Saturday, August 13

Covid-19 – to test or not to test?

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IT was ‘durian runtuh’ season for some clinics after the Movement Control Order (MCO), when workers were required to obtain a medical certificate to say they were fit to return to work.

As doctors, we know that if we really wanted to identify Covid-19 infected workers, laboratory confirmation is needed. SARS-Cov2 RT-PCR nasal swab tests costs RM380 to RM450 each in drive-through laboratories. Are the cheaper (RM50+) rapid antigen or antibody tests cost-effective and safe public health alternatives?

I hope this article will help cost-conscious decision-makers understand Covid-19 testing – what negative tests mean and the limitations of relying on single-point-in-time tests to protect anyone from infected Covid cases in the long term.

The Covid-19 Immunity Passport may be based more on faith than on science – until it can be scientifically proven that current positive tests for antibodies are absolutely correlated to significant, protective, and durable immunity.

Research and policies must not be driven by industry, politics or early-bird dash for fame or fortune. All manufacturers’ claims, industry-sponsored research, and listed companies’ press releases based on unverified, non-peer reviewed findings should be coldly scrutinised for bias, even fraud.

The socioeconomic, mental, and public health opportunity and real costs arising from inaccurate or defective diagnostic tests are huge. Hence the need for stricter, scientific, independent validation to identify and blacklist fraudulent manufacturers.

Covid-19 is a fast-evolving science and current guidelines may change with new peer-reviewed publications. At this point in time, as a public health specialist and a practising paediatrician, this is what I have learnt and can share with you. Please check with your own medical provider before making any decisions.

Medical reports without testing

Without laboratory testing, medical examination (complete with full PPE or from a safe distance of six feet) and history-taking, can only give a false sense of security. The worker may say he is well and act well, desperate to get the medical passport to work. Any GP has to give him the benefit of doubt.

The worker may not tell the doctor the truth, the whole truth, and nothing but the truth. Indeed, many healthcare workers have been infected by cases who ‘forget’ to say that they had travelled or had been in contact with known cases. Even when they have symptoms, which they suspect is Covid, patients may tell the front desk they have some other condition, so they can be seen by the doctor they know and trust.

But, perhaps on the day he was at the clinic, he indeed felt well and did not know he had been infected. In the first five to six days of infection, cases are pre-symptomatic and virus shedders. Or, he could be one of the lucky 25 per cent symptom-free infected and infectious cases (being young, with no preexisting risk factors, eg obesity, hypertension, immunocompromised by age, disease, or chemotherapy).

A retrospective study of the hospital records of 36 infected children (mean age 8.3 years) in China found 17 had mild symptoms and 10 (27.7 per cent) with no symptoms. (Lancet Infect Dis 2020).

You get it. Doctors can give a medical note to say that your staff member, who looks, feels, and says he is well, is well. We cannot say he is Covid-free, even on that clinic day.

So which test should you invest in, if at all?

Covid-19 Tests

The Ministry of Health does not recommend Covid-19 Antibody IgM/IgG Rapid tests because a negative antibody test only tells us the person does not have antibody to Covid (Director General MOH, May 11, ‘Rapid Antibody test can’t diagnose Covid-19’ – CodeBlue article). It does not guarantee that he is not infected. At all.

It takes the immune system one to two weeks after the invasion of a new virus to develop detectable antibodies to the viral proteins. IgM is the first antibody to appear, peaks in two weeks and fades off. IgG peaks within a month and persists (but its duration and protective efficacy is under research). Finger-prick Antibody tests combine IgM and IgG for higher detection rates.

As antibody levels in the blood rise and fall after an infection, the timing of the blood taking is crucial. In the first one to two weeks, the test may not be sensitive enough to pick up low antibody levels. This result is a false negative, and may give a false sense of security that he is not infected. He may go back to work or celebrate and become a super-spreader!

To exclude false negatives, a repeat test must be done a few days later. If the first or repeat antibody test is positive, nasal swab for RTPCR testing will still be needed to make sure he is not still positive for the virus.

Wide variability in performance of tests

The global health non-profit Foundation for Innovative New Diagnostics (FIND) based in Geneva, lists more than 200 serologic tests and 318 RT-PCR tests now available or in development for Covid-19 (https://www.finddx.org). Only 12 antibody tests have received emergency use authorisation (EUA) from the US Food and Drug Administration, which gives companies permission to deploy a product without providing the same amount of supportive evidence as required in the typical approval process. On May 4, the FDA announced it would heighten the scrutiny of these tests after being criticised for the flawed tests and the inconsistency of the manufacturers’ claims (Washington Post, Laurie McGiniey, May 4). The FDA’s action follows a report by more than 50 scientists, which found that only three out of 14 antibody tests gave consistently reliable results, and that even the best had flaws. (Coronavirus Antibody Tests: Can You Trust the Results? New York Times, April 20).

Nearly AU$18.9 million worth of rapid antibody tests purchased by the Australian federal government were inaccurate. Independent testing by the Doherty Institute for Infection and Immunity found the overall sensitivity was just 51.8 per cent (Sydney Morning Herald, Liam Mannix, May18).

Independent evaluations needed

The Covid-19 Testing Project on RTAb, a multidisciplinary team of researchers and physicians ran head-to-head comparisons of commercially available RT Serological tests, including an evaluation of the test performance by time from symptom onset.

It found that the ability to detect antibodies in people who tested positive for the virus increases over time, rising to 81 to 100 per cent when more than 20 days had elapsed since symptoms began. Therefore, a negative antibody result may simply mean that a person had not yet developed detectable antibodies to the infection.

They ran tests on blood samples, collected pre-Covid, from Red Cross blood donors, to find out if they could detect antibodies in these ‘never infected’ donors.

The false positive rates when done on these pre-Covid negative controls range from 0 to 16 per cent (Pre-Print, April 29 – covidtestingproject.org).

False positive antibody tests are dangerous: for healthcare workers who get sent back to the frontlines, perhaps with less protective gear; for the average person, who may overestimate immunity and underestimate risks; for policymakers who may opt out of the harder tasks of reviewing the work or living place crowding, ventilation, sanitation, enforcing masks, providing hand washing facilities, paid time-out, and paid medical care for sick staff.

Since we know that the virus shedding (infectivity) is maximal early on in the Covid infection and for the first 10 to 11 days (Singapore study), an antibody test that is only positive in the second or third week will misdiagnose most cases when they are most infectious. Antibody tests are thus not good for timely epidemic control measures.

Rapid Antigen tests

RTPCR tests are the gold standard for detecting Covid, but test results are often delayed by logistics 48 to 72 hours or longer. They may not reflect the current state of the worker by the time he returns to work unless he has been totally isolated!

Antigen RTK tests from SD Biosensor Inc South Korea have been approved for use in Malaysia starting this month. They are reported to have a sensitivity rate of 84.4 per cent and a specificity rate of 100 per cent. Test results are available within 30 to 45 minutes, and 15 tests can be done simultaneously. Nasal swab samples can be tested at the point of care, instead of having to be sent to selected laboratories for RTPCR.

Rapid Antigen tests detect the presence of protein structures called spikes, unique to SARS-Cov2. They are very specific for the virus, but are not as sensitive as RTPCR. Negative antigen results do not rule out infection and will need to be confirmed with a repeat test a few days later to rule out false negatives.

A clinically suspicious case with a negative antigen test will be retested with RTPCR prior to making treatment decisions and to prevent the spread of the virus.

The FDA authorised the first rapid antigen test on May 9, 2020 for emergency use in the USA.

It has received adverse event reports that suggest some users are getting inaccurate negative results. The agency is aware of some scientific studies that have identified accuracy issues with the particular test used. It is investigating whether it could be due to the types of swabs used or the type of viral transport media or user errors that have affected performance.

FIND plans to evaluate antigen-based tests by enrolling thousands of people with suspected Covid infection. Volunteers will agree to be swabbed twice. One sample will be tested for RTPCR and the other, an antigen test. I have not seen the reports yet.

FIND has been testing RT-PCR test kits and found variations in accuracy between manufacturers too. It will be a while before we find the real gold standard SARS-Cov2 test. We will talk about RT-PCR next time.

Take home message

If you are still tempted to go for the Covid Rapid Tests, on offer for RM48.88, ask first, “Blood or nasal swab?” If it is blood from a finger prick, it is an antibody test. If nasal swab and result is ready within 30 minutes, probably antigen. RTPCR will cost seven to 10 times more and results take at least 24 hours (their promo advert may say ‘Five minutes to be screened’ – they mean that’s how long it will take for their poor sweaty guys in full PPE to take your nasal swabs and make you gag).

If order-online DIY test kits are on sale, be warned. You might be buying some of those millions of defective tests returned to sender. Good luck. You will need it.

Dr Tan Poh Tin has an MBBS (Malaya), MSc Community Health for Developing Countries (LSTMH), MRCP Paediatrics, and Diploma in Public Health UK. She is a public health specialist with ground-zero experience in epidemic control of DHF, Malaria, EV71 etc in Sarawak, as well as a paediatric trainer.