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How meaningful are the PCR tests for Sars-CoV-2?

Sars-CoV-2 diagnostics
The number of corona infections is increasing rapidly in most countries. At the same time, there is criticism of the PCR tests. We show how meaningful the tests really are.
The proportion of positive PCR tests for Sars-CoV-2 is currently increasing.

You have to know that

  • PCR tests can detect an infection with the coronavirus, although there are many tests from different manufacturers.
  • In particular, strongly positive test results indicate an acute infection.
  • The proportion of positive results is independent of how many tests are carried out.
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Are the PCR tests for the Sars-CoV-2 virus even suitable for detecting infections? How reliable are the tests? Can't the increase in positive cases be explained solely by increased testing and a high error rate?

This is how a PCR test works

A human sample is required to perform a PCR test. With Sars-CoV-2, a smear is taken from the throat, which can be reached through the mouth or nose. If there are whole viruses or fragments of them on the smear, you can isolate the genetic material from it, which consists of RNA in the Sars-CoV-2 virus. In a first step, an enzyme translates this RNA into DNA. Next, the DNA has to be replicated in order to obtain a sufficiently large amount of it that it can be detected. This replication requires small pieces of DNA, so-called primers, which attach to the virus genome and copy it off, i.e. copy it. In this way, more and more DNA chains are created in several runs. The name of the test is derived from this: PCR stands for polymerase chain reaction. If the smear does not contain viruses, copies cannot be made. If the desired viral genetic material is contained in the sample, the number of copies increases continuously with each run of this procedure.

The resulting DNA copies are made visible with the help of fluorescent substances. The result is shown on the basis of a curve which shows the increase in the DNA content as a function of the repeated test runs. If this is below a certain threshold value, the test is considered negative. If the curve exceeds the threshold value, the result is positive.

Does the PCR test detect an infection?

A PCR test detects whether or not certain sequences from the genetic material of the Sars-CoV-2 virus are present in a sample. Most of the tests used detect two different sections of the virus genome, some even three. The following applies: the more genes the test detects, the more certain the result. Nevertheless, one hears again and again the argument that these detected RNA segments do not necessarily mean an infection. Experts also seem to disagree on this question. A look at the medical lexicon "Pschyrembel" provides clarification: An infection is defined here as "the penetration of pathogenic microorganisms such as bacteria or viruses into an organism with subsequent colonization and reproduction".

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With the detection of the viral RNA, the first part of the definition is fulfilled: the virus has entered the human body. This usually happens passively, for example when a person inhales the virus and thus brings it to their mucous membranes. But what does the test say about the second part of the medical definition? Has the detected virus already multiplied and thus infected its carrier?

In principle, it is possible that a virus is detected that has not yet reproduced. But: "The virus quantities are then so small that the result is at most weakly positive," says Jürg Böni, head of the Diagnostics and Development Department at the Institute for Medical Virology at the University of Zurich. Böni estimates that such weakly positive results make up around 0.1 percent.

In such a case, the result must be checked. Be it through another analysis of the sample or another test on the person concerned. Weak positive results do not simply show up as positive cases in the statistics. "At the University Hospital Zurich, we only report results that are clearly positive," says virologist Böni. "Here we find up to several billion viruses". And: Such concentrations are not possible without an increase in the virus and thus an acute infection. What the PCR test does not say, however, is whether the focus of infection is still active and the person is thus contagious. Because one does not know whether the detected RNA sections are only fragments or a complete virus.

When can the virus be detected and for how long?

Usually the test is positive one to two days before symptoms appear and two to three weeks afterwards. The viral load in the body is highest when the symptoms set in. The test detects an infection even if the person shows no symptoms. However, contrary to previously assumed, these asymptomatic cases only account for around 20 percent of all infections, as a current study by the University of Bern shows. This figure is based on an analysis of 79 studies published between January and June this year and includes data from over 6,500 patients.

How reliable are PCR tests?

In order to answer this question, it is important first of all: There is not just one but countless different PCR tests from different manufacturers. The first PCR test protocol was developed by a team led by virologist Christian Drosten at the German Center for Infection Research at Charité Berlin in January 2020. The University of Zurich also used this protocol in a slightly modified form in the early phase of the corona crisis. Soon after, commercial tests from China hit the market. However, these occasionally had problems with contamination and were also not approved for diagnostic purposes in the European Union. However, there is now a large number of different PCR tests for Sars-CoV-2 that have been tested and CE-marked.
"Most laboratories have now switched from homemade to commercial tests," says Jürg Böni. Each laboratory can freely choose which test is used. But it is obliged to validate the reliability of the test, explains Jürg Böni. Only when a test is reliable, i.e. correctly identifying people with and without Sars-CoV-2, is it actually used in practice. The test results are then monitored with control samples that are routinely included in every PCR reaction.

How well individual tests work and how cleanly different laboratories work can be seen using so-called round robin tests. The scientific specialist society instant e.V. carried out one of these in April 2020. The independent German institute sent positive and negative Sars-CoV-2 samples to 463 laboratories from 36 countries. The results show: Regardless of the gene region examined, the tests showed between 98.9 and 99.7 percent really positive and between 97.8 and 98.6 percent really negative results. However, this is an average of all laboratories - some tests are more reliable, others less. “These cross-comparisons help the laboratories to see where they stand,” says Böni. And whether it might be worth using a different test that delivers more reliable results. In this way, the test accuracy is permanently adjusted upwards.

In addition to the internal laboratory controls, the Swiss Federal Office of Public Health has introduced a double check of the results. At the beginning of the corona pandemic, all laboratories sent their samples to the National Reference Laboratory in Geneva for control. Because the number of samples soon overloaded the reference laboratory, other large centers, such as the University of Zurich, were also set up as control bodies. “It went on until you saw that it was running reliably,” explains Jürg Böni. Only then did a laboratory receive approval to test independently.

Are the positive cases increasing because more tests are being carried out?

Basically, the more you test, the more infected people can potentially be detected. However, more tests do not automatically lead to more cases due to an increased number of false positives, as is sometimes claimed. This is shown by two facts:

First: So far, there have been three phases in Switzerland in which more tests have taken place: At the beginning of the pandemic in March, now in June and currently for about two months. The second phase in June is particularly meaningful: the tests increased, but the positive cases did not.

Secondly: The fact that the number of infections is actually increasing is shown by the fact that the proportion of positive tests is steadily increasing compared to the total number of all tests carried out. A month ago, between three and four percent of the tests were positive. It is currently eight to ten percent. Ascending trend.

Classification of the increasing number of cases

The number of cases is currently increasing daily and is now for the first time since the lockdown at over 1000 new infections. However, there is a crucial difference between the current figures and those in spring: the amount of unreported cases. According to a study by the University of Bern in March, this was a factor of ten. Today, however, with a factor of two or three, as the epidemiologist and study author Christian Althaus said in an interview with the Tagesanzeiger. This can be explained by the test capacities, which were much lower in spring than today. The study is only preliminary and has not yet been reviewed by specialist colleagues. If these figures are correct, however, around 10,000 people would have been infected every day in March. Currently it would be two to three thousand people a day.
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