A Perspective on COVID-19 Disease
Published on 8 March 2020
There are many unknowns about COVID-19, the respiratory disease that is currently sweeping the globe. Here is what is known about the virus (SARS-CoV-2) that lives in bats and jumps to humans via an unconfirmed intermediate host.
According to the World Health Organization (WHO), there are eight diseases prioritized as epidemic threats and they have no clear preventive measures in place. The priority pathogens are Ebola, Zika, SARS and pathogen that causes Disease X. They are all viruses. They are zoonotic, having animal origin and spillover to humans. They reproduce very quickly and are capable of amplifying their potential to turn pathogenic through random mutations. The virus will re-group in a reservoir before the spillover.
The COVID-19 Virus
Name of the disease is COVID-19 – coronavirus disease 2019 – as the first case of pneumonia was discovered in Wuhan, China in December 2019. The name of the virus is SARS-CoV-2, since it is a variant of the coronavirus that caused SARS in 2002-2003. It is named as the new pathogen, Severe Acute Respiratory Syndrome-related Coronavirus 2. COVID-19 is capable of spreading through human-to-human contact. WHO states it spreads through sneezing, coughing and germs left on inanimate objects. Human-to-human transmission is seen between close contacts.
The virus spreads through the nose and mouth predominantly and eyes can be susceptible too. The illness is capable of spreading before the symptoms show. Not everyone gets infected. Around 20 percent of the patients become severely ill, leading to pneumonia and respiratory failure.
Originally, out of the 40 cases of pneumonia reported, 14 of them including patient zero, had no contact with the seafood market, where the virus seems to have originated. Initially, it started with pneumonia of unknown etiology. Viral pneumonia clusters in older patients were identified though CT scan and demonstrated ground-glass opacities (GGO), another lead to evaluate the severity and extent of COVID-19 pneumonia.
Coronavirus belongs to a family of viruses called Coronaviridae and order Nidovirales, which infect mammals and birds. SARS and SARS-CoV-2 both belong to genus, Betacoronavirus. They do not infect reptiles like snakes. Genetic sequencing has confirmed that the new virus has a uniform genome with very limited genetic variation and is similar to the ones circulating in bats, from the samples studied in Southeast Asia. Incubation period, which is the time between infection and symptoms, initially was 10 to 14 days, and as of 11 February 2020, is 24 days. Asymptomatic spread happens for nine days.
The SARS-CoV-2 virus uses Chinese horseshoe bats as natural reservoirs and is transmitted via intermediate hosts to humans. According to the Chinese scientists, the virus has crossed the species barrier from the bats to pangolins to humans. Urban population in China is dense and people live in close contact with the wild animals which harbor viruses.
The long-snouted mammal called pangolin, often used in traditional Chinese medicine and one of the most trafficked wildlife species in the world, is believed to be the probable intermediate animal source of the infection, rather than the snake. This was based on a genetic comparison of coronavirus taken from the animal and humans infected in the outbreak.
It should be noted that civet was confirmed as the intermediate host of SARS, as the SARS coronavirus shared 99.8 percent of genome similarity with the civet coronavirus. The closest match to the COVID-19 virus, with a genetic similarity of 96 percent, was found in the coronavirus of bats from China’s Yunnan province. The bats could not have passed the virus directly to humans, as there are differences between the receptor-binding domain (RBD) sites of the two viruses. This means there is an intermediate host. Pangolin and human viruses only share 90.3 percent of their DNA and hence, it is doubtful if pangolins are the true intermediate hosts.
Whether COVID-19 jumped from an infected animal to a person or from many infected animals remains an open question.
SARS, MERS and Ebola viruses were contagious only when the symptoms appeared. So it was easy to contain the spread by isolating and treating the patients. But with COVID-19, there are symptom-less spreaders or super-spreaders or super-shedders. In such a case, it becomes difficult to contain the spread. Children are normally super-spreaders. It is a good idea to shut down schools during such a disease outbreak. If a virus infects a person, it will run its course naturally and die out, but if the patient comes into contact with a large crowd, then the infection spreads rapidly. In the city of Daegu, in South Korea, a super-spreading event in a crowded place, where one person infected 40 others is deemed responsible for the huge jump in new cases of COVID-19 in South Korea. The outbreak is rapidly spreading across the world, which means that the containment measures have not worked so far.
COVID-19 spreads easily in crowded confined spaces – homes, hospitals, cruise ships and places of worship. When a sick person coughs, sneezes, talks or even breathes, the virus gets transmitted via droplets and can travel nearly six feet away. In the case of measles, chicken pox and tuberculosis, the pathogens in the air can travel 100 feet away and survive for many hours. In HIV or hepatitis, the infection spreads by coming into contact with the body fluids of the infected.
COVID-19 Versus Other Coronaviruses
SARS-CoV-2 is new to humans. It has a similar genetic sequence to other coronaviruses that live in bats, but yet distinctly different from SARS and MERS coronaviruses implicated in previous epidemics. This coronavirus family is responsible for the common mild cold.
SARS coronavirus primarily affected the lungs, whereas COVID-19 is an upper respiratory tract infection and so it is easier for this infection to spread from the throat. People with low immunity, the elderly, and those with pre-existing health conditions are impacted.
In the case of SARS in 2003, there was an outbreak in an apartment complex in Hong Kong and the modality of transmission was through plumbing. There was a vertical transmission of the virus from floor to floor through toilet flushing. In the case of COVID-19, the virus was highly transmissible and amplified in the cruise ship where infected patients were placed in a closed space.
It is confirmed that COVID-19 is more contagious than SARS and MERS. Lethality of SARS was 6 percent. Fatality rate of seasonal flu is less than one in 1000 people. The transmissibility or severity of COVID-19 is not yet known with certainty. Among the 45,000 confirmed cases in China, less than 1 percent of the healthy people died from the disease. People above the age of 80 were at risk, although deaths occurred in every age group, except for children below the age of nine. But the fatality rate for people with cardiovascular disease was 10.5 percent, diabetes was 7. 3 percent and 6 percent for those with cancer, hypertension and chronic respiratory disease. Another interesting finding is that COVID-19 impacted men more than women. It is speculated that it is due to the protective effect of hormone estrogen in women, and men, who are more likely to be smokers, already have compromised lungs.
According to the Chinese researchers, this new virus is different from all the other coronaviruses as it launches a dual attack on the human cells. A mutated gene, similar to the one found in HIV, Ebola and avian influenza, is found exclusively in SARS-CoV-2. A typical first move for all coronaviruses is to enter the human cell through the attachment of the spike (S) protein to the human target cell – angiotensin converting enzyme 2 or ACE2. What makes SARS-CoV-2 different is its second mechanism of action – it has a furin-cleaving site, which tricks the human furin protein to cut and activate the spike protein, leading to direct fusion of the two cells. This is stated as the main reason for the rapid spread of the COVID-19 virus.
The International Global Initiative on Sharing All Influenza Data (GISAID) is a database set up to help researchers look for possible new strains of SARS-CoV-2.
Drug Targets and Diagnostic Assays
There is a global race to create a vaccine, the timeline ranging from 6 to 18 months. To help develop diagnostics, the full genome of SARS-CoV-2 was deciphered and published. Drugs targeting the furin enzyme will prevent the virus replication in the host. The spike is also the main target of neutralizing antibodies and very important for vaccine and therapeutic design. Blocking ACE2 can kill SARS-CoV-2, according to a study by German and Russian scientists.
Certain viruses can form biofilm just like the bacterial biofilms, which are protective mechanisms against the immune system and help the cells to spread from cell to cell. Viral biofilms are a major mechanism of propagation for some viruses, involved in many persistent viral infections and so an effective target for therapeutics. A study in 2019 by researchers from Wuhan, China, have shown that microbial biofilms are like protective clothing against extreme environmental stressors.
Viral genes unique to SARS-CoV-2 are targeted for developing diagnostic assays. Initially, the assay was developed from genetic similarities between SARS-CoV-2 and SARS and was later refined after the whole genome of the virus was sequenced. The current SARS-CoV-2 assay works by detecting the E gene, which codes for the viral envelope, and the RdRP gene that codes for the enzyme – RNA-dependent RNA polymerase, which helps the viral RNA replicate from an RNA template. This is used as a screening test for COVID-19.
To quickly verify a dangerous pathogen, a laboratory diagnosis is key. It helps in identifying the source of the infection, route of transmission, distribution in animal reservoirs or vectors, infectivity of patients and safety measures for healthcare personnel and recommendations for the general public.
Blood parameters are analyzed in infected patients in a lab. Polymerase Chain Reaction (PCR) technique is used for pathogen detection and to check for the presence of specific antibodies. Working with dangerous pathogens involves great risks for all healthcare professionals. They don Hazmat suits and breathe air purified and pumped by respirators mounted on their belts. It is documented that research on bat coronaviruses in labs pose grave danger to the researchers. Such research labs should be isolated and situated away from densely populated areas. Non-invasive method includes saliva testing, and a swab test of the mouth, nose and throat is done.
It was found that SARS-CoV-2 could be shed through multiple routes. Oral swabs followed by molecular diagnosis confirmed the presence of the virus in the infected patients. Many coronaviruses can also be transmitted through the oral-fecal route, as confirmed by the presence of the virus in blood and anal swabs, in a later stage of the infection. Both the molecular and serological tests are needed to confirm the infection.
A PCR-based diagnostic protocol for COVID-19, using swabbed samples from a patient’s nose and throat, was first put forth by a group of German scientists. The turnaround time for test results is 24-48 hours. This is adopted by WHO for distribution around the world. The US Centers for Disease Control and Prevention (CDC) has developed its own assay. The turnaround time for test results is 24-72 hours. Rapid turnaround time for COVID-19 test results helps to triage people and plays a crucial role in mitigating the trajectory of the infectious epidemic.
Gain-of-Function Research (GOFR)
Chinese scientists in the past have created chimeric or hybrid viruses by mixing genes of H5N1 and H1N1 responsible for the swine flu pandemic. They demonstrated how this hybrid virus can spread through the air between guinea pigs. Although these rodents are not good models for human pathogenicity and gain-of-function research (GOFR) is critical to understanding pandemics, such transmissible strains are a biosecurity threat. Through a natural process known as reassortment, different flu viruses infect the same cell, exchange genes and have led to human pandemics in the past.
A study in 2015 by researchers from US, China and Switzerland found that there was a constant threat from closely related SARS-like viruses circulating in Chinese bat populations, which may pose a serious disease outbreak in the future. The hybrid version of coronavirus found in horseshoe bat was engineered in a lab. It was found that bat coronavirus could directly infect humans without needing an intermediate animal vector.
There was a federal ban for three years from 2014 and it ended in 2017. A moratorium was imposed on funding research that alters germs to make them more lethal, only if benefits justify the risks. The studies must be scientifically sound and rigorous, and done in a high-security lab. The pathogen must pose a serious threat to human health, a vaccine must be produced for it, and must prove that there are no other safer ways to do the research – only then the grant will be given.
Such disease-enhancing experiments gave modest results and no contribution towards pandemic preparedness. It only showcased that a new non-natural risk could be created in a lab. Due to the pandemic potential of the chimeric SARS-like virus, the research was deemed too risky to continue. GOFR is a hotly debated topic among scientists.
Stand United or Fall Divided
As the viruses and illnesses disappear, the funding for such research also goes down. It has been 25 years since the discovery of HIV-1 as the causative agent for AIDS and still there is no vaccine for it! It takes decades to create a drug or vaccine for a new pathogen, and by the time it is ready for testing in humans, the infection dies down. The RNA virus infections are responsible for nearly 86 percent of the global disease burden. The idea is to find a broad-spectrum drug that can be the perfect biodefense tool for newly emerging and re-emerging infectious diseases. Funding for research on the mechanism of action (MOA), as well as, research on basic sciences should not be neglected. Medical professionals, veterinarians, microbiologists, and wildlife specialists must work together alongside technologists, instead of being siloed into their own specialties.
According to the experts, this is not the first global pandemic and it certainly will not be the last. It is challenging to predict pandemics due to global hyperconnectedness, trade and travel, changing climate and unplanned urbanization. Changes in temperature and rainfall can affect agricultural practices, which in turn can intensify the spread of disease-causing pathogens. Altered human behavior, environmental degradation, population growth and migration, dwindling freshwater resources, and effective solid waste management can all impact the spread of vector-borne diseases. In such a scenario, transmission patterns of pathogens can go any which way.
Black Death in Europe wiped out 50 million people in the 14th century, mainly due to human overcrowding and inadequate sanitary conditions. With the development of cheaper and faster rail and air travel, infectious diseases effortlessly spread across the globe in the 21st century. But during the SARS outbreak in 2003, only a few hundred died. This is attributed to the tremendous advancements in science and technology. Our global health systems are better prepared now than ever before to combat pandemics. There are incalculable risks from the COVID-19 outbreak which can hurt the global economy. China’s aggressive approach to preventing the spread and changing the curve of COVID-19 must be followed by other countries as well.
Putting up walls and strengthening border patrol are helpful, but an airborne virus knows no borders.