On December 31, 2020 the four UK Chief Medical Officers (CMOs) published a statement announcing changes to the dosing schedule for the second dose of the Pfizer/BioNTech and University of Oxford/AstraZeneca vaccines. It stated that the interval between the first and second dose should be extended from 3–4 weeks to up to 12 weeks. This rapid response examines the evidence behind this decision.
- The most important features of a COVID-19 diagnostic test are accuracy and reliability; no diagnostic test is 100% accurate.
- No one test is best suited to all the purposes they can be used for. Some tests are better at detecting people with an infection, while others are better at ruling out people who do not have an infection.
- Lateral flow tests detect active infections, with results in minutes. However, the evidence base about their performance is incomplete but developing. A key point is the need for a better understanding of their potential to detect the virus at different points in an infection.
- Lateral flow tests could be a useful tool to detect people at the most infectious point in an infection, which could be viewed as an advantage when mass testing over highly sensitive PCR tests that can give positive results even when people are less infectious.
- They are a cheap technology and could be a useful tool to identify people with asymptomatic infections who would not otherwise be detected.
- Evaluations of mass testing using one brand of lateral flow test in asymptomatic people show that there is a very low chance that somebody without an infection would be incorrectly given a positive result. They can also detect some infected people who would not otherwise have been identified. The current view of their sensitivity is likely to be between 40–76%, meaning that up to half of infected people may be missed.
- There are mixed opinions in the scientific community about how useful lateral flow tests are as a tool to control the transmission of infection.
- Lateral flow tests are likely to have most benefit if they are repeated and targeted effectively, especially in groups and settings where infections are prevalent. They are not recommended as a tool to enable an activity that may be high risk, such as allowing someone to visit a care home.
- Planned roll outs of lateral flow tests in schools were paused because of concerns about the risk of missing cases caused by the new and more transmissible SARS-CoV-2 variant.
At least 20% of people with SARS-CoV-2 infection do not have any symptoms. While evidence suggests they are likely to be less infectious than people with symptoms, they can still transmit the virus. Therefore, approaches to detect this group of people are important. Testing large groups of largely healthy (asymptomatic) people to see if they have COVID-19 is being used nationally by the UK Government.
This requires accurate tests that are cheap, easy to use and that give a result in a matter of minutes. The Government has proposed that mass population testing in a range of settings – schools, workplaces, care homes and cultural venues – is an approach that could limit the need for restrictions on daily life while COVID vaccines are rolled out. The intention is to use them for three different purposes:
- Test to protect. Protecting vulnerable people, such as by testing care home staff (at intervals between more accurate but less rapid PCR testing).
- Test to release. Release people from quarantine, such as key workers.
- Test to enable. Testing people in order for them to participate in activities usually subject to restrictions, such as visting care homes or attending sporting events.
This article explains how reliable these tests are, the results from studies to see how well they work as a mass testing tool, and the strengths and weaknesses of using them in this context.
Accuracy of lateral flow tests for COVID-19
Lateral flow tests are a type of disposable molecular test used to detect an active infection. No laboratory processing is needed, so they can be used on the spot near the person being tested. They are a cheap technology that can be made in large volumes; this suits mass testing for which large quantities of tests are needed. A nose and throat swab fluid sample is applied to an absorbent pad. The test kit contains antibodies that bind to SARS-CoV-2 proteins on the virus. A positive result is seen as a dark band or a fluorescent glow on the test strip, with a result in about 30 minutes.
How is accuracy measured?
As with any diagnostic test, data about their accuracy and reliability are crucial; no test can claim 100% accuracy. The most important terms used in describing accuracy are:
- Sensitivity: the proportion of people with SARS-CoV-2 infection who test positive. For example, a test with sensitivity of 95% would mean that 5 in 100 people who have COVID-19 would test negative (false negative). They have an infection, but the test says that they don’t.
- Specificity: the proportion of people without SARS-CoV-2 infection who test negative. For example, a test with specificity of 90% means that 10 in 100 people who are not infected still test positive (false positive). They do not have an infection, but the test says that they do.
Several factors influence overall accuracy when tests are used in real-world settings. This means that manufacturers’ claims of accuracy do not tell the whole story. When levels of infection in the population being tested are high, a test with a high level of sensitivity will be very good at identifying people with an infection but less good at detecting people that do not. Conversely if the level of infection in a population is low, then a higher specificity becomes more important because it will be better at identifying the people that don’t have the infection than it is at detecting the people that do. You can read more about this in this article on interpreting COVID-19 test accuracy and the implications for how they are used. You can also find out more about how the levels of infection impact on lateral flow test accuracy in our last article about them.
What test features are most important for mass testing?
No one test is suited to all the purposes they can be used for. A test for mass screening would need to be sensitive enough to detect infected people; but very high specificity becomes much more important if tests are used to screen lots of healthy people.
While there may be a greater degree of tolerance for false positive and negative results in mass screening compared with diagnostic testing in a hospital, the implications of incorrect results are significant because, even for a test with high sensitivity and specificity, large numbers of people would get a false positive (and be required to self-isolate) or a false negative (and potentially go on to infect other people).
The amount of virus a person has in their body is also relevant – this is called the viral load. Tests vary in how sensitive they are at detecting different viral loads and this viral load changes over the course of an infection. Typically, a nose and throat swab from someone very recently infected will contain very little virus, but this increases until it peaks a couple of days later and then declines as the person recovers.
The trade-off when using LFTs is that their lower sensitivity means that they are less accurate at identifying people who have an infection. One research study outlines a view that test sensitivity should be considered as secondary to the speed with which results can be obtained and if tests can be repeated frequently. This is based on modelling studies of different testing scenarios. The use of repeated and frequent testing to overcome the limitations of using tests with poor sensitivity was noted by SAGE in a paper on mass testing dated 31 August 2020.
UK Government evaluation of point-of-care lateral flow tests
The Government has been evaluating multiple rapid point-of-care tests, of which lateral flow tests are one type. As numerous tests have become commercially available the Government has focused its resources on detailed evaluations of a limited number of tests in order to make decisions about which ones to use in national and regional programmes. Three lateral flow devices have passed the Government’s minimum standards for quality:
- Healgen Coronavirus Antigen Rapid Test.
- SD Biosensor Lateral Flow Test.
- Innova SARS-CoV-2 Antigen test.
Public Health England (PHE) Porton Down and the University of Oxford are evaluating these tests for the UK Government. There is a 4-stage process, with tests progressing according to how well they meet specified standards – details of this are available in our previous article about lateral flow tests.
Data so far show that the three tests show moderate sensitivity (about 70%) when compared with highly sensitive PCR tests and are better at picking up infections in people who have high viral loads. One test was rolled out nationally in December 2020, on the basis of an incomplete evaluation, and is discussed in the next section. It is not clear whether the Government’s time limited SARS-CoV-2 test and development evaluation programme (which includes lateral flow tests) has concluded.
On 23 December the Medicines and Healthcare products Regulatory Agency issued an authorisation to the Department of Health and Social Care, permitting the use of lateral flow tests by members of the public to detect infection in asymptomatic people. The brand of test to which this authorisation applies to is not clear but is described as the “NHS Test and Trace Self-Test kit”.
The Innova SARS-CoV-2 Antigen Rapid Qualitative Test
The Innova SARS-CoV-2 Antigen Rapid Qualitative Test was evaluated by PHE for the Government last autumn, with some preliminary data published on 11 November. Other data about the test’s performance comes from the manufacturer. Innova claims that that test has 100% specificity and 96% sensitivity. This is based on their evaluation of its performance on 25 samples from symptomatic people infected with SARS-CoV-2 and 25 samples without the virus. The manufacturer’s test kit information sheet sets out that a negative result does not rule out a COVID-19 infection.
PHE’s independent evaluation of how the test worked in a number of community settings reported very high specificity at 99.68%. This would mean that for every 1,000 people tested, only 3 people would get a false positive result and subsequently be required to self-isolate. However, the test’s overall sensitivity was 76.8% meaning that about a quarter of infected people would not be identified (false negative results). The sensitivity varied according to who performed the test, showing that performance results not only from a test’s physical features, but how it is used in real life:
- laboratory scientists: 79%.
- healthcare workers: 73%.
- self-trained members of the public following instructions: 58%.
A government evidence summary on lateral flow tests states that the chance of false negatives is likely to decrease over 2 weeks as operators gain experience in taking samples and using test kits.
The test’s sensitivity diminishes significantly according to how much virus someone has (viral load). The data show that the test works better (is more sensitive) in people who have a higher viral load. There is at least a 90% chance that infections will be detected when viral loads are high (over 100,000 copies of viral RNA) but this decreases to less than 60% for lower levels of virus. The Innova test evaluation report states that there is little difference in the test’s ability to pick up virus in people whether or not they have symptoms, but the sample of people tested was too small to draw meaningful conclusions that are statistically valid.
- Using this test would mean that very few people would be falsely diagnosed as SARS-CoV-2 positive and so be required to self-isolate unnecessarily.
- They will detect some infected people that would not otherwise have been identified.
- A negative result does not necessarily exclude COVID-19.
- A significant number of infected people would not be identified.
Mass testing pilots using lateral flow tests
Pilots of rapid tests have taken places in communities, education and healthcare settings. The best studied example is mass testing in Liverpool. The Innova test was chosen by the Government for a community testing pilot in Liverpool (SMART – systematic, meaningful, asymptomatic, repeated testing) in November 2020. Liverpool was chosen as it has had high levels of infection, with Tier 3 restrictions in force from 14 October. Trained operators took nose and throat swabs and interpreted the results. Positive results were confirmed with a laboratory PCR test.
Preliminary data from a research group evaluating the pilot have been reported in two ways and at different times. One report dated 25 November was considered by SAGE on 26 November (and published by SAGE on 11 December). This analysis sought to examine the test’s sensitivity, reporting it at 48.9%. Based on concerns about the poor sensitivity of the test shown in this data, the Liverpool Health Protection Board paused plans to use lateral flow tests to enable visitor access to care homes.
A fuller interim evaluation was published on 23 December. It reported that of 498,000 residents 25% had a lateral flow test and 36% had lateral flow test or PCR test. 897 people were identified as having COVID-19 using an LFT and 2,902 infected people were detected using PCR tests. Part of the pilot evaluated the performance of the Innova LFT against PCR testing, using data from 5,869 people. The overall sensitivity of the Innova test was reported to be 40%, meaning that 60% of infected people would not be detected. However, the test performed better for detecting cases in people with higher viral loads, with test sensitivity in this group at 66.7%. The test specificity was 99.9%; this means it was good at detecting almost everyone who was not infected.
The evaluation reported that people from the least deprived background were twice as likely to come forward for testing than people from more deprived backgrounds where infection rates are higher. An economic evaluation was outside the scope of the report so the question of whether this approach is value for money is unknown. There is no evidence so far that mass testing in the community reduced cases of COVID or hospital admissions.
Healthcare settings and care homes
The Health Secretary also announced that the Innova lateral flow test will be rolled out as part of twice-weekly testing of NHS staff across England. Staff will swab and test themselves, with any positive result confirmed with a laboratory PCR test.
The Government has published guidance on the use of lateral flow test in care settings, to be used as an extra tool to reduce the risk of infection from allowing visitor access. The Government has also published “an evidence summary for the use of lateral flow tests in relation to care homes”. The information in this summary comes from the mass testing pilot in Liverpool and PHE Innova test evaluation; there is no specific data on any pilots of lateral flow testing carried out specifically in care homes, although a study is taking place in Liverpool.
Mass testing in schools
Pilots of mass testing in some schools have been underway since October. On 10 November, the Government announced that mass testing would start immediately in secondary schools following a surge in cases in 11–18 year olds. This approach was intended to keep schools and pupil bubbles open, with infected pupils self-isolating at home. The Government also announced that testing would be offered to staff in schools and school-based nurseries. On 20 January plans for daily testing of pupils were paused, with concerns over the risk of missing infections caused by the new variant of the virus. Evaluation of the tests in pilot studies in some schools will continue.
Scientific advice to government on mass testing
At a meeting in November, SAGE stated that effective repeated mass testing could reduce the prevalence of infections if it is targeted to the groups where the benefits are greatest. This would only be effective if people come forward for tests and adhere to self-isolation. Repeated tests would have more impact than a single round, but there is evidence from other infectious diseases that it is often the people at highest risk who are the least likely to present for testing. SAGE concluded that lateral flow tests should not be used alone as a way of enabling high-risk activities, but are a tool that could be used to reduce the risk of other activities. SAGE endorsed an approach to use LFTs for repeated and targeted testing of high-risk groups and settings to reduce risk when activities are already occurring (such as reducing the number of infectious people entering an indoor environment). They noted that the duration of reassurance from a negative test is short.
Scientific opinion on the value of mass testing is mixed
There are mixed views about the value of screening for SARS-CoV-2 using mass testing. Some researchers think that mass tests provide a useful additional tool with which to monitor the transmission of the virus, to identify areas of high prevalence and to inform where interventions are needed. The value of tests also depends on the context and the intended purpose.
There are several arguments put forward to support their use. Although lateral flow tests detect fewer infections than PCR tests, it is suggested that they do identify people who are asymptomatically infected at their most infectious point and this could be an advantage over PCR. PCR tests are so sensitive that they can detect viral genetic material even after someone ceases to be infectious or when they are less infectious. The LFT technology is cheaper than lab tests, they are portable, simple to use and can be made in large volumes so are well-suited to testing large numbers of people.
Other views are that they are inappropriate for use as a ‘test to enable’ tool because they are not accurate enough. There are also concerns that people may be falsely reassured by a negative result, which might mean that they behave in a way that puts others at risk. Some also point out that there should be better information about test performance, so that people have a better context in which to interpret their test result.
There is also criticism of the Government’s approach to mass testing in respect of rolling out programmes before test evaluations are complete, a lack of transparent standards for evaluation, and the extent to which such a programme diverts resources from other approaches for which the evidence base is stronger (prioritising testing of symptomatic people to break transmission chains). There are also ethical concerns regarding a lack of clarity about informed consent and data privacy and sharing. It is also unclear what the impacts of these tests will be on transmission; the current trial data did not demonstrate that mass testing was stopping transmission chains.
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