Living with covid-19 will need a testing transformation

Dealing with lower COVID-19 levels will require improved understanding of what diagnostic tests are best used for. It will also need more accurate tests, but as testing demand will fall, delivering that needs incentive-based support.

As future COVID-19 prevalence varies across time, health authorities must revolutionise testing to see if people are infected. COVID-19 testing technologies and understanding of their capabilities must both improve argues Gerald Kost, founding director of the Point-of-Care Testing Center for Teaching and Research at University of California, Davis, US. "A huge knowledge gap needs to be filled," said Kost.

In a January 2022 paper Kost explores how changing prevalence affects the COVID-19 rapid antigen tests, also known as lateral flow tests (LFTs). False negatives from low sensitivity, the probability that a positive test result truly reflects an infection, are problematic with some such tests. In approved tests, this sensitivity can sometimes be 75% or lower. And such low sensitivity may enable COVID-19 to spread during outbreaks with prevalence above 10% of the population being infected, Kost said.

False negatives often happen when infected people are pre-symptomatic, said Yuka Manabe, associate director of global health research and innovation at Johns Hopkins Center for Global Health, Maryland, US. The probability that a negative test result truly indicates that a person is not infected, known as specificity, is another key measure. Even though approved tests exceed 93% specificity, during periods when SARS-CoV-2 levels are low the likelihood of LFT false positives relative to true positives increases, Manabe explained.

LFTs are valuable, however, in confirming infection when people have symptoms, she added, especially as they cost just $1 or less. But she stressed that "if it's negative, it doesn't guarantee that you don't have COVID". Lab-based molecular real-time polymerase chain reaction (RT-PCR) tests offer higher sensitivity thresholds above 90%, and specificity exceeding 99%. RT-PCR specificity is better suited to screening many people without symptoms, but Manabe stressed that "they are not economical".

An intermediate option between LFTs and RT-PCR is isothermal amplification, Manabe explained. It amplifies amounts of genetic molecules, copying and multiplying strands, like PCR. But whereas PCR cycles between high and low temperatures, isothermal loop amplified polymerase (LAMP) testing, "can be used at one temperature", said Manabe. "They tend to be less expensive but slightly less sensitive than RT-PCR.".

LFTs' benefits are context-dependent, said Marta García-Fiñana, professor of biostatistics at the University of Liverpool, UK. She based that on the world's first evaluation of large-scale voluntary rapid antigen testing for people without COVID-19 symptoms, in Liverpool from 6 November 2020 to 30 April 2021. She and her colleagues found that LFTs pick up most cases where people have high viral loads in their bodies and are infectious but can miss some. "This meant that LFT needed to be considered with caution in high-risk settings, like for example in care homes," García-Fiñana said, especially before vaccinations were available.

García-Fiñana stressed that it's important for everyone to understand such aspects of how tests perform, and how they add value despite some weaknesses. She noted that reporting single sensitivity values for LFTs has caused avoidable confusion. Different attempts to measure sensitivity have given contradictory values because it strongly depends on a person's viral load, García-Fiñana said. "Estimation of the overall sensitivity can be very different depending on the phase of the epidemic curve at the time the study takes place," she explained. "Differences in viral load distributions can explain much of the difference in overall sensitivity reported across different empirical studies."

Yet for Iain Buchan, professor of public health and clinical informatics at the University of Liverpool, UK, who led the evaluation, discussions of diagnostic accuracy are not enough. "Testing is more than a test," he said. "End-to-end testing in a pandemic is a complex public health intervention and not a clinical diagnostic test." He highlighted LFTs' speed and self-testing capability. "Rapid tests provide rapid risk mitigation," said Buchan. Buchan revealed the pilot's soon-to-be-published findings that rapid LFT community testing raised case detection by around a fifth, and reduced case rates by around a fifth and hospitalisation by around a third compared to other areas.

Some hospitals in the UK's National Health Service offered LAMP tests twice weekly, but it has not been popular. LAMP uptake is only around 25% in Liverpool's main hospital. Even with full uptake it may not have been frequent enough to arrest the spread of the omicron variant, Buchan revealed. Meanwhile, staff preferred the convenience of doing LFTs at home. As such the LAMP experiment is being wound down in favour of an LFT-based process. Yet Buchan asserted that "RT-LAMP and other emerging rapid nucleic acid tests" are "vital technologies for rapid screening for infections, particularly early phases of infection, in clinical settings".

Anders Wolff, professor at the Technical University of Denmark in Copenhagen, agrees with Buchan that rapid testing is important. So, the ideal test must combine sensitivity, specificity, speed, and price. Wolff leads CORONADX, a European research project that has developed a LAMP-based rapid COVID-19 testing instrument called PATHPOD. "It's very specific and has a sensitivity comparable to that of PCR," said Wolff. "You're going to have the answer in one hour. People prefer this, rather than having to wait one or two days." CORONADX is now seeking to commercialise PATHPOD, perhaps by partnering with a large company.

Wolff highlighted Denmark's unique mass COVID-19 testing programme, in spring 2021, in which every citizen could get a free RT-PCR test. It screened more than 8% of the population per day. As the COVID-19 pandemic eases, it would take a "real breakthrough" to see governments fund anything similar, Wolff said. Instead, approaches like LAMP will enable regular focused testing of vulnerable groups, such as nursing homes, he added.

For Kost, a reasonable minimum performance level for future monitoring is 95% sensitivity and 97.5% specificity. LAMP is a potential solution but vaccinations will blunt the demand needed to support its development in a market-led model, he added. "However, need for focused testing will create niche markets where shrewd entrepreneurs can leap in to continue development," Kost predicted. "We need to prepare for the next pandemic. That will require comprehensive retooling of public health and incentive-based development of affordable point-of-care molecular diagnostics."

Provided by iCube Programme