So now, more than six months after this pandemic was officially declared, some experts are telling us that the COVID-19 testing that we have been doing is all wrong, and that a totally different form of testing could be an effective way to end the pandemic. What they are saying is that the scientific emphasis on highly accurate tests, which sometimes take a week or longer to get a result, makes those tests virtually useless if the goal is to contain the spread of the disease. That is because in the period between the time the person is tested and the results of the test are known, that person could be highly contagious and spread the disease to multiple other persons.
Clinicians demand a high degree of accuracy in a test, particularly for an infectious disease. Quality standards are measured in terms of false positives and false negatives. A false positive test result is one in which the test erroneously reports that the test subject has a specific infection or disease. A false positive would then lead the clinician to initiate treatment for that disease, even though the test subject does not have the specific disease being tested for. On the other hand, a false negative would indicate that the test subject does not have that specific disease or infection, even though he or she does indeed have that disease. Health-care providers are highly aware of the risks that either false positives of false negatives could lead to – in the case of a false positive, instituting treatment that is unnecessary and possibly harmful, and in the case of a false negative, omitting treatment for a disease with a potentially dire outcome.
Most tests for COVID-19 use the PCR method, which employs polymerase chain reactions (PCR) to make up to billions of copies of a specific genetic sample. In the case of the coronavirus that causes COVID-19, the PCR method copies the RNA of the virus. The test was developed by the CDC and submitted to the FDA of February 2 of this year, and the FDA issued an Emergency Use Authorization the next day. This test, the Real Time Reverse Transcriptase (RT) PCR Diagnostic Panel, with some essential modifications, has been the most widely-used COVID-19 test.
>PCR testing directly detects the presence of the virus – the antigen – rather than signs of the body’s immune response, which could be any of several antibodies. The virus is present before antibodies form and before any symptoms of the disease occur. So, at least in theory, widespread PCR testing could give a more rapid indication of the spread of the disease than other forms of testing, which mostly rely on antibodies. However, actually carrying out the test, in the stages beyond taking the nasal swab from the test subject, can be labor-intensive and time consuming. There are ample opportunities for errors in the process, and false negatives can occur up to 30% of the time, particularly in cases where only tiny amounts of the virus are present.
The New York Times about a week ago provided an example of delays in getting testing results. A woman named Natalie Magnus was tested in Winnebago County, Illinois, on July 14, and still did not have the results 22 days later, by which time she had completed a 14-day home quarantine. She observed that at that point her test results were of no consequence to her. Her brother and sister-in-law, each of whom was tested twice at separate facilities in Colorado, received only one set of results after a 17-day delay.
From the standpoint of the individual patient, accurate testing is obviously a high priority. However, the test results become much less relevant if they are only received after a quarantine period, or after the onset of symptoms. A Harvard Medical School epidemiologist, Dr Michael Mina, points out that the PCR tests can detect the presence of coronavirus particles even after a patient has recovered from the infection. Dr Mina says that means that “the vast majority of PCR positive tests we currently collect in this country are actually finding people long after they have ceased to be infectious. The astounding realization is that all we’re doing with all of this testing is clogging up the testing infrastructure, and essentially finding people for whom we can’t even act because they are done transmitting.”
Dr Mina compared the highly sensitive tests for the coronavirus to a fire alarm system:
“Imagine you are a fire department and you want to make sure that you catch all the fires that are burning so you can put them out. You don’t want a test that’s going to detect every time somebody lights a match in their house — that would be crazy: you’d be driving everywhere and having absolutely no effect. You want a test that can detect every time somebody is walking the streets with a flame-thrower.”
Mina’s analogy is certainly dramatic, but in my opinion it greatly overstates the degree of difference between the sensitive tests such as the PCR test, and less sensitive tests that would yield results much more quickly. Mina points out that the virus can be detected by the most sensitive tests about three to five days after it has invaded the subject. These PCR tests can detect minute quantities of the virus, but the virus multiplies at an exponentially rapid rate, so “even if a rapid test is 1,000 times less sensitive than a PCR test, the virus is increasing so rapidly that the test will probably turn positive within eight to 15 or 24 hours. So the real window of time that we’re discussing here – the difference in sensitivity that makes people uncomfortable – is so small that public-health officers would be missing very few asymptomatic people taking the test in that narrow window of time.”
Dr Mina’s focus is on people who are infected but are as yet asymptomatic. These are likely to be the most dangerous spreaders of the coronavirus. They have, as yet, no reason to seek testing, especially when testing is not readily available and results take so long. And they have no reason, also as yet, to self-quarantine, since they have no notion that they themselves are infected nor that they can pass on the infection to any person with whom they come in contact. Mina’s preferred solution would be cheap, quick, and easy tests. He believes that the most effective means of identifying and isolating infectious individuals before they develop symptoms would be essentially for everyone to be tested every few days. The test would be a paper-based at-home test. Everyone would wake up in the morning, add saliva or mucous to a little tube of chemicals, wait 15 minutes, and then dip a paper strip in the tube and read the results. He asserts that such tests are feasible, and suggests that companies such as E25Bio and Sherlock Biosciences have the capacity to deliver such quick, easy, and cheap tests. However, the tests have not made it to the marketplace because their sensitivity is being compared with the much more sensitive PCR tests.
To recapitulate, PCR tests and other highly sensitive tests can detect minute quantities of SARS-CoV-2, the villainous coronavirus, usually in three to five days after the virus invades the patient. But at that point the virus multiplies exponentially, so that in a few hours the patient’s viral load has increased by a factor of a thousand, or even more. At that point, the coronavirus could easily be detected by the quick tests that Mina and other public health epidemiologists are advocating.
In terms of transmission of the virus, the difference in effectiveness between the most sensitive tests and less sensitive tests that would provide much quicker results is colossal. The time lag between taking the sensitive test and getting the result allows for a week or more in which the virus can be transmitted unknowingly. A less sensitive test, administered more frequently, would identify those virus spreaders as much as a week sooner than the more sensitive tests now in use, during which time the subject may unknowingly transmit the virus.
Several epidemiologists have suggested tests of a different type – lateral flow assays, which are widely used for rapid point-of-care testing. These tests are used in several areas beyond human health, such as environmental testing, testing of pharmaceuticals, animal health testing, food testing, and plant and crop health. In human health, they are commonly used by the patient, as described by Dr Mina. Ideally, they would be similar to pregnancy tests, which are lateral flow assays. The tests typically use saliva rather than nasal swabs, which need to be administered by a health worker and are highly uncomfortable for the patient. Signs of the presence of the virus can then be detected by bringing the saliva sample into contact with a chemical reagent, which can be added to the sample, or sometimes impregnated onto a test strip, which is then dipped into the saliva sample.
There are a great many saliva-based tests; however, the great majority of these tests are antibody tests. Antibodies are generated by the human immune system in response to the presence of an invader, whether a bacterium or a virus. Antibodies generally take a few days to emerge in sufficient quantities to be detected. What is needed is a test that would detect the presence of the invader itself, in this case the coronavirus. The coronavirus, SARS-Cov-2, is an antigen, not an antibody. The tests listed below are antigen tests.
A few faster tests have received FDA emergency use authorization (EUA)
On August 15, the