Test, test, testing, 1, 2, 3 is this thing on? Are covid tests reliable enough for us to proceed with business-as-usual?
Diagnostic testing is far from fail safe. Can we have faith in the testing avalanche that is set to sweep the globe? How accurate is accurate?
New Zealand is now moving into the next phase of the pandemic. After overcoming the first major hurdle and getting 90% of the country immunised in a massive nationwide vaccination drive, the likes of which have not been seen since the polio vaccine efforts of the 1960s, New Zealand will now increasingly test for covid 19 as a means to contain the spread.
These immunisation numbers mean that the country will be opening up travel restrictions as well as other social activities. Logically this will result in covid spreading, not only delta, but eventually the omicron variant too. On top of covid, we will have a resurgence in influenza and common cold cases too. These infectious agents had record low levels of infectiousness in 2020, largely due to increased hygiene protocols, social distancing and lockdown.
I thought it would be pertinent to examine what’s in store for us in terms of testing and what the future will hold as there are several new testing methods and diagnostic tools being developed. There are so many new approaches, that the US Federal Drug Advisory (FDA) is working around the clock - literally - trying to validate and approve these novel and less invasive testing modalities.
If you haven’t yet had the privilege of having an elongated Q-tip or cotton swab stuck up your nose to take a sample from the nasopharyngeal space at the back of your throat, count yourself lucky. Though largely harmless, this type of diagnostic sample procedure truly does feel like your brain is being probed and is not a fun experience at all. But if you’re complaining about this being intrusive, imagine arriving at the airport in Shanghai and having a customs official ask you to step into a back room, remove your clothes and bend over for an anal swab to test for covid. Exactly, suddenly the nasopharyngeal swab seems less invasive and almost relaxing.
In all seriousness though, it must be stated, again and again: These tests are by no means a guarantee that you do not have the covid virus inside your system.
Method of sample collection is super important
As a seasoned veteran of diagnostics, I can say that I have some serious doubts in any form of public health initiative moving forward that relies too heavily on testing as a cornerstone with which to move our country out of this cautious quarantine approach that has kept us safe these last two years. Having analysed over 200 000 samples of faecal material and nearly 10 000 litres of saliva, blood and urine in my lifetime, I can tell you that these tests are not fail safe, not by any standard.
On the contrary, some of these covid tests will show false positives or worse, false negatives, and these sometimes up to 50% of the time! More detail below.
So while I can understand the need and demand for accurate testing, the reality is that we cannot afford to lean into the complacency which large scale testing tends to confer. Not now, after our country has done so well with early lockdowns and a world leading performance in terms of per capita immunisations.
For starters, it is important to know who is doing the sampling - expert sampling is a true skill not to be underestimated. The exact spot where these tiny virally infected cells are multiplying and churning out new viruses can get missed - it simply depends on the amount of virus (viral load) and where the infection first occurs if you are getting sampled within a short period of time from when you were infected. Whenever you approach a home test kit from now on, moving forward, I want you to imagine this virus in all of its complexity; its tiny nanometres in diameter and the fact that it may have not been replicating for very long so as to render a very low viral load whenever you take a sample of your mucous/saliva or blood from your throat, nose, nasopharyngeal space of the tip of your finger.
Really try to put yourself in the shoes of the virus, imagine it has landed in the back of your throat and has just infected its first epithelial cell. If you are vaccinated this should not be a problem and the vaccine primed immune cells will go to work looking for the spike receptor protein and eliminating the virus and any cells that have been infected. The chances of getting a positive test result back after being vaccinated are slim for reasons outlined at the beginning of this paragraph. Slim does not mean impossible as every immune system is different and especially now with omicron potentially circulating in the country, we need to be a lot more vigilant with our predictions and subsequent behavioural adjustments.
A negative test result does not mean you are not contagious
If you happen to belong to that segment of the population who is not vaccinated, in the case of New Zealand that is still not an insignificant number of people. 10% of the country still works out to be nearly half a million individuals, I want you to really pay attention now. Even if you have been tested and the test shows up negative, this DOES NOT mean that you do not have the virus in your body. Especially if you have done this test at home - home testing kits will be available by the boatload shortly, and their accuracy is still not super reliable. Again, as mentioned above, you may be asymptomatic and still have the virus, you may be sick with covid and still obtain a negative test result. One major flaw in both Europe and the US’s early reliance on home testing kits, was that it helped breed complacency in people who were convinced they were negative after testing so and having acted accordingly, whilst unbeknownst to them spreading the virus further.
After all, we are human and if once we have that little itch in the back of our throat, the first thing we think about is “could it be covid?” - once we get tested and the results come back negative, we are relieved internally and as such might let our guard down. That can translate to an unguarded cough, forgetting to wash hands or being negligible with our mask wearing.
Even if you have tested negative, act as though you have covid, that should be the golden rule for the next two years at least. Especially now when we are opening the country up and even some officials close to the government are advising a more relaxed approach. The government motto seems to have gone from eliminating the spread to mitigating the risk associated with hospitalisation. In my mind this is a little negligent of the real danger that this virus still poses to our community but I do understand why this is happening.
So testing is going to be our future, what are the options?
The most obvious front line defense we have is measuring a person’s temperature. If someone presents with a fever, there is a likelihood that they have a viral infection and that this could be caused by covid. During the middle of the pandemic in China, when people were eased out of lockdown, dual infrared thermometer lasers were used at every shopping mall, airport and restaurant to gauge people’s temperature. This can be a fairly accurate way of testing how sick someone is, but in that cohort of the population that present as asymptomatic carriers, is largely ineffective at containing covid. So all we have left then is sampling fluids.
The main two fluid sample methods:
Testing the saliva/mucous: these samples are obtained by either having the back of your throat and or nose swabbed or by spitting into a collection tube. If it is the former method of swabbing the nose, moth or nasopharyngeal space, it is important that this is done by a professional for the aforementioned reasons.
Testing the blood via pin pricking the tip of the finger so as to access a small amount of blood.
Polymerase Chain Reaction
Once the saliva has been secured, in most cases it will be sent off for testing via a process called Polymerase Chain Reaction (PCR) which tests for the presence of covid RNA (for a history lesson on how this particular molecular testing approach was invented - and won the Nobel prize - click here and go to the chapter entitled “Kary Mullis and the invention of PCR” - it is an amazing story.) If we want to go into a little more detail, the full name of this approach is RT-PCR where the RT stands for reverse transcriptase. RT is an enzyme that we isolated from HIV in the 1980s and the miraculous thing about this enzyme is that it has the ability to turn RNA into DNA. As mentioned in previous articles, as opposed to influenza covid is an RNA based virus, which means it only has a single strand of RNA inside it as opposed to a double strand of DNA like influenza. This means that in order for PCR (which tests for DNA) to work, we need to turn the viral RNA back into DNA and use nucleotide (DNA base pairs) primers to test for viral sequences that exist in covid but not the human genome. If this doesn’t make sense (as it didn’t to me the first time I learned about it) please don’t hesitate to ask in the questions below.
PCR is really the absolute ideal benchmark when it comes to testing for the presence of a virus inside you but as with other tests, it is not 100% - in fact one recent British Medical Journal study suggested that the false negative test rate can be from 2% all the way up to 29% - other studies have revealed the false negative to be around 10-15%. This can be worrying and is one of the reasons, most experts warn against major public health policies framed around testing.
As PCR it is quite a complex procedure and takes a while to run, several other tests have been developed.
Lateral Flow Tests
One is the so called Lateral Flow Test (LFT) or what is also called the antigen test. An antigen is nothing more than a protein, mostly a cell receptor that doesn’t exist within the human body and as such will elicit an immune response and particularly the production of antibodies, if it gets inside the body. The mechanics of this test are similar to that of a pregnancy test in that it works via capillary motion to drag a sample through a receptacle. In the case of covid, the LFT is looking for the spike protein antigen and it is doing so via laboratory-produced antibodies that bind this antigen in the testing kit and produce a positive result once they bind. This is the same approach we use to test for the presence of salmonella in a stool sample. The main advantages of this type of testing are not quality focused and more efficiency based. The testing can be done within minutes and doesn't require samples to be sent off to a lab.
This convenience comes at a cost though, whilst false positives are rare(ish) in that they arise once in every thousand tests, leading to a 99.9% positive accuracy, the false negative test rate lies around the 50% mark - which is a major worry. The other downside with this type of testing is the fact that it only really works in people with a high viral load, again for the reasons outlined above, if the virus has not multiplied sufficiently, it will not be present in all saliva/mucous samples you may provide. This is physics.
Serology Tests
One of the most reliable testing modalities we have at our disposal are serology based tests. These are the ones that require a little blood sample to assess the presence of not RNA, DNA or antigens, but of our specific antibodies which have been produced as a direct result of being exposed to the virus. The benefits of these types of tests is that they yield results within minutes and are highly accurate. With a serology test, you can also establish what type of antibody is being expressed in your body - there are three main types IgA, IGM and IgG, where the IG stands for immunoglobulin and the G version is the one that is most ubiquitous in the human body and is used to fight off viral infections such as covid.
The other upside to blood sampling is that one can accurately predict the stage of infection that the donor is at, whether the antibodies produced are the result of a new infection or are still circulating from an infection that the recipient has since recovered from.
Future tests - the stuff of science fiction
One new technique that is in testing right now is a breathalyser that can analyse and detect certain compounds that get produced in a human after infection with a microorganism. These compounds are called Volatile Organic Compounds (VOCs) and are chemicals (organic means containing the element carbon) that have a low boiling point and as such display high vapour pressure at room temperature - volatility refers to their ability to change from liquid to gas easily. This volatility can be measured in real time with a breathalyser much like the ones used by the police to measure alcohol levels.
Another future test that is being developed by several laboratories around the world relies on the gene splicing technology knowns as CRISPR (clustered regularly interspaced short palindromic repeats) which is highly sensitive to gene variations and can detect the presence of viral genes within a human sample faster and better than regular PCR. CRISPR works as a type of modified knife or sewing machine that can cut up gene fragments more quickly and specifically than regular primer based PCR initiatives.
Another gene technology currently in development are called isothermal molecular amplification that performs a PCR based test, but just quicker and in a much smaller machine than regular PCRs - a machine that any physician could have in their office, saving the time consuming step of having to send off the sample to a laboratory. These tests may be used to offer a kind of precautionary test, a “gauging the viral status” of a person, whereby if they do test positive, a second swab will still be sent off to an external laboratory for standard PCR testing.
Exercise caution, even with a negative test result
Speaking of precautionary, I hope this article made some of you understand the fallibility of current testing modalities and the importance of having a professional do the sample gathering and testing. If home testing ever does take off in New Zealand, it should never replace the need for vaccinations and should also never make anyone feel 100% certain that they have not contracted covid. It is merely a tool by which we can gauge the epidemiology of the virus and the pattern of how and why it is spreading.
Testing should never give you the peace of mind that you have not contracted covid, especially if you are showing symptoms.
Again, the best advice is to get vaccinated, act as if you are infected at all times and wash your hands and practice social distancing, especially when outside of your bubble.
This isn’t over yet.
REFERENCES
Interpreting a covid-19 test result
https://www.bmj.com/content/bmj/369/bmj.m1808.full.pdf
Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection
https://pubmed.ncbi.nlm.nih.gov/34319857/
Are the new COVID-19 swab tests accurate?
https://patient.info/news-and-features/are-the-new-covid-19-swab-tests-accurate-should-you-get-one-do-they-hurt-and-other-questions-answered
Lateral flow device specificity in phase 4 (post-marketing) surveillance
https://www.gov.uk/government/publications/lateral-flow-device-specificity-in-phase-4-post-marketing-surveillance/lateral-flow-device-specificity-in-phase-4-post-marketing-surveillance
Pros and Cons of the Common Types of COVID-19 Tests
https://www.biospace.com/article/pros-and-cons-of-the-common-types-of-covid-19-tests/
Vaccination rates around New Zealand
https://covid19.govt.nz/news-and-data/covid-19-vaccination-rates-around-new-zealand/
Volatile organic compounds
https://www.epa.gov/indoor-air-quality-iaq/what-are-volatile-organic-compounds-vocs#:~:text=Volatile%20organic%20compounds%20(VOCs)%20are,ten%20times%20 higher
Thanks for reading and subscribing to these articles. It has been a real pleasure this year writing for you and I hope you have learned something in the process. If not that, I hope that I have at least entertained you.
Beyond my paid subscriptions for this Substack, I don’t receive any funds for my work.
I am primarily doing this to help people understand and to give you a certain level of insight into vaccines and immunology - beyond what the news may give you. As knowledge is power and knowledge also helps to stave off the anxiety that stems from ignorance.
To further this cause, last week I gave a seminar on the importance of vaccines to our local community, who, as opposed to the rest of New Zealand, have a super low vaccination rate. The talk was aimed to animate people to get vaccinated and following the talk one of the local nurses here in Golden Bay even wrote to tell me that she had seen a marked increase in vaccination scheduling - which really made me happy. Along with all the praise (one local ambulance driver cried in front of me and proceeded to put a $20 bill into my pocket as “thank you”, I did receive a fair amount of not so nice emails and evil stares from people over the last week. Oh well. Overall the seminar was well received and the local paper, the Nelson Mail, even made a little video about the event, which was nice.
So this will be my last written entry before 2022, I have one more podcast to release, so until next year I wish you all the best and enjoy your much deserved break as I will too.
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Confucius
Chris,
This was a great article. Very informative and a great breakdown of the different testing methods.
I hear a lot about the idea that the higher the cycle threshold the result comes back positive on RT-PCR, the harder it is to know what stage of infection someone is at with sars-cov-2, especially if they are not showing symptoms of Covid-19. I do not have the expertise to know, but is there a difference between a positive PCR case at different cycle thresholds?
This question would only make sense depending on the above but…If PCR by itself has room to not paint the entire picture, do you think if you got a positive PCR result above a particular CT value + are immunised + have the blood prick test(Or other?) to show you have a strong, potentially previously developed immune response, that should mean something in regards to quarantine/managed isolation/risk of spreading infection?
My concern is, do we run the risk of the public becoming unsettled/loss of trust in govt if we do not manage more dynamically (sometime over the next 12 months) case identification, lockdowns and individuals needing to isolate? If we take a more blanket approach for another two years, it is hard to see the public continually being so supportive to "follow the rules", and it may result in a growing lack of trust, which may weaken public response to future events when high public trust will be crucial. However, you may have already mentioned the solution to this in your article if the solution lies in "new & better" testing technologies.
Sorry for the two-part question. The 1st part, I am sure, will be easier to answer. The 2nd part ties into more social/cultural trends developing. Although not as much of an acute problem right now, these social trends may be a lasting "rash" we may have to deal with long after covid is behind us. There is probably no black/white answer to this, but macro population trends do not always follow the science no matter how well communicated it is, as most people/populations are not scientists. Anxiety, fear, and frustration are powerful emotions when experienced at a population level, especially how they can affect an individual's rational decision-making and how they act as "collective" individuals in society. I worry that if these types of emotional factors are not addressed, then that anxiety, fear and frustration can turn to anger. I don't think anyone on either side of these issues wants to see significantly large populations of people displaying emotions of anger. How do we avoid that in a world of differing opinions? Who knows! But could using the same strategies that put us there in the first place, rightly or wrongly, may only exacerbate the problem?
This may be just one of the many risk/benefit scenarios that we simply have to deal with, which is impossible to have a perfect outcome or accurately predict what effect it will have. I am sure we have some good economists at the decision-making table giving input with the scientist on this!