of Pharmacy , University of Oslo , Oslo , Norway
• 7 Division of Mental Health , Norwegian Institute of Public Health , Oslo , Norway
• 8 Department of Family Medicine and Public Health , University of Tartu , Tartu , Estonia
• 9 Department of Medical Informatics, Erasmus University Medical Center , Erasmus University Rotterdam , Rotterdam , Zuid-Holland , Netherlands
• Correspondence to Prof Daniel Prieto-Alhambra, Pharmaco- and Device Epidemiology Group, Health Data Sciences, Botnar Research Centre, NDORMS, University of Oxford, Oxford, UK; daniel.prietoalhambra{at}ndorms.ox.ac.uk

Objective To study the association between COVID-19 vaccination and the risk of post-COVID-19 cardiac and thromboembolic complications.

Methods We conducted a staggered cohort study based on national vaccination campaigns using electronic health records from the UK, Spain and Estonia. Vaccine rollout was grouped into four stages with predefined enrolment periods. Each stage included all individuals eligible for vaccination, with no previous SARS-CoV-2 infection or COVID-19 vaccine at the start date. Vaccination status was used as a time-varying exposure. Outcomes included heart failure (HF), venous thromboembolism (VTE) and arterial thrombosis/thromboembolism (ATE) recorded in four time windows after SARS-CoV-2 infection: 0–30, 31–90, 91–180 and 181–365 days. Propensity score overlap weighting and empirical calibration were used to minimise observed and unobserved confounding, respectively.

Fine-Gray models estimated subdistribution hazard ratios (sHR). Random effect meta-analyses were conducted across staggered cohorts and databases.

Results The study included 10.17 million vaccinated and 10.39 million unvaccinated people. Vaccination was associated with reduced risks of acute (30-day) and post-acute COVID-19 VTE, ATE and HF: for example, meta-analytic sHR of 0.22 (95% CI 0.17 to 0.29), 0.53 (0.44 to 0.63) and 0.45 (0.38 to 0.53), respectively, for 0–30 days after SARS-CoV-2 infection, while in the 91–180 days sHR were 0.53 (0.40 to 0.70), 0.72 (0.58 to 0.88) and 0.61 (0.51 to 0.73), respectively.

Conclusions COVID-19 vaccination reduced the risk of post-COVID-19 cardiac and thromboembolic outcomes. These effects were more pronounced for acute COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough versus unvaccinated SARS-CoV-2 infection.

• Epidemiology
• PUBLIC HEALTH
• Electronic Health Records

Data availability statement

Data may be obtained from a third party and are not publicly available. CPRD: CPRD data were obtained under the CPRD multi-study license held by the University of Oxford after Research Data Governance (RDG) approval. Direct data sharing is not allowed. SIDIAP: In accordance with current European and national law, the data used in this study is only available for the researchers participating in this study. Thus, we are not allowed to distribute or make publicly available the data to other parties. However, researchers from public institutions can request data from SIDIAP if they comply with certain requirements. Further information is available online ( https://www.sidiap.org/index.php/menu-solicitudesen/application-proccedure ) or by contacting SIDIAP ([email protected]). CORIVA: CORIVA data were obtained under the approval of Research Ethics Committee of the University of Tartu and the patient level data sharing is not allowed. All analyses in this study were conducted in a federated manner, where analytical code and aggregated (anonymised) results were shared, but no patient-level data was transferred across the collaborating institutions.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:  https://creativecommons.org/licenses/by/4.0/ .

https://doi.org/10.1136/heartjnl-2023-323483

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WHAT IS ALREADY KNOWN ON THIS TOPIC

COVID-19 vaccines proved to be highly effective in reducing the severity of acute SARS-CoV-2 infection.

While COVID-19 vaccines were associated with increased risk for cardiac and thromboembolic events, such as myocarditis and thrombosis, the risk of complications was substantially higher due to SARS-CoV-2 infection.

WHAT THIS STUDY ADDS

COVID-19 vaccination reduced the risk of heart failure, venous thromboembolism and arterial thrombosis/thromboembolism in the acute (30 days) and post-acute (31 to 365 days) phase following SARS-CoV-2 infection. This effect was stronger in the acute phase.

The overall additive effect of vaccination on the risk of post-vaccine and/or post-COVID thromboembolic and cardiac events needs further research.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

COVID-19 vaccines proved to be highly effective in reducing the risk of post-COVID cardiovascular and thromboembolic complications.

Introduction

COVID-19 vaccines were approved under emergency authorisation in December 2020 and showed high effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalisation and death. 1 2 However, concerns were raised after spontaneous reports of unusual thromboembolic events following adenovirus-based COVID-19 vaccines, an association that was further assessed in observational studies. 3 4 More recently, mRNA-based vaccines were found to be associated with a risk of rare myocarditis events. 5 6

On the other hand, SARS-CoV-2 infection can trigger cardiac and thromboembolic complications. 7 8 Previous studies showed that, while slowly decreasing over time, the risk for serious complications remain high for up to a year after infection. 9 10 Although acute and post-acute cardiac and thromboembolic complications following COVID-19 are rare, they present a substantial burden to the affected patients, and the absolute number of cases globally could become substantial.

Recent studies suggest that COVID-19 vaccination could protect against cardiac and thromboembolic complications attributable to COVID-19. 11 12 However, most studies did not include long-term complications and were conducted among specific populations.

Evidence is still scarce as to whether the combined effects of COVID-19 vaccines protecting against SARS-CoV-2 infection and reducing post-COVID-19 cardiac and thromboembolic outcomes, outweigh any risks of these complications potentially associated with vaccination.

We therefore used large, representative data sources from three European countries to assess the overall effect of COVID-19 vaccines on the risk of acute and post-acute COVID-19 complications including venous thromboembolism (VTE), arterial thrombosis/thromboembolism (ATE) and other cardiac events. Additionally, we studied the comparative effects of ChAdOx1 versus BNT162b2 on the risk of these same outcomes.

Data sources

We used four routinely collected population-based healthcare datasets from three European countries: the UK, Spain and Estonia.

For the UK, we used data from two primary care databases—namely, Clinical Practice Research Datalink, CPRD Aurum 13 and CPRD Gold. 14 CPRD Aurum currently covers 13 million people from predominantly English practices, while CPRD Gold comprises 3.1 million active participants mostly from GP practices in Wales and Scotland. Spanish data were provided by the Information System for the Development of Research in Primary Care (SIDIAP), 15 which encompasses primary care records from 6 million active patients (around 75% of the population in the region of Catalonia) linked to hospital admissions data (Conjunt Mínim Bàsic de Dades d’Alta Hospitalària). Finally, the CORIVA dataset based on national health claims data from Estonia was used. It contains all COVID-19 cases from the first year of the pandemic and ~440 000 randomly selected controls. CORIVA was linked to the death registry and all COVID-19 testing from the national health information system.

Databases included sociodemographic information, diagnoses, measurements, prescriptions and secondary care referrals and were linked to vaccine registries, including records of all administered vaccines from all healthcare settings. Data availability for CPRD Gold ended in December 2021, CPRD Aurum in January 2022, SIDIAP in June 2022 and CORIVA in December 2022.

All databases were mapped to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) 16 to facilitate federated analytics.

Multinational network staggered cohort study: study design and participants

The study design has been published in detail elsewhere. 17 Briefly, we used a staggered cohort design considering vaccination as a time-varying exposure. Four staggered cohorts were designed with each cohort representing a country-specific vaccination rollout phase (eg, dates when people became eligible for vaccination, and eligibility criteria).

The source population comprised all adults registered in the respective database for at least 180 days at the start of the study (4 January 2021 for CPRD Gold and Aurum, 20 February 2021 for SIDIAP and 28 January 2021 for CORIVA). Subsequently, each staggered cohort corresponded to an enrolment period: all people eligible for vaccination during this time were included in the cohort and people with a history of SARS-CoV-2 infection or COVID-19 vaccination before the start of the enrolment period were excluded. Across countries, cohort 1 comprised older age groups, whereas cohort 2 comprised individuals at risk for severe COVID-19. Cohort 3 included people aged ≥40 and cohort 4 enrolled people aged ≥18.

In each cohort, people receiving a first vaccine dose during the enrolment period were allocated to the vaccinated group, with their index date being the date of vaccination. Individuals who did not receive a vaccine dose comprised the unvaccinated group and their index date was assigned within the enrolment period, based on the distribution of index dates in the vaccinated group. People with COVID-19 before the index date were excluded.

Follow-up started from the index date until the earliest of end of available data, death, change in exposure status (first vaccine dose for those unvaccinated) or outcome of interest.

COVID-19 vaccination

All vaccines approved within the study period from January 2021 to July 2021—namely, ChAdOx1 (Oxford/AstraZeneca), BNT162b2 (BioNTech/Pfizer]) Ad26.COV2.S (Janssen) and mRNA-1273 (Moderna), were included for this study.

Post-COVID-19 outcomes of interest

Outcomes of interest were defined as SARS-CoV-2 infection followed by a predefined thromboembolic or cardiac event of interest within a year after infection, and with no record of the same clinical event in the 6 months before COVID-19. Outcome date was set as the corresponding SARS-CoV-2 infection date.

COVID-19 was identified from either a positive SARS-CoV-2 test (polymerase chain reaction (PCR) or antigen), or a clinical COVID-19 diagnosis, with no record of COVID-19 in the previous 6 weeks. This wash-out period was imposed to exclude re-recordings of the same COVID-19 episode.

Post-COVID-19 outcome events were selected based on previous studies. 11–13 Events comprised ischaemic stroke (IS), haemorrhagic stroke (HS), transient ischaemic attack (TIA), ventricular arrhythmia/cardiac arrest (VACA), myocarditis/pericarditis (MP), myocardial infarction (MI), heart failure (HF), pulmonary embolism (PE) and deep vein thrombosis (DVT). We used two composite outcomes: (1) VTE, as an aggregate of PE and DVT and (2) ATE, as a composite of IS, TIA and MI. To avoid re-recording of the same complication we imposed a wash-out period of 90 days between records. Phenotypes for these complications were based on previously published studies. 3 4 8 18

All outcomes were ascertained in four different time periods following SARS-CoV-2 infection: the first period described the acute infection phase—that is, 0–30 days after COVID-19, whereas the later periods - which are 31–90 days, 91–180 days and 181–365 days, illustrate the post-acute phase ( figure 1 ).

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Study outcome design. Study outcomes of interest are defined as a COVID-19 infection followed by one of the complications in the figure, within a year after infection. Outcomes were ascertained in four different time windows after SARS-CoV-2 infection: 0–30 days (namely the acute phase), 31–90 days, 91–180 days and 181–365 days (these last three comprise the post-acute phase).

Negative control outcomes

Negative control outcomes (NCOs) were used to detect residual confounding. NCOs are outcomes which are not believed to be causally associated with the exposure, but share the same bias structure with the exposure and outcome of interest. Therefore, no significant association between exposure and NCO is to be expected. Our study used 43 different NCOs from previous work assessing vaccine effectiveness. 19

Statistical analysis

Federated network analyses.

A template for an analytical script was developed and subsequently tailored to include the country-specific aspects (eg, dates, priority groups) for the vaccination rollout. Analyses were conducted locally for each database. Only aggregated data were shared and person counts <5 were clouded.

Propensity score weighting

Large-scale propensity scores (PS) were calculated to estimate the likelihood of a person receiving the vaccine based on their demographic and health-related characteristics (eg, conditions, medications) prior to the index date. PS were then used to minimise observed confounding by creating a weighted population (overlap weighting 20 ), in which individuals contributed with a different weight based on their PS and vaccination status.

Prespecified key variables included in the PS comprised age, sex, location, index date, prior observation time in the database, number of previous outpatient visits and previous SARS-CoV-2 PCR/antigen tests. Regional vaccination, testing and COVID-19 incidence rates were also forced into the PS equation for the UK databases 21 and SIDIAP. 22 In addition, least absolute shrinkage and selection operator (LASSO) regression, a technique for variable selection, was used to identify additional variables from all recorded conditions and prescriptions within 0–30 days, 31–180 days and 181-any time (conditions only) before the index date that had a prevalence of >0.5% in the study population.

PS were then separately estimated for each staggered cohort and analysis. We considered covariate balance to be achieved if absolute standardised mean differences (ASMDs) were ≤0.1 after weighting. Baseline characteristics such as demographics and comorbidities were reported.

Effect estimation

To account for the competing risk of death associated with COVID-19, Fine-and-Grey models 23 were used to calculate subdistribution hazard ratios (sHRs). Subsequently, sHRs and confidence intervals were empirically calibrated from NCO estimates 24 to account for unmeasured confounding. To calibrate the estimates, the empirical null distribution was derived from NCO estimates and was used to compute calibrated confidence intervals. For each outcome, sHRs from the four staggered cohorts were pooled using random-effect meta-analysis, both separately for each database and across all four databases.

Sensitivity analysis

Sensitivity analyses comprised 1) censoring follow-up for vaccinated people at the time when they received their second vaccine dose and 2) considering only the first post-COVID-19 outcome within the year after infection ( online supplemental figure S1 ). In addition, comparative effectiveness analyses were conducted for BNT162b2 versus ChAdOx1.

Supplemental material

Data and code availability.

All analytic code for the study is available in GitHub ( https://github.com/oxford-pharmacoepi/vaccineEffectOnPostCovidCardiacThromboembolicEvents ), including code lists for vaccines, COVID-19 tests and diagnoses, cardiac and thromboembolic events, NCO and health conditions to prioritise patients for vaccination in each country. We used R version 4.2.3 and statistical packages survival (3.5–3), Empirical Calibration (3.1.1), glmnet (4.1-7), and Hmisc (5.0–1).

Patient and public involvement

Owing to the nature of the study and the limitations regarding data privacy, the study design, analysis, interpretation of data and revision of the manuscript did not involve any patients or members of the public.

All aggregated results are available in a web application ( https://dpa-pde-oxford.shinyapps.io/PostCovidComplications/ ).

We included over 10.17 million vaccinated individuals (1 618 395 from CPRD Gold; 5 729 800 from CPRD Aurum; 2 744 821 from SIDIAP and 77 603 from CORIVA) and 10.39 million unvaccinated individuals (1 640 371; 5 860 564; 2 588 518 and 302 267, respectively). Online supplemental figures S2-5 illustrate study inclusion for each database.

Adequate covariate balance was achieved after PS weighting in most studies: CORIVA (all cohorts) and SIDIAP (cohorts 1 and 4) did not contribute to ChAdOx1 subanalyses owing to sample size and covariate imbalance. ASMD results are accessible in the web application.

NCO analyses suggested residual bias after PS weighting, with a majority of NCOs associated positively with vaccination. Therefore, calibrated estimates are reported in this manuscript. Uncalibrated effect estimates and NCO analyses are available in the web interface.

Population characteristics

Table 1 presents baseline characteristics for the weighted populations in CPRD Aurum, for illustrative purposes. Online supplemental tables S1-25 summarise baseline characteristics for weighted and unweighted populations for each database and comparison. Across databases and cohorts, populations followed similar patterns: cohort 1 represented an older subpopulation (around 80 years old) with a high proportion of women (57%). Median age was lowest in cohort 4 ranging between 30 and 40 years.

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Characteristics of weighted populations in CPRD Aurum database, stratified by staggered cohort and exposure status. Exposure is any COVID-19 vaccine

COVID-19 vaccination and post-COVID-19 complications

Table 2 shows the incidence of post-COVID-19 VTE, ATE and HF, the three most common post-COVID-19 conditions among the studied outcomes. Outcome counts are presented separately for 0–30, 31–90, 91–180 and 181–365 days after SARS-CoV-2 infection. Online supplemental tables S26-36 include all studied complications, also for the sensitivity and subanalyses. Similar pattern for incidences were observed across all databases: higher outcome rates in the older populations (cohort 1) and decreasing frequency with increasing time after infection in all cohorts.

Number of records (and risk per 10 000 individuals) for acute and post-acute COVID-19 cardiac and thromboembolic complications, across cohorts and databases for any COVID-19 vaccination

Forest plots for the effect of COVID-19 vaccines on post-COVID-19 cardiac and thromboembolic complications; meta-analysis across cohorts and databases. Dashed line represents a level of heterogeneity I 2 >0.4. ATE, arterial thrombosis/thromboembolism; CD+HS, cardiac diseases and haemorrhagic stroke; VTE, venous thromboembolism.

Results from calibrated estimates pooled in meta-analysis across cohorts and databases are shown in figure 2 .

Reduced risk associated with vaccination is observed for acute and post-acute VTE, DVT, and PE: acute meta-analytic sHR are 0.22 (95% CI, 0.17–0.29); 0.36 (0.28–0.45); and 0.19 (0.15–0.25), respectively. For VTE in the post-acute phase, sHR estimates are 0.43 (0.34–0.53), 0.53 (0.40–0.70) and 0.50 (0.36–0.70) for 31–90, 91–180, and 181–365 days post COVID-19, respectively. Reduced risk of VTE outcomes was observed in vaccinated across databases and cohorts, see online supplemental figures S14–22 .

Similarly, the risk of ATE, IS and MI in the acute phase after infection was reduced for the vaccinated group, sHR of 0.53 (0.44–0.63), 0.55 (0.43–0.70) and 0.49 (0.38–0.62), respectively. Reduced risk associated with vaccination persisted for post-acute ATE, with sHR of 0.74 (0.60–0.92), 0.72 (0.58–0.88) and 0.62 (0.48–0.80) for 31–90, 91–180 and 181–365 days post-COVID-19, respectively. Risk of post-acute MI remained lower for vaccinated in the 31–90 and 91–180 days after COVID-19, with sHR of 0.64 (0.46–0.87) and 0.64 (0.45–0.90), respectively. Vaccination effect on post-COVID-19 TIA was seen only in the 181–365 days, with sHR of 0.51 (0.31–0.82). Online supplemental figures S23-31 show database-specific and cohort-specific estimates for ATE-related complications.

Risk of post-COVID-19 cardiac complications was reduced in vaccinated individuals. Meta-analytic estimates in the acute phase showed sHR of 0.45 (0.38–0.53) for HF, 0.41 (0.26–0.66) for MP and 0.41 (0.27–0.63) for VACA. Reduced risk persisted for post-acute COVID-19 HF: sHR 0.61 (0.51–0.73) for 31–90 days, 0.61 (0.51–0.73) for 91–180 days and 0.52 (0.43–0.63) for 181–365 days. For post-acute MP, risk was only lowered in the first post-acute window (31–90 days), with sHR of 0.43 (0.21–0.85). Vaccination showed no association with post-COVID-19 HS. Database-specific and cohort-specific results for these cardiac diseases are shown in online supplemental figures S32-40 .

Stratified analyses by vaccine showed similar associations, except for ChAdOx1 which was not associated with reduced VTE and ATE risk in the last post-acute window. Sensitivity analyses were consistent with main results ( online supplemental figures S6-13 ).

Figure 3 shows the results of comparative effects of BNT162b2 versus ChAdOx1, based on UK data. Meta-analytic estimates favoured BNT162b2 (sHR of 0.66 (0.46–0.93)) for VTE in the 0–30 days after infection, but no differences were seen for post-acute VTE or for any of the other outcomes. Results from sensitivity analyses, database-specific and cohort-specific estimates were in line with the main findings ( online supplemental figures S41-51 ).

Forest plots for comparative vaccine effect (BNT162b2 vs ChAdOx1); meta-analysis across cohorts and databases. ATE, arterial thrombosis/thromboembolism; CD+HS, cardiac diseases and haemorrhagic stroke; VTE, venous thromboembolism.

Key findings

Our analyses showed a substantial reduction of risk (45–81%) for thromboembolic and cardiac events in the acute phase of COVID-19 associated with vaccination. This finding was consistent across four databases and three different European countries. Risks for post-acute COVID-19 VTE, ATE and HF were reduced to a lesser extent (24–58%), whereas a reduced risk for post-COVID-19 MP and VACA in vaccinated people was seen only in the acute phase.

Results in context

The relationship between SARS-CoV-2 infection, COVID-19 vaccines and thromboembolic and/or cardiac complications is tangled. Some large studies report an increased risk of VTE and ATE following both ChAdOx1 and BNT162b2 vaccination, 7 whereas other studies have not identified such a risk. 25 Elevated risk of VTE has also been reported among patients with COVID-19 and its occurrence can lead to poor prognosis and mortality. 26 27 Similarly, several observational studies have found an association between COVID-19 mRNA vaccination and a short-term increased risk of myocarditis, particularly among younger male individuals. 5 6 For instance, a self-controlled case series study conducted in England revealed about 30% increased risk of hospital admission due to myocarditis within 28 days following both ChAdOx1 and BNT162b2 vaccines. However, this same study also found a ninefold higher risk for myocarditis following a positive SARS-CoV-2 test, clearly offsetting the observed post-vaccine risk.

COVID-19 vaccines have demonstrated high efficacy and effectiveness in preventing infection and reducing the severity of acute-phase infection. However, with the emergence of newer variants of the virus, such as omicron, and the waning protective effect of the vaccine over time, there is a growing interest in understanding whether the vaccine can also reduce the risk of complications after breakthrough infections. Recent studies suggested that COVID-19 vaccination could potentially protect against acute post-COVID-19 cardiac and thromboembolic events. 11 12 A large prospective cohort study 11 reports risk of VTE after SARS-CoV-2 infection to be substantially reduced in fully vaccinated ambulatory patients. Likewise, Al-Aly et al 12 suggest a reduced risk for post-acute COVID-19 conditions in breakthrough infection versus SARS-CoV-2 infection without prior vaccination. However, the populations were limited to SARS-CoV-2 infected individuals and estimates did not include the effect of the vaccine to prevent COVID-19 in the first place. Other studies on post-acute COVID-19 conditions and symptoms have been conducted, 28 29 but there has been limited reporting on the condition-specific risks associated with COVID-19, even though the prognosis for different complications can vary significantly.

In line with previous studies, our findings suggest a potential benefit of vaccination in reducing the risk of post-COVID-19 thromboembolic and cardiac complications. We included broader populations, estimated the risk in both acute and post-acute infection phases and replicated these using four large independent observational databases. By pooling results across different settings, we provided the most up-to-date and robust evidence on this topic.

Strengths and limitations

The study has several strengths. Our multinational study covering different healthcare systems and settings showed consistent results across all databases, which highlights the robustness and replicability of our findings. All databases had complete recordings of vaccination status (date and vaccine) and are representative of the respective general population. Algorithms to identify study outcomes were used in previous published network studies, including regulatory-funded research. 3 4 8 18 Other strengths are the staggered cohort design which minimises confounding by indication and immortal time bias. PS overlap weighting and NCO empirical calibration have been shown to adequately minimise bias in vaccine effectiveness studies. 19 Furthermore, our estimates include the vaccine effectiveness against COVID-19, which is crucial in the pathway to experience post-COVID-19 complications.

Our study has some limitations. The use of real-world data comes with inherent limitations including data quality concerns and risk of confounding. To deal with these limitations, we employed state-of-the-art methods, including large-scale propensity score weighting and calibration of effect estimates using NCO. 19 24 A recent study 30 has demonstrated that methodologically sound observational studies based on routinely collected data can produce results similar to those of clinical trials. We acknowledge that results from NCO were positively associated with vaccination, and estimates might still be influenced by residual bias despite using calibration. Another limitation is potential under-reporting of post-COVID-19 complications: some asymptomatic and mild COVID-19 infections might have not been recorded. Additionally, post-COVID-19 outcomes of interest might be under-recorded in primary care databases (CPRD Aurum and Gold) without hospital linkage, which represent a large proportion of the data in the study. However, results in SIDIAP and CORIVA, which include secondary care data, were similar. Also, our study included a small number of young men and male teenagers, who were the main population concerned with increased risks of myocarditis/pericarditis following vaccination.

Conclusions

Vaccination against SARS-CoV-2 substantially reduced the risk of acute post-COVID-19 thromboembolic and cardiac complications, probably through a reduction in the risk of SARS-CoV-2 infection and the severity of COVID-19 disease due to vaccine-induced immunity. Reduced risk in vaccinated people lasted for up to 1 year for post-COVID-19 VTE, ATE and HF, but not clearly for other complications. Findings from this study highlight yet another benefit of COVID-19 vaccination. However, further research is needed on the possible waning of the risk reduction over time and on the impact of booster vaccination.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

The study was approved by the CPRD’s Research Data Governance Process, Protocol No 21_000557 and the Clinical Research Ethics committee of Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol) (approval number 4R22/133) and the Research Ethics Committee of the University of Tartu (approval No. 330/T-10).

Acknowledgments

This study is based in part on data from the Clinical Practice Research Datalink (CPRD) obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. We thank the patients who provided these data, and the NHS who collected the data as part of their care and support. All interpretations, conclusions and views expressed in this publication are those of the authors alone and not necessarily those of CPRD. We would also like to thank the healthcare professionals in the Catalan healthcare system involved in the management of COVID-19 during these challenging times, from primary care to intensive care units; the Institut de Català de la Salut and the Program d’Analítica de Dades per a la Recerca i la Innovació en Salut for providing access to the different data sources accessible through The System for the Development of Research in Primary Care (SIDIAP).

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

AMJ and MC are joint senior authors.

Contributors DPA and AMJ led the conceptualisation of the study with contributions from MC and NM-B. AMJ, TD-S, ER, AU and NTHT adapted the study design with respect to the local vaccine rollouts. AD and WYM mapped and curated CPRD data. MC and NM-B developed code with methodological contributions advice from MTS-S and CP. DPA, MC, NTHT, TD-S, HMEN, XL, CR and AMJ clinically interpreted the results. NM-B, XL, AMJ and DPA wrote the first draft of the manuscript, and all authors read, revised and approved the final version. DPA and AMJ obtained the funding for this research. DPA is responsible for the overall content as guarantor: he accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish.

Funding The research was supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC). DPA is funded through a NIHR Senior Research Fellowship (Grant number SRF-2018–11-ST2-004). Funding to perform the study in the SIDIAP database was provided by the Real World Epidemiology (RWEpi) research group at IDIAPJGol. Costs of databases mapping to OMOP CDM were covered by the European Health Data and Evidence Network (EHDEN).

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Effects of COVID-19 Shutdowns on Domestic Violence in the U.S.

This chapter examines the impact of COVID-19 shutdowns on domestic violence (DV) in the United States. Despite widespread concerns that pandemic shutdowns could increase DV, initial studies found mixed evidence that varied across data sources and locations. We review the evolving literature on the effects of the pandemic and highlight results from studies that examine multiple measures of DV across a common set of large cities. These studies show that the conflicting early results are due to opposite effects of pandemic shutdowns on two measures of DV in police data: an increase in domestic violence 911 calls and a decrease in DV crime reports. In theory, this divergence can come from either higher DV reporting rates, possibly because of additional media attention to DV and greater third-party calling, or from lower policing intensity for DV crimes. Prior evidence from police data and other sources supports the conclusion that the increase in calls came from greater reporting, while the incidence of criminal DV decreased. Finally, we present new evidence drawing on police and hospitals records from across the state of California to show that DV crimes and hospital emergency department (ED) visits were both lower during pandemic shutdowns.

We acknowledge financial support from the IZA COVID-19 Research Thrust and from the Bill and Melinda Gates Foundation, through the NBER Gender in the Economy Study Group Research Grants on Women, Victimization, and COVID-19. We have no competing interests to disclose. The views expressed herein are those of the authors and do not necessarily reflect the views of the National Bureau of Economic Research.

MARC RIS BibTeΧ

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Hawaii International Conference on System Sciences 2023

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We are so pleased to release the proceedings of the 56th Hawaii International Conference on System Sciences (HICSS).

The pandemic has at least three positive effects on the shaping of the research at HICSS. Overall, judging from the massive amount of reviews of the 1,429 papers submitted for the conference, the quality of papers have significantly increased, and the overall total score of the accepted papers have jumped to an all-time high. With a target acceptance rate set at 47%, HICSS welcomes 678 papers to its 2023 Proceedings.

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We have seen a high number of research papers on the effect of COVID-19 pandemic on a wide spectrum of MIS topics from technology-supported collaboration to the future of work. We also notice an increasing number of research on the pandemic effect on the “dark side of technology” – negative impacts on people’s health and the dissemination of misinformation. As a consequence, various aspects of cyber security are another key feature of this year’s research at HICSS.

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Published on 1.4.2024 in Vol 26 (2024)

Response of Unvaccinated US Adults to Official Information About the Pause in Use of the Johnson & Johnson–Janssen COVID-19 Vaccine: Cross-Sectional Survey Study

Response of unvaccinated us adults to official information about the pause in use of the johnson & johnson–janssen covid-19 vaccine: cross-sectional survey study.

Authors of this article:

Research Letter

• Vishala Mishra 1 * , MBBS, MMCi   ; 
• Joseph P Dexter 2, 3, 4 * , PhD  

1 Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, United States

2 Data Science Initiative, Harvard University, Allston, MA, United States

3 Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, United States

4 Institute of Collaborative Innovation, University of Macau, Taipa, Macao

*all authors contributed equally

Corresponding Author:

Joseph P Dexter, PhD

Data Science Initiative

Harvard University

Science and Engineering Complex 1.312-10

150 Western Avenue

Allston, MA, 02134

United States

Phone: 1 8023381330

Email: [email protected]

Using a rapid response web-based survey, we identified gaps in public understanding of the Centers for Disease Control and Prevention’s messaging about the pause in use of the Johnson & Johnson–Janssen COVID-19 vaccine and estimated changes in vaccine hesitancy using counterfactual questions.

Introduction

On April 13, 2021, the Centers for Disease Control and Prevention (CDC) and Food and Drug Administration recommended a pause in use of the Johnson & Johnson (J&J)–Janssen COVID-19 vaccine due to 6 reports of cerebral venous sinus thrombosis in recently vaccinated individuals [ 1 ]. The announcement of the pause required development of a coordinated communication strategy under extreme time pressure and careful messaging by stakeholders to mitigate reduced public confidence in COVID-19 vaccines [ 2 ]. Moreover, official communication efforts had to consider the potential influence of already widespread misinformation about the vaccines on attitudes toward the pause [ 3 , 4 ]. In this survey study, we evaluated understanding and impressions of the CDC’s public web-based information about the J&J-Janssen pause among unvaccinated US adults.

Web-Based Survey About J&J-Janssen Pause

We administered the web-based survey to two cohorts of US adults recruited through Prolific between April 19-21, 2021 (cohort A), and April 21-23, 2021 (cohort B). Both cohorts were assembled using convenience sampling of unvaccinated adults. To obtain information about a population that especially needed targeted vaccine communication, the first cohort was restricted to individuals expressing neutral or negative sentiments about COVID-19 vaccines. The survey design and recruitment strategy are described in Multimedia Appendix 1 ; the survey questions are provided in Multimedia Appendices 2 and 3 .

Ethical Considerations

The study was approved by Harvard University’s Committee on the Use of Human Subjects (IRB20-2089), and participants agreed to a consent statement on the first page of the survey. Participants were paid US $2 for taking the survey. All study data were collected anonymously.

A total of 271 and 286 participants were included in cohorts A and B, respectively (demographic characteristics listed in Table 1 ). Across participants, the median number of correct responses to the comprehension questions was 6 in both cohort A (IQR 1.5; range 0-7) and cohort B (IQR 1.0; range 1-7). The total number of correct responses was negatively associated with intention not to seek vaccination in both cohort A (odds ratio 0.61, 95% CI 0.45-0.82; P =.001) and cohort B (odds ratio 0.48, 95% CI 0.31-0.74; P =.001; Multimedia Appendix 4 ). Although a majority of participants rated the passages as “clear and easy to read” (cohort A: n=229, 84.5%; cohort B: n=243, 85%), fewer indicated that they would be likely to share them on social media (cohort A: n=53, 19.6%; cohort B: n=75, 26.3%).

The web page mentioned “a small number of reports” of cerebral venous sinus thrombosis in individuals who received the J&J-Janssen vaccine. When asked to guess a specific number, 188 (69.4%) and 133 (46.5%) respondents in cohorts A and B, respectively, estimated 100 or more cases, at least an order of magnitude higher than the actual value; 176 (64.9%) and 128 (44.8%) respondents in cohorts A and B, respectively, estimated 10 or more deaths after vaccination ( Figure 1 ).

Responding to a counterfactual question, 127 (46.9%) and 139 (48.6%) participants in cohorts A and B, respectively, indicated that the pause reduced their confidence in the J&J-Janssen vaccine’s safety ( Figure 1 ). Most participants reported no change in their confidence in COVID-19 vaccines’ safety in general (cohort A: n=182, 67.2%; cohort B: n=194, 67.8%) or intention to receive the Pfizer-BioNTech or Moderna vaccine (cohort A: n=206, 76%; cohort B: n=211, 73.8%).

a Participants could select more than one option.

b Includes participants who selected “American Indian or Alaska Native,” “Native Hawaiian or Other Pacific Islander,” or “Another option not listed here.”

c Number of participants who gave the correct answer to each question.

d Number of participants who gave the indicated number of correct answers across all questions.

e Number of participants who answered “Strongly agree” or “Agree” about each description on a 6-point Likert scale.

In our web-based survey about the CDC’s messaging around the J&J-Janssen vaccine pause, many respondents overestimated the number of case reports that prompted the pause, often by several orders of magnitude. Since verbal descriptors are elastic concepts that can be misinterpreted, grounding them with numbers can reduce variability in risk perception and promote informed decision-making [ 5 ].

Respondents also expressed reduced confidence in the safety of the J&J-Janssen vaccine, highlighting the potential danger of conveying piecemeal information about risk during a pandemic response [ 3 ]. Encouragingly, the reduced confidence did not extend to mRNA COVID-19 vaccines, consistent with previous findings that overall vaccine hesitancy remained stable following the pause [ 6 ]. These results were obtained using the counterfactual format, which is less susceptible to overestimating shifts in beliefs than the change format ( Multimedia Appendix 1 ). The negative association between understanding of the passage and self-reported vaccine hesitancy suggests that more targeted messaging may have been useful to promote vaccine confidence [ 7 , 8 ].

Consistent with uncertainty management theory [ 9 ], individuals likely viewed the pause in different ways, leading to a spectrum of emotional responses and changes in behavior. Despite being a safety precaution, the pause introduced new uncertainties requiring effective management through clear and consistent messaging, highlighting the balance that must be maintained between fostering trust and preventing unnecessary alarm [ 10 ]. Given the limitations of the deficit model of scientific communication [ 11 ], just providing technically correct information is insufficient for effective communication during public health crises. Instead, attention should be given to the accessibility of information across diverse socioeconomic groups, in line with the knowledge gap hypothesis [ 12 ], and to countering misinformation by providing easy-to-use official guidance [ 6 , 7 ].

The study is limited by the convenience sampling strategy; the participants recruited were not representative of the US population as a whole, and the findings should not be generalized to other contexts. Since the study was conducted on the web, individuals with lower internet and health literacy may have been excluded.

Acknowledgments

We thank Vasudha Mishra, MBBS, for assistance with graphic design. This work was supported by a CoronaVirusFacts Alliance Grant from the Poynter Institute, a Harvard Data Science Fellowship, and the Institute of Collaborative Innovation at the University of Macau.

Data Availability

The data sets generated during this study are available from the corresponding author upon reasonable request.

Conflicts of Interest

None declared.

Additional information about survey methodology.

Survey administered to cohort A.

Survey administered to cohort B.

Supplemental tables about survey questions and ordinal logistic regression analysis.

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Abbreviations

Edited by A Mavragani; submitted 25.08.22; peer-reviewed by M Graham, T Ginossar, A Scherer; comments to author 25.01.23; revised version received 26.05.23; accepted 29.12.23; published 01.04.24.

©Vishala Mishra, Joseph P Dexter. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 01.04.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.