CLINICAL MATTERS

The Covid-19 pandemic introduced the word “RT-PCR” into the mainstream. RT-PCR, which stands for Reverse-Transcription Polymerase Chain Reaction was the only test available for diagnosing Covid-19 when the pandemic was just starting. World Health Organization director general Tedros Ghebreyesus remarked that an important action point to fight the pandemic was for countries to, “Test, test, test.” This was because it was important to track the spread of the virus into different countries and for governments to act accordingly.

Countries responded by massively increasing their RT-PCR capacity to unprecedented levels. Unfortunately, this caused an acute shortage of PCR machines and consumables needed to perform these tests. Prices skyrocketed and poorer countries found themselves unable to compete with richer nations for these essential tests. Ill-advised campaigns for mass testing exacerbated the shortage, even as scientists and infectious diseases experts warned that RT-PCR tests were not suited for mass testing due to its propensity to remain positive even after recovery. Worse, due to the extreme fear of releasing a possibly still infectious patient, people who had recovered were required to get two negative RT-PCR tests which turned out to be extremely wasteful and resulted in unnecessary prolonged isolation. Targeted testing as well as time-based recovery strategies turned out to be more sustainable and less wasteful strategies which pragmatic governments, including the Philippines, eventually adopted after the noise died down. 

As resource-limited countries struggled to acquire and perform RT-PCRs for their needs, new tests started to come up. Rapid antibody tests were the next to be produced, but these turned out to be useless for diagnosing acute disease since it took about 14 days to produce a detectable antibody response. By then, most patients were no longer infectious and had already exposed their close contacts. Many countries bought and stockpiled these relatively cheap tests but struggled to find a practical use for them. A lot of money was wasted on needless antibody testing, which never really correlated with acute disease or protection from infection. 

The Department of Health, on the recommendation from the Health Technology Assessment Council and from the Technical Advisory Group not to use rapid antibody tests, refused to procure these tests because of its shortcomings. Unfortunately, some local government units and private groups pushed through in acquiring these tests despite the scientific advice against their use and ended up wasting a lot of money and causing a lot of needless anxiety. Many workers were isolated and not allowed to return to work when their antibody tests came back positive since this was misinterpreted as active disease. It takes weeks to months for the antibody test to turn negative even if people were no longer infectious. 

When rapid antigen tests finally arrived, these were treated cautiously. After the disastrous failure of antibody testing that looked very similar to the rapid antibody test’s lateral flow format, many people didn’t think these would be useful. Antigen tests were eventually shown to correlate closely with infectiousness and so these could be used along with time-based recovery strategies to better estimate the presence or absence of infectious virus. This was a major advantage over RT-PCR.  

RT-PCR however was still better at detecting early disease even before symptoms occurred so negative antigen tests in those with known exposure still ended up being checked with RT-PCR. A positive antigen however was almost always a true positive and did help conserve resources. When self-administered tests started to come to market, many people opted to test themselves if they developed symptoms rather than going out for an RT-PCR and potentially infecting others. RT-PCR testing was increasingly used only for sicker patients and as confirmatory tests if treatment was needed. By then, the use case for testing had shifted from containment to mitigation since there was already widespread community transmission and most people were already vaccinated.

All these lessons gave rise to a better awareness and understanding of the importance of diagnostics, not just among the general public, but also among physicians and public health authorities. One test in a specific situation could be appropriate for containment but not as a test for cure. Another test could be good for documenting past infection but not for present infection. Cost and technological requirements are also important considerations. These different use cases gave rise to the relatively new field of diagnostic stewardship. Judicious use of diagnostics is more important than ever since the pandemic spurred major advances in the field, including the availability and use of molecular diagnostic panels.

As more people were vaccinated and fewer cases of Covid-19 occurred in the community, it became increasingly difficult to distinguish whether patients presenting with respiratory symptoms had Covid-19 or not. This was especially true during flu season and among children who typically had other respiratory virus outbreaks like RSV (respiratory syncytial virus). This prompted the US Centers for Disease Control to recommend the use of diagnostic panels that test for multiple pathogens at the same time. The simplest panels did RT-PCR to check for SARS-CoV-2, influenza A and B, and RSV from the same specimen to guide treatment. It served not only to rule out Covid-19, but the detection of influenza or RSV allowed for targeted antivirals for the flu (oseltamivir/zanamivir) and other treatments (monoclonal antibodies) for RSV while avoiding unnecessary anti-viral use against Covid-19. 

The major drawbacks of these tests are still the same for RT-PCR—it does not distinguish between active and recent infection—but when used in symptomatic patients, results were more likely to be clinically significant. These tests are also more expensive than a single test for Covid-19, but considering that they can potentially avoid hospitalization, unnecessary isolation, or unnecessary use of medications (a course of Paxlovid is ₱20,000), these can be cost-effective if used judiciously. This so-called syndromic approach is a new approach to infectious diseases using the power of molecular diagnostic panels.

Syndromic diagnostic panels aren’t for everyone and should be used mostly in symptomatic patients and those with more severe disease. The main reasons these should be used properly are cost and the possibility of a false positive from recent infection. Molecular diagnostic panels can also be used by public health authorities for disease surveillance. There is a very extensive panel that can test for hundreds of different pathogens including bacteria, viruses and fungi plus thousands of bacterial resistance genes. These huge and very expensive panels aren’t used for routine patient care but are more useful to health departments to detect potential outbreaks early. The more commonly used molecular respiratory panels in patient care test for anywhere from four to 20 different viruses and a few bacteria off of a single nasopharyngeal swab. The cost can range from ₱8,000 to ₱30,000 pesos which isn’t too bad if you count each pathogen tested as a single PCR or RT-PCR test which would otherwise cost ₱3,000 to ₱5,000 per single test. This is however still nowhere near as affordable as an antigen test. With more users and competition over time, it is expected that the costs for these panels will drop to more reasonable levels.

As always, the practice of good medicine remains both an art and a science. Physicians need to balance the cost of testing with the benefit of knowing the correct pathogen, giving the correct treatment in a timely fashion, and avoiding unnecessary interventions. At the very least, these new diagnostics give us more options and tools than we have ever had before. When used properly, they can keep us safe and healthy in this post-pandemic world and better prepare us for the next big outbreak.