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COVID-19 testing: Why, how, and when to test for SARS-COV-2 virus

Detection of infected individuals is needed, but this is difficult. Symptoms are of little help. They are non-specific and multicomprehensive, with the majority of cases being asymptomatic or undetected. A significant amount of the spread is fuelled by the silent transmission from positive asymptomatics; the reason for social isolation and lockdown.

Thus, COVID-19 testing would be of paramount importance. Would be … as we are far from being able to perform large-scale reliable tests. Up to now, the countries that have made their data publicly available have, on average, performed tests on only 1.4% of the population. No country has tested more than 14% of their inhabitants.

And anyway, which test is best?

There are two broad categories: those that rely on a nasal or throat (but also saliva) swab and those based on drawn blood. The first looks for the presence of the viral RNA in the collected biological sample by means of:

(i) reverse transcription–PCR (RT–PCR) which is the most accurate method but it takes time (at least 4 hours);

(ii) isothermal amplification assay, a more rapid method (provides results in 5 min) but it is less accurate than RT–PCR; and

(iii) detection of a viral protein, usually a surface spike protein, by an antigen.

All of these need to be performed by professionals.

One of the problems with tests involving nasal or throat swabs is that they can only detect the virus during the first week of infection. Later on, the virus disappears from the throat while continuing to multiply in the lower airways and to be infective. For people tested in the second week, after the presence of symptoms, alternative biological material should be considered from the deep airways by bronchoalveolar lavage (BAL), or sputum.

The second category is based on the search in serum for antibodies to SARS-COV-2 including IgM and IgG which, generally, become detectable several days (around ten days) after the infection, with a peak at around the 28th day. There are more than 100 different diagnostic systems under development. Once duly validated, serology tests will be important to determine the spread of the infection, to establish a sort of immune ‘memory’ for the population, and also therapeutically.

People who have tested positive with serological testing and have developed antibodies are presumed to be immune. Some countries are tempted to issue an ‘immunity passport’, a sort of risk-free certificate enabling work, travel, and return to a normal life.

In principle this sounds like a good idea!

But … there is no evidence that people who have antibodies are protected against re-infection. Actually, this is not true. This is because there are two types of antibodies: the neutralizing antibodies, which kill the virus, and the binding antibodies which bind to the virus but do not kill it, they simply make the virus more ‘visible’ and amenable to destruction by the immune system. Unfortunately, the available tests detect only binding, rather than neutralizing, antibodies.

As a result, on 24 April 2020, the World Health Organization, stated ‘there is no evidence that people who have recovered from COVID-19 and have antibodies are protected from a second infection’.

When and who to test

The simple answer is ‘early and as many people as possible’. Ideally, everybody should be tested and eventually isolated before showing symptoms. Almost 50% of the viral transmission occurs within 2–3 days before the occurrence of symptoms and this is the best time for a test; however, there are no ‘fortune tellers’ able to read the future. All citizens should be tested, a mission nigh on impossible due to cost, availability of personnel, and material. Currently, the majority of European countries aim for 100 000 tests per day. To achieve this, they are re-converting industries into diagnostics laboratories and testing infrastructures, and are implementing mobile and easy-testing programmes.

With the current restrictions, priority should be given to groups at high risk, such as:

  • patients suspected to be infected,
  • health providers,
  • retirement homes and communities,
  • employees in high-density workplaces, and
  • anyone who has had close contact with known COVID-19 patients or known positive individuals.

Why can tests be unreliable?

This is due to the usual ‘battle’ between viruses and man.

The goal of a virus is to ‘invade’ as many cells as possible, take the lead and replicate millions of copies, without if possible killing the host organism. We humans are the favourite victims: we are many (7.7 billion), complex, and we do travel a lot. Spreading is inevitable!

Respiratory viruses, such as the SARS-Cov-2, after having replicated sufficiently, need to leave the lower respiratory system, preferably after having reached the lungs, as quickly as possible in order to be back in the air and move to infect other victims.

Man’s goal is to avoid all of this as soon as possible: initially by blocking the virus physically in the mucous of the upper airway tract, thanks to the turbulence created in the entering air flow, and, biologically, with IgA antibodies in the mucous, trying to break the virus structure.

A swab will detect the presence of the virus in the mucous, without providing any detail on its virulence, because of its presence in the air of the environment. There is, however, no certainty as to whether the active virus has reached, or will reach, the lower airways and has successfully started to replicate (in testing jargon, this is known as a false positive). Equally, if the swab is taken from the sputum or a sneeze, it will tell us the presence of the virus which, actually, has just been expelled (another false positive). In the case that the virus has overcome the mucous (and it is going deeper and deeper to kill the lower airways’ cells) the swab will be a false negative! So, what now?

Somebody said: nobody is perfect! This is also true for COVID-19 testing. These are the reasons why relying on testing alone, as I pointed out several months ago in my Newsletters, will not defeat this virus.