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ACB Expert briefing: The role of antibody testing in the control of COVID-19, and how to ensure that direct molecular detection of the virus is part of a quality pathology system

14/05/2020 15:05:08

Testing for infection with COVID-19 novel virus Credit Lancashire Teaching Hospitals Image credit: Lancashire Teaching Hospitals

As we look towards the next phase of the UK’s response to COVID-19 the Association for Clinical Biochemistry & Laboratory Medicine (ACB) President, Professor Neil Anderson, Dr Rob Shorten, Chair of the ACB Microbiology Professional Committee, Dr Liz Bateman, Chair of the ACB Immunology Professional Committee & Dr Rachel Wheeler, Consultant Immunologist, explain two aspects of laboratory diagnostics that will be key in the battle against this disease; antibody tests and the use of viral detection by public health colleagues. 

Antibody tests

What are antibody tests and what do they tell us?

Antibodies are proteins that are produced by some white blood cells to tackle an invading germ or pathogen, such as bacteria and viruses. Different types of antibodies are produced at different times in a disease process and they can continue to exist for varying lengths of time depending on the infection.

Antibody tests work by mixing the patient’s blood sample with prepared virus proteins, and then detecting whether any of the patient’s antibodies have stuck to the virus proteins. Some antibodies work better than others to give protection against viruses. These antibodies are said to ‘neutralise’ the virus, i.e. stop it infecting cells.

The presence of antibodies in a patient’s blood suggests that infection has occurred in the past. Antibody tests are commonly used for many infections, such as hepatitis viruses. To date however, antibody tests have not been routinely used for this purpose in infections caused by respiratory viruses. Several hundred different antibody tests for SARS-CoV-2 are being offered by manufacturers in response to the pandemic.

How and where are these tests performed?

Blood samples taken from patients are analysed in a laboratory, where large numbers of tests can be performed using automation. These tests are performed by skilled, regulated scientific staff and require expert interpretation.

Near-patient or point-of-care (POC) tests are based on similar technology but detect antibodies in blood from a finger-prick. This small volume of blood is applied to a small device like a pregnancy test and ‘bands’ are visible if the test is positive. These can be performed anywhere by trained healthcare staff or patients themselves, but tend to be less sensitive than laboratory-based tests. 

How can these tests be used to direct the response to COVID-19 and what are the limitations of our knowledge?

There is increasing evidence that most people who have been infected with SARS-CoV-2 produce antibodies in the second and third weeks following infection. It is not clear for how long these antibodies will remain and how protective they will be against re-infection. Looking at evidence from other human coronaviruses, it is likely that the antibodies will give some protection against re-infection for approximately a year.

Most antibody studies so far have been performed on patients who were hospitalised. What is less clear is the level of antibody response in patients who have had milder or asymptomatic infections, and this group of individuals will make up the vast majority of cases.

If reliable tests can be introduced at scale, then testing large numbers of individuals will give us some indication of how many of the population have been infected.  However, it is likely that immunity will fade over time, so the value of the presence of antibodies in any individual person is uncertain, particularly when making decisions such as when an individual can return to work or visit a care home. For this reason, issuing ‘immunity passports’ based on these tests should be approached with great caution as we don’t yet understand whether ‘neutralising’ antibodies are produced and, if so, what levels would be protective.  

Molecular detection of the virus by PCR

What are NAAT or PCR tests and what do they tell us?

Swabs are taken from patients and tested in a laboratory to detect the genetic material (RNA) of the virus. This shows whether there is an active infection. This is performed using a nucleic acid amplification test (NAAT) more often called PCR (polymerase chain reaction).

This is not an ‘antigen test’ as has been widely reported. An antigen is a protein that causes an immune response, such as the production of antibodies. PCR tests detect and amplify genetic material rather than a protein and as such are very sensitive.  

How does testing hundreds of thousands of people for the presence of the virus using PCR testing help to control the outbreak?

Two possible routes of mass testing have been proposed. We take each in turn:

‘Test, track & trace’, or contact tracing

Individuals, should they develop symptoms, are asked to self-isolate along with their household. These patients are tested as quickly as possible to assess if they actually have a current infection. If the PCR test is positive, individuals who came into contact with the patient within the period when they were thought to be infectious are then also asked to self-isolate. Some may develop symptoms, some may not, but this process is intended to stop chains of transmission and therefore bring the outbreak under control. 

Regular testing of asymptomatic people

As we find out more about this virus, it is clear that some transmission of infection occurs from people when they are asymptomatic or pre-symptomatic (i.e. carrying the virus, but they don’t feel unwell yet). Some have advocated mass testing of everyone on a regular basis. A positive result would be managed as above; the individual and their contacts would be asked to self-isolate to break chains of transmission.

However, PCR tests for COVID-19 were never designed as screening tools in well people and this approach creates some issues. To examine this, we need to consider the terms sensitivity and specificity.

Sensitivity is a measure of how certain we are that we can believe a negative result. If a test is 99% sensitive, then if we test 100 patients with a disease, the test will detect 99 of them. The remaining one is a false negative.   

Specificity is a measure of how certain we are that we can believe a positive result. If a test is 99% specific and we test 100 patients without a disease, the test will give a negative result 99 times out of 100. The remaining one is a false positive.  

Even if a test has a seemingly high sensitivity and specificity, this is no guarantee of performance. This is particularly true when the prevalence of a disease is low, and we have no firm grasp on the true prevalence of COVID-19 in the UK population. Issuing false negative and false positive results will lead to inappropriate public health actions. No diagnostic test is 100% sensitive and specific, and we need to be aware of, and take into account these limitations.

How do we make sure that testing at scale is effective?

Tests for notifiable infectious diseases, such as COVID-19, when performed in NHS and Public Health Laboratories are of a high quality standard. Laboratories are accredited and scientists are registered and regulated to ensure that standards are maintained. These systems are well connected to ensure that results are rapidly communicated to Public Health teams. Colleagues in Public Health can then intervene swiftly and capture surveillance data to help to control outbreaks.

High volume testing centres add welcome capacity to the system and must operate to the same high standards. Increased testing has introduced additional challenges to the testing process. Patients are being asked to take their own swabs, either via postal sampling kits, or at drive-through centres. Saliva testing is also being considered. Without clear instruction or supervision, both of these processes risk inferior sample collection and the increased potential for false negative results.  

Pathology services underpin good healthcare. The requirement for high quality sampling, testing, interpretation, and communication with other healthcare systems has never been greater.

 

About the Association for Clinical Biochemistry and Laboratory Medicine

The Association for Clinical Biochemistry and Laboratory Medicine (ACB) is dedicated to the practice and promotion of Clinical Laboratory Medicine. We promote better science, better testing and better care through our membership comprising of Clinical Scientists, Medical Practitioners, Clinical Academics, laboratory healthcare scientists and leading diagnostic companies.

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