While recent news headlines of a successful vaccine trial is reassuring, it is widely acknowledged that until a Covid-19 vaccine is widely available to all in the UK, virus screening offers the best solution to getting the country back to work. The country's PCR testing capacity is continuing to ramp-up and a range of new headline-grabbing 'rapid test' solutions are now in early-stage use.
Are these rapid tests the silver bullet we're all hoping for and how will they impact workplace testing, both in the immediate future and further down the line?
PCR Antigen: the gold standard test
At the start of the pandemic, PCR was the only option available to test for SARS-COV-2. Highly accurate and reliable, it has remained the go-to method for virus testing to date. In the context of the pandemic PCR Antigen tests have been used as both a diagnostic tool (people with recognised symptoms are tested via NHS Test & Trace / in hospitals to confirm virus presence) and in routine asymptomatic screening (people without symptoms are tested regularly to prevent outbreaks in healthcare / workplace contexts).
Tests are processed in a lab in two stages: viral RNA is extracted from nose & throat swab / saliva samples and converted into DNA copies, these are then amplified in a PCR machine which cycles the test temperature, producing billions of DNA copies for every strand of viral RNA present. Amplification allows detection of even a very small 'viral load'. This is particularly relevant in a screening context where the aim is to identify 'silent transmitters' who are unaware that they are carrying the virus.
The main drawback of PCR is speed. Although the test itself runs relatively quickly, the logistics (samples must be collected and shipped to a lab, unpacked, prepared and processed by skilled technicians) mean that it is difficult to return a result in under 24 hours. A cost-effective test requiring no lab processing would be a game-changer in both diagnostic and screening contexts, provided it was accurate and reliable.
Understanding test performance
All new tests are validated by comparing their sensitivity and specificity against PCR. Sensitivity indicates a test's likelihood to detect a positive case. If test sensitivity is 99% it is likely to detect 99 out of 100 positive cases - the lower the sensitivity, the more likely a test is to return false negative results.
Specificity indicates a test's likelihood of accurately detecting a negative case. If test specificity is 99% it is likely to return negative results for 99 out of 100 negative cases - the lower the specificity, the more likely a test is to return a false positive result. A test's accuracy is also affected by a third variable: pre-test probability. In assessing a test, this refers to the virus prevalence in the population being tested.
Anyone planning to implement workplace testing should look to understand a test's specificity and sensitivity and consider the implications of each - beyond the waste of financial resources - of false results.
It is also important to be aware of where test performance data comes from. A new test that performs extremely well in small-scale clinical validation trials may respond differently in real-world settings. In addition, while PCR is known to detect a very wide range of viral load (because it involves amplification), a test that is very accurate in the context of individuals with high viral loads (e.g. symptomatic people who are being diagnosed in a hospital setting) may be less so in a context where individuals have lower viral loads (e.g. people who have an early-stage infection and are asymptomatic at the point of testing).
Does a rapid screening test need to be as accurate as PCR?
The consensus is yes, it should be as close as possible.
Using a lower specificity test (more false positives) and double-checking positive cases with a second (PCR) test has been mooted however this would present significant challenges for screening at scale. Not double-checking would result in considerable unnecessary economic damage and stress: true and false positive individuals, their households and close contacts would all need to isolate. Behavioural compliance in positive individuals is a problem even now and doubts as to test accuracy are likely to make this considerably worse.
Using a lower sensitivity test (more false negatives) may miss a key group of 'silent transmitters' that asymptomatic screening is designed to identify - i.e. positive people with the low viral loads typical in early stage infection. The increased sense of confidence which follows from a negative test result, however clearly people are informed that they must continue to wear masks and observe social distancing, could actually make an outbreak more likely than no testing at all.
The following Rapid Test solutions are attracting widespread press attention. Read on for our full analysis of each test and what they mean for a programme of testing in the workplace.
1. LAMP testing without RNA extraction
Standard Loop-mediated isothermal amplification is in many ways similar to PCR: viral RNA is extracted from throat & nose swabs / saliva samples, converted to a DNA copy and amplified. Unlike PCR, LAMP machines amplify at a constant temperature and produce higher amplification than in PCR. In a positive sample, this turns the reagent mixture cloudy (accuracy can be improved using fluorescent / colour changing dyes), allowing a detection by clinician with the naked eye. LAMP testing can be speeded up by skipping the RNA extraction stage and it is only in this context that LAMP is considered 'rapid.'
Turnaround: 60-90 mins if LAMP is carried out with no RNA extraction, assuming a machine is used near point-of-care (LAMP with RNA extraction requires lab processing and turnaround times are similar to PCR).
UK use: LAMP tests are available at Heathrow airport for travellers who need fitness to fly certification. Hospitals in Manchester, Southampton and Birmingham are currently running a pilot, testing asymptomatic NHS staff using the OptiGene LAMP test.
Accuracy: Data on SARS-CoV-2 detection using LAMP without RNA extraction is limited. According to the OptiGene kit instructions, when the test is used without extraction, it should be 'as a screening test to identify very strong positive samples' and the validation data supplied by the company suggests that while the test is almost as accurate as PCR in the context of high viral loads, sensitivity drops markedly where viral load is lower. In short, compared to PCR, this test is likely to return a significantly higher number of false negative results in the context of low viral load.
Please note, LAMP testing should not be confused with LamPORE, a test designed by Oxford Nanopore which combines LAMP technology with next-generation-DNA sequencing. LamPORE was initially billed as a 90 minute rapid solution however end-to-end turnaround is actually 6-7 hours and the 450 000 LamPORE tests purchased by the Government are likely to be used alongside PCR in laboratory settings to expand central testing capacity. Early research suggests that LamPORE has comparable accuracy to PCR with the advantage of significantly greater throughput. Partly this is down to less handling and preparation in the lab, partly this is because the technology is both individual and pooled at the same time: multiple samples are batched in a single test but if a positive is detected, it is possible to identify its origin without having to re-test the individual samples as is the case with PCR.
2. COVID Nudge
This is a new proprietary technology described as 'lab-free RT-PCR' by its developers, DnaNudge. A nose & throat swab is taken from a donor and loaded onto a cassette which is processed at point of care in the COVID Nudge 'lab-in-a-box'.
Turnaround: According to a Government press release the machine can process one sample in approx. 90 minutes (15 in a 24 hour period).
UK use: COVID Nudge was validated in hospital settings and is currently authorised for clinical use only. The UK government purchased 5000 machines earlier in the autumn and according to the DnaNudge website, they are now being deployed in clinical settings nationwide.
Accuracy: Initial research published in mid-September, comparing COVID Nudge with PCR lab testing indicated overall
sensitivity of 94% and specificity of 100%. Further data on performance in routine practice is pending.
3. Lateral Flow tests
In the context of Covid-19, most lateral flow tests are designed to detect the presence of nucleocapsid proteins from the SARS-CoV-2 virus. Unlike PCR and LAMP, there is no amplification and no need for lab processing. While some lateral flow tests require a point-of-care machine to read results, others essentially operate like a pregnancy test and require no additional equipment. There were no lateral flow antigen tests available for SARS-CoV-2 at the start of the pandemic but a number are now in use / being trialled. In September the WHO gave emergency approval to two tests made by SD Biosensor and Abbott and it is hoped that these two tests in particular will pave the way in providing an effective solution for lower and middle-income economies (the Abbott test costs 5 dollars) with limited PCR availability.
Turnaround: approx. 15 minutes
UK use: Selected Boots pharmacies are offering £120 lateral flow tests using the LumiraDX machine which analyses nasal swabs in 12 minutes. In August, NHS Scotland signed a deal to purchase LumiraDX machines and tests with the intention to deploy in rural and island communities. The UK Government is trialling a number of lateral-flow solutions and has purchased 20 million saliva tests from the company Innova Tried and Tested.
Accuracy: there is currently a lack of reliable data around lateral flow test performance in real-world settings. According to LumiraDX's website, their tests are comparable to PCR in the 12 days following symptom onset however Boots is only offering them to asymptomatic customers with the aim of providing 'peace of mind' as the test is not currently accepted to prove fit-to-fly status. An independent evaluation of SD Biosensor's test by the Foundation for Innovative New Diagnostics reported a sensitivity of 76.6% and specificity of 99.3% from samples taken in Germany. This increased likelihood of false negative results compared with PCR may be because lateral flow doesn't involve amplification and the tests are missing mild / early-stage cases with lower viral loads. The Innova tests have undergone clinical validation but still require operational testing. According to the instruction information, the Innova tests are intended for use "within the first 5 days of onset of symptoms," indicating that they are not a suitable solution for asymptomatic screening. The information also states that tests should be used by "trained clinical laboratory personnel specifically trained and instructed in the techniques of in-vitro diagnostic procedures."
Rapid Testing: our opinion on implications for workplaces
There is currently a lack of real-world data on rapid tests; particularly in the context of asymptomatic screening. This does not mean that they are not effective but it does mean that it's difficult right now to tell precisely how effective. Screening with a test that is significantly less accurate than PCR could have major consequences in terms of false results and using a test that proves inaccurate could destroy employee confidence in testing altogether, waste considerable amounts of money and has the potential to be detrimental to employee health.
Where rapid tests require machine-processing they currently also require skilled, trained staff to operate and results must be interpreted by a clinician. Where no additional equipment is required, all of the rapid tests available must still be supervised and interpreted by a healthcare specialist: there's nothing suitable for home-use yet.
In the immediate term, RT PCR is the most 'known quantity' as a testing solution. It is also relatively cost effective, at a cost of as little as £37 / test for at-scale testing. As such we think it likely that most employers will continue to choose PCR Antigen testing over the winter months. That said, these developments in rapid testing are extremely exciting and the evidence base around efficacy is set to grow quickly. At Covid Testing Network we will continue to keep an eye on all new solutions in the constantly changing testing landscape and who knows, the silver bullet may be just a little further down the line.