By Karen Taylor, Director, and Maria João Cruz, Research Analyst, Centre for Health Solutions

According to the World Health Organization (WHO), rapid testing of patients who meet the suspected case definition for COVID-19 is a priority for determining the clinical management and policy response to control the outbreak.¹ Diagnostic testing for COVID-19 is critical to track the spread of this novel virus, understand its epidemiology, inform health managers of each case, and suppress transmission.² Currently, different countries have implemented different testing strategies, depending on the availability of diagnostics kits and reagents, and on the capacity and capability of the healthcare system. However, there has been a global call to increase the speed and capacity for testing to help isolate cases and flatten the peak. This week’s blog explores the importance of testing, what tests can be done and which are already available.

Why is testing important?

The WHO defines a confirmed case as ‘a person with laboratory confirmation of COVID-19 infection, irrespective of clinical signs and symptoms’.³ Indeed, testing is the only way of knowing if a person is infected. This will not only ensure they receive adequate care, but will also allow measures aimed at reducing transmission to be implemented.⁴ Importantly, testing also helps the scientific and medical communities understanding how infectious and dangerous a disease is.⁵ Testing provides us with numbers that are critical for determining the best strategy to fight an infectious disease. Strategies to fight infectious diseases that spread easily but with low fatality rates are markedly different from those to fight diseases that spread slowly but are far more deadly.⁶

It is important to understand the difference between confirmed cases and total cases (Figure 1). We know the number of cases that have been confirmed by testing. However, mild and asymptomatic cases, particularly in situations of active community transmission, are not generally being tested for COVID-19 and, consequently, not being counted.⁷ This has direct implications for the calculation of the COVID-19 case fatality rate, as the ratio uses confirmed and not total cases.⁸ Therefore, the bigger the difference between the number of confirmed cases and the number of actual cases, the less accurate are the fatality rates being calculated.⁹

Figure 1. Iceberg analogy to illustrate the difference between confirmed cases and total cases

Note: the illustration is not at scale in terms of the ratio of the different types of illness/severity, as differences are country-specific and the total numbers are unknown.
Source: adapted from illustration developed by Debby Bogaert.

What tests can be done?

There are two main types of diagnostic tests (Figure 2): molecular assays (PCR antigen tests) that rely on nucleic acid amplification tests (NAAT) for detection of genetic sequences of the SARS-CoV-2 (the virus that causes COVID-19 disease); or immunoassays (antibody tests) that can be used to detect the presence of antigens by targeting the viral envelope or to detect antibodies that have been produced against the virus during the immune response.¹⁰

Figure 2. Two main testing methods for COVID-19

Source: Financial Times.¹¹

Globally, suspected cases are currently screened using the NAAT tests, which are based on the detection of genetic sequences that are unique to the COVID-19 virus, using real-time reverse-transcription polymerase chain reaction (RT-PCR), as recommended by the WHO.¹² RT-PCR, a technique that completely revolutionised biological science when it was developed some 30 years ago, is now used routinely all over the world to detect the presence of viruses that cause respiratory infections.^13,14 A reliable NAAT (RT-PCR) protocol test for SARS-CoV-2 was published on 23 January, soon after the public release of the SARS-CoV-2 viral genome sequence on 10 January.^15,16 Importantly, this type of testing is only reliable for use in suspected cases during the acute phase of infection, but not once people are no longer infectious.

The second testing method relies on viral serology, in which samples are analysed to diagnose disease through detection of viral antigens or to assess the immune response against the virus.¹⁷ These tests are faster than NAAT, with results in a few minutes rather than hours.¹⁸ During the 2003 SARS epidemic, we learnt that the serologic diagnosis of the immune responses detected the viral-specific antibodies IgM and IgG.¹⁹ IgM antibodies, are produced during the primary antibody response to an infection and are relatively short-lived, disappearing a few days or a couple of weeks after infection.^20,21 IgG antibodies, are more durable and stable virus-neutralising antibodies that are produced in the secondary immune response.²² While the immune response to COVID-19 is not yet fully understood, scientists have shown that COVID-19 patients have a similar serologic response to that described during SARS.²³ Therefore, serologic tests that can detect SARS-CoV-2-specific IgM/IgG will be essential to show whether individuals have had the infection, even if with mild or no symptoms.²⁴

In addition, immunoassays can also be designed to detect viral proteins. Although our knowledge of the biochemical nature of SARS-CoV-2 is still evolving, global research efforts have led to unprecedented levels of rapidly published discoveries. In late March, the spike protein presented in the outer-coat (the ‘crown’, hence the name coronavirus) was fully characterised.²⁵ Coronaviruses use this spike protein to enter the cells of infected individuals and the body then produces antibodies to neutralise this protein to stop the entering in the cells from happening.²⁶ Thanks to the recent findings, teams around the world can now work on developing rapid tests to diagnose acute infections by detecting the presence of this spike protein.²⁷

What tests are available?

The Foundation for Innovative New Diagnostics (FIND), a global non-profit organisation, is ‘driving innovation in the development and delivery of diagnostics’. It is also a WHO Collaborating Centre for Laboratory Strengthening and Diagnostic Technology Evaluation and has compiled a list of COVID-19 tests that exist worldwide.²⁸ It should be noted that this list is not exhaustive, as it relies on publicly available information and on information directly provided by test suppliers. According to FIND, there are currently over 220 molecular assays or NAAT (of which over 180 are being commercialised) and over 210 immunoassays (of which over 160 are being commercialised) for COVID-19.^29,30

Importantly, availability cannot be equated with reliability. Both false-negatives and false-positives can and do occur and this can have a big impact on the quality of care that is provided. Before any test is rolled-out, public health authorities need to ensure they can trust the reliability and accuracy of tests they use to confirm cases at a national level.^31,32 In fact, just this week, the UK Government acknowledged that none of the antibody tests obtained so far has proved to be accurate enough to be used and was working with the companies concerned to improve their quality.³³

Conclusion

Developing reliable and rapid diagnostic tests for COVID-19 to increase the capacity to respond to this pandemic, is now of the highest priority. NAAT based on RT-PCR are extremely accurate tests but can only be used during acute infections. Antibody tests still hold a great promise to inform health authorities of who, in the general public, has been exposed to the virus and is now immune. This will help answer two critical questions:

• how widely has this novel coronavirus actually spread across the population?
• how many people had mild or no symptoms of COVID-19?

The answers to these questions will be crucial to our understanding of how infectious and deadly COVID-19 really is and, importantly, to help all countries getting the outbreak under control. However, accuracy and quality should not be compromised for speed in this fight against the pandemic.

Karen Taylor - Director, UK Centre for Health Solutions

Karen is the Research Director of the Centre for Health Solutions. She supports the Healthcare and Life Sciences practice by driving independent and objective business research and analysis into key industry challenges and associated solutions; generating evidence based insights and points of view on issues from pharmaceuticals and technology innovation to healthcare management and reform.

Email | LinkedIn

Maria João Cruz - Research Analyst, Centre for Health Solutions

Maria João is a Research Analyst for The Centre for Health Solutions, the independent research hub of the Healthcare and Life Sciences team. At the Centre she conducts rigorous analysis and research to generate insights that support the practice across Life Sciences and Healthcare. She loves a good challenge and is always passionately curious. Before joining Deloitte, Maria João was a postgraduate researcher in Bioengineering at Imperial College London, jointly working with Instituto Superior Técnico, University of Lisbon. She holds a BSc and MSc in Biological Engineering from IST, Lisbon.

Email | LinkedIn

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¹ https://www.who.int/publications-detail/laboratory-testing-for-2019-novel-coronavirus-in-suspected-human-cases-20200117
² https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200323-sitrep-63-covid-19.pdf?sfvrsn=d97cb6dd_2
³ https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200316-sitrep-56-covid-19.pdf?sfvrsn=9fda7db2_6
⁴ https://www.ft.com/content/fa747fbd-c19e-4bac-9c37-d46afc9393fb
⁵ https://ourworldindata.org/coronavirus#testing-for-covid-19
⁶ https://ourworldindata.org/coronavirus#testing-for-covid-19
⁷ https://ourworldindata.org/coronavirus#cases-of-covid-19
⁸ https://ourworldindata.org/coronavirus#what-do-we-know-about-the-risk-of-dying-from-covid-19
⁹ https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930244-9
¹⁰ https://www.finddx.org/covid-19/
¹¹ https://www.ft.com/content/0faf8e7a-d966-44a5-b4ee-8213841da688
¹² https://apps.who.int/iris/handle/10665/331329
¹³ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430684/
¹⁴ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988269/pdf/eurosurv-25-3-5.pdf
¹⁵ http://virological.org/t/novel-2019-coronavirus-genome/319
¹⁶ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988269/pdf/eurosurv-25-3-5.pdf
¹⁷ https://www.ouh.nhs.uk/microbiology/diagnostic-tests/serological-testing.aspx
¹⁸ https://www.the-scientist.com/news-opinion/how-sars-cov-2-tests-work-and-whats-next-in-covid-19-diagnostics-67210
¹⁹ https://jcm.asm.org/content/42/5/2306.long
²⁰ https://www.sciencedirect.com/science/article/pii/S0161589001000256
²¹ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747358/#R1
²² https://www.frontiersin.org/articles/10.3389/fimmu.2014.00520/full
²³ https://www.nature.com/articles/s41586-020-2012-7
²⁴ https://www.ft.com/content/0faf8e7a-d966-44a5-b4ee-8213841da688
²⁵ https://www.nature.com/articles/s41467-020-15562-9
²⁶ https://www.tandfonline.com/doi/full/10.4161/mabs.2.1.10788
²⁷ https://www.sciencemag.org/news/2020/03/new-blood-tests-antibodies-could-show-true-scale-coronavirus-pandemic
²⁸ https://www.finddx.org/covid-19/pipeline/
²⁹ https://www.finddx.org/covid-19/pipeline/?avance=all&type=all&status=all&section=molecular-assays#diag_tab
³⁰ https://www.finddx.org/covid-19/pipeline/?section=immunoassays#diag_tab
³¹ https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2020/03/guidance-and-sop-covid-19-virus-testing-in-nhs-laboratories-v1.pdf
³² https://www.ft.com/content/0faf8e7a-d966-44a5-b4ee-8213841da688
³³ https://www.ft.com/content/f28e26a0-bf64-4fac-acfb-b3a618ca659d