COVID-19

Site: ISRRT e-Learning
Course: International Covid-19 support for Radiographers and Radiological Technologists
Book: COVID-19
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Date: Friday, 19 August 2022, 7:26 AM

1. What should we call this new “coronavirus”? And why is this virus different?

There are a number of different names for this virus. This is partly because this virus is new, and as our knowledge of it improves, alongside how it relates to other viruses, so our name for it has changed. This section will cover some of the basics of what the virus is, how it is so named, and why it is different to viruses that we have encountered to date.

Originally called the “Wuhan coronavirus”, and subsequently “2019-nCoV”, this virus is technically called Severe Acute Respiratory Syndrome CoronaVirus 2, or SARS-CoV-2. It is often still referred to as just “novel coronavirus”. COVID-19 (Coronavirus disease 2019) is the disease that the virus causes, not the virus itself. Patients with COVID-19 tend to present with pneumonia (with associated fever, cough, and dyspnea) and as such, chest imaging is critical to the ongoing care pathway.

SARS-CoV-2 was first reported in Wuhan, China, in December 2019, and has since been declared a pandemic by the World Health Organisation. It is genetically related to a prior pandemic in 2003, SARS-CoV-1 (which at the time was called just “SARS”), which originated in Guangdong, China, MERS (Middle East respiratory syndrome, also called “camel ‘flu”) was also a coronavirus that caused an epidemic across the Arabian Peninsula in 2012. The number of cases and deaths attributed to SARS and MERS were very different from one another; SARS caused over 8,000 cases in more than 26 countries but killed only about 800 whereas only 2000 cases of MERS have been reported, but one-third of those infected died. By comparison, at the time of writing, there have been over 1,345,000 cases of SARS-CoV-2 worldwide across 185 countries.


https://vac-lshtm.shinyapps.io/ncov_tracker/


2. Why is it called “novel” coronavirus?

Coronaviruses are common in non-human animals , but SARS-CoV-2 has never been previously seen in humans (hence “novel”). Coronaviruses are most common in birds and bats – indeed, bats host thousands of types of virus without succumbing to illness. It is now widely believed that SARS-CoV-2 originated in bats and was acquired by humans at a wildlife market in Wuhan, China, in late 2019. However, whether humans acquired the virus directly from bats themselves or from pangolins, which acted as an intermediary “amplification” host for the virus, remains debated. As there has been no previous human exposure to this virus, there has been little opportunity for humans to develop immunity to it, and this, combined with its ability to easily spread and cause disease, is why such draconian measures are needed to control SARS-Cov-2. Although new, given our knowledge of the genetically related SARS-CoV-1, investigations are underway as to whether previous exposure to SARS-CoV-1 can protect against this new virus, and whether knowledge gained from the previous outbreak can be applied to this one [ Ref: https://doi.org/10.1016/j.it.2020.03.007].


3. This is not ‘flu.

As we covered earlier, viruses need to hijack human cellular machinery to replicate themselves – in the case of the influenza virus, SARS-CoV-1 and SARS-CoV-2, these cells are mainly in the throat and lungs. The symptoms tend to follow the spread of the infection: You get a fever because your immune system reacts to the infection; You cough because of the need to clear your airways and protect your lungs; the virus hijacks this to spread itself.

Although the initial symptoms of SARS-CoV-2 are “influenza-like” – it is important to distinguish it from Influenza. With ‘flu, the classical symptoms of fever, malaise, aches come on after a few days, usually at about the same time as you become infectious. Practically-speaking, this means that those infected usually self-isolate at the most important time of the infection cycle, and there is little chance of spreading the ‘flu further.

Symptoms
Symptoms of COVID-19


This is not the case with SARS-CoV-2. Unlike ‘flu, most of the spread SARS-CoV-2 is before the onset of symptoms. With this virus, symptoms tend to start 5-11 days (mean 5.2 days) after exposure,  which may be several days after you became infectious. This allows for this virus to be spread widely, quickly>


Think about this difference: With ‘flu, you would socially isolate at the point of being infectious, but with SARS-CoV-2 you might not – you could continue to interact with people for days at exactly the time when you are spreading the infection. This is why social isolation for this disease, even in the absence of symptoms, is so important.

From the perspective of taking x-rays, you may not think of this as an issue; most patients admitted into this part of the care pathway are often exhibiting symptoms. But what about people admitted because of an accident, or if you are simultaneously treating patients without symptoms? We will cover how the virus is transmitted, later in this document.

4. What makes it lethal; why do some people die and others have minimal symptoms

COVID-19 disease is much more complicated than ‘flu. COVID-19 can be asymptomatic, or can result in mild to severe symptomatic disease. Furthermore, developing COVID-19 is significantly more fatal than, say, H1N1 swine ‘flu: the fatality rate for H1N1 was 0.02% of the infections (or 1 out of every 5,000). Although control measures and reports vary between different countries, the latest estimates  of rate of COVID-19 fatalities from South Korea, who are likely to be the more accurate due to them having among the highest levels of population testing for SARS-CoV-2, is between 1-2% [Latest data: https://coronavirus.jhu.edu/map.html]. This section will explore what is happening and why this is the case.

As discussed, all viruses bind to cells via interaction between two proteins: one on the virus, and one on the surface of the host cell. In SARS-CoV-1 and 2 the virus attaches to cells via the angiotensin-converting enzyme 2 (ACE2) receptor: what is striking is that ACE2 is abundantly present in humans in the nasopharynx, the epithelia of the lungs, and vascular endothelium more generally, which explains some of the significant early symptoms such as loss of taste and/or smell, and why the virus predominantly attacks the lungs [Ref: doi.org/10.1002/path.1570]. MERS, by way of contrast, attached to DPP4 (dipeptidyl peptidase IV) receptors, which is rarely detected in the surface epithelium of the nasopharynx, and marginally in distal airways, which explains why it was harder to spread – due to a lack of virus binding in the upper airway.

The open question, however, is why does the virus cause major symptoms in some people, and not in others? We don’t yet have all of the answers for this, especially as there is still uncertainty regarding confounding risk factors, however older age (>65 years old) is consistently associated with a severe COVID-19 reaction; other factors include: male sex, hypertension, diabetes and cardiovascular disease [Ref: doi.org/10.1101/2020.04.05.20054155].

Another factor to consider is that of secondary infection. Some studies have found that one in seven patients hospitalized with COVID-19 had acquired a secondary bacterial infection, 50% of which died. It is important to appropriately treat secondary bacterial infection, ensuring that problems such as antimicrobial resistance are not exacerbated. Secondary lung infections may also obfuscate diagnosis of COVID-19, which will be covered elsewhere in this resource.


5. How is SARS-CoV-2 transmitted and how can transmission be minimised?

SARS-CoV-2, like many viruses, spreads via aerosol or respiratory water droplets, especially via coughing/sneezing droplets onto mucous membranes in the eyes, nose and mouth. Therefore, the greatest risk of transmission is through close contact with patients (< 2m). Personal protective equipment is essential: face masks can reduce transmission by up to 80%, however due to viral particle survival on surfaces, reuse of PPE such as respirators (despite shortage of supply) is not recommended.

Reuse of respirators is not recommended, but if absolutely necessary there are some guidelines in the literature:

A two-step disinfection process can be used, based on an initial storage of PPE for ≥4 days, followed by ultraviolet light (UVC), dry heat treatment, or chemical disinfection.

The applied UVC dose should be at least 2,000 mJ/cm2 on both sides of masks, as well as heat treatment at 60°C for 90 minutes.

Note that treatments involving certain liquids and vapors may require caution, as steam, alcohol, and bleach all led to degradation in filtration efficiency, leaving the user vulnerable to viral aerosols: Vaporized hydrogen peroxide treatment was tolerated to at least 5 cycles by N95 masks. Standard autoclave treatment has been associated with no loss of structural or functional integrity to a minimum of 10 cycles for the 3 pleated mask models.

References:

https://doi.org/10.1101/2020.04.01.20050443

https://doi.org/10.1101/2020.04.02.20051409

https://doi.org/10.1101/2020.04.05.20049346


The virus can also be transmitted via contact with respiratory secretions; survival of SARS-CoV-2 for multiple days on touch surfaces (up to 72 hours on plastics). Decontamination of any surface that may have come into contact with respiratory droplets: door handles, touch surfaces, and imaging equipment (CT and MRI gantries, ultrasound probes) is essential. Washing hands with soap regularly, or using an alcohol-based hand gel, and avoiding touching the eyes, nose and mouth wherever possible, is the single most important method of reducing transmission.

Particularly for radiographers, - clean techniques for imaging are recommended to reduce transmission, including dual working where possible. Mobile imaging, avoiding transfer of the patient wherever possible, or “clean” transfer of patients to imaging departments when mobile imaging is not appropriate, is recommended.


6. Diagnosis of COVID-19

Three types of diagnostic test are being used, or are being actively developed. Each has its own benefits and weaknesses. These can be split into two types, that either diagnose active infection (i.e. someone has the virus now), or test whether they have historically had an infection sometime in the past.



7. Real-time RT-PCR for the routine diagnosis of COVID19

There is currently only one test routinely used to diagnose active SARS-CoV-2 infection. This is RT-PCR (“real-time reverse transcriptase polymerase chain reaction”), which specifically detects the presence of viral nucleic acid in clinical samples. The test takes a few hours to complete.

PCR is a widely used technique in molecular biology that is able to target a specific region of a genome and make billions of copies of it. In the context of diagnostics, this means that PCR can be used to detect even very low numbers of viral genomes in clinical material. However, PCR only works on DNA, not RNA. Since SARS-CoV2 has an RNA genome, it must be first converted into DNA before it can be added to a PCR test. This is achieved using an enzyme called reverse transcriptase (RT). The DNA produced by reverse transcriptase is commonly known as cDNA (short for complimentary DNA) and is the right sort of “template” for PCR. Viral RNA is first extracted from swabs of the nose or throat or samples of sputum using commercial RNA extraction kits. The extracted RNA is added to a “one step” reaction mix that combines the RT and the PCR stages of the assay. The PCR targets a small fragment of a gene called RdRP. This PCr is not actually SARS-Cov2 specific, but will detect all “Sabecoviruses”, including SARS-CoV1 and many very similar viruses that have been detected in bats around the world. To distinguish SARS-CoV2 from these other viruses, a probe specific to SARS-CoV-2 is included in the reaction mix that produces a fluorescent signal when it specifically binds to the amplified RdRP fragment. The amount of fluorescence produced is directly proportional to the number of copies of the SARS-Co-V-2 RdRP gene fragment, hence the viral load can be measured.

Evaluation of the SARS-CoV-2 real-time RT-PCR assay has indicated that its limit of detection is about 4 viral RNA molecules – i.e. it is exquisitely sensitive. Furthermore, evaluation has failed to detect non-specificity – the assay only detects SARS-Cov2 RNA and not RNA from any other coronavirus (or anything else). Laboratories routinely performing the SARS-CoV-2 RT-PCR assays employ stringent control measures to ensure that assays work correctly (i.e. positive and negative controls) and that cross-contamination of RNA between samples does not occur.

    


8. Antibody detection tests

An alternative approach to diagnosing infections is to look for a specific host response to infection, rather than detect the pathogen itself. The most common means of doing this is to measure antibodies in patient serum. The detection of (for example) SARS-CoV-2 antibodies does not indicate that a patient has ongoing infection, but rather that they have been exposed to the virus at some point in the past.

Indeed, it takes the body about 10 days to mount a measurable antibody response to an infection, which may mean antibodies are not detectable until the latter stages of illness. Once an infection is cleared, the level of antibodies in serum tends to decline over time, but can vary from person to person and is very dependent on the pathogen that provoked their production (humans respond to some pathogens with a much stronger antibody response than others).

 Because the production of antibodies in response to infection is delayed, tests measuring antibodies are not very useful for patient management. However, because antibodies persist for some time after infection, antibody assays are a valuable tool for infection surveillance – for example, quantifying what proportion of the population have been exposed to/infected with SARS-Cov2.

There is currently no one antibody assay that has been universally adopted for SARS-CoV-2 surveillance.  Different countries are using, to a greater or lesser extent, assays that have been developed by their national public health agencies and/or by private manufacturers. Most of the commercially-produced assays are “qualitative lateral flow immunochromatographic assays” – this format is akin to that commonly used to determine pregnancy and thus can be done easily by patients themselves (or at least at point-of-care) without the need for specialist equipment of technical training. This format makes it feasible for huge numbers of people to be tested. However, the sensitivity and specificity of these assays are currently considered inadequate by many; in particular, there is widespread concern about false negative results resulting from assays being unable to detect lower concentrations of antibodies in the sera of some recovered patients.

Viruses recognise and bind to target cells by the interaction of molecules on their surface, with those on the target cell. These are called “surface receptors” – and work a little like a lock and key: a virus can only invade a cell is its surface molecule (the key), matches the receptor (the lock) on the host cell. The SARS-CoV-2 key is the spike protein which matches the ACE2 receptor lock on target cells.  

After binding to target cells, virus particles enter the cell either by fusion of the lipid envelope with the host cell membrane (e.g. HIV) or receptor-mediated endocytosis (e.g. influenza virus or coronavirus), in which receptor binding triggers the cell to engulf the virus particle. Once inside the cell, the viral capsid dissolves, uncoating the viral genome, which can then be replicated. New viruses are now made by the host replication and synthesis machinery. Finally mature virus progeny exit the host cell. Enveloped viruses do this by budding, picking up a coating of lipids from the host cell membrane on the way out. Box 1 shows the size of virus particles, but also some of the surface receptors on coronaviruses and influenza virus.

Figure 3 A diagram, depicting the general trend of associated with a typical time-course of SARS-CoV-2 infection following infection. The initial peak of viraemia is detectable by either PCR or antigen-based methods. Following an assumed immune response, antibodies can instead be detected by serology, however the length of time these remain detectable for remains poorly understood.
Click on images to enlarge

9. Antigen detection tests

Rapid antigen detection tests, using the same lateral flow immunochromatographic format described above, are being developed as an alternative to the real-time RT-PCR to demonstrate the presence of virus in clinical samples. Rather than detecting viral RNA, these assays use laboratory-produced anti-SARS-CoV-2 antibodies to capture and detect antigens on the surface of the virus.  Various commercial manufacturers are developing and marketing antigen detection tests as a cheaper, quicker alternative to RT-PCR that can be delivered at point-of-care.    


10. SARS-CoV-2 Treatment and Vaccine Development

There is no vaccine for any SARS coronavirus. Nevertheless, aided by worldwide efforts to sequence the genome of the virus, four companies and academic institutions have reported vaccine candidates they have been testing in animals, and human trials are beginning. Nevertheless, there are many barriers before global immunisation is feasible and it is estimated that vaccines will not be available for at least 12 months, in order to make a vaccine that is long-lasting and suitable for everyone.

Interestingly, the Bacille Calmette Guerin (BCG) vaccine has previously been shown to have some protective effects on viral infections, as well as long-term efficacy against tuberculosis; Randomised clinical trials are underway to study whether health care workers can be better protected (via reduced intensity of infection, not full immunity) via BCG stimulation of innate immunity.