A Change in the Testing Process as a Way to End the COVID-19 Pandemic – and a Couple of Other Possibly Promising Innovations

Doc Gumshoe looks at testing, herd immunity, and a few updates in diabetes and lung cancer

By Michael Jorrin, "Doc Gumshoe", September 10, 2020

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 FDA issued an EUA to the Yale School of Public Health for its SalivaDirect COVID-19 diagnostic test, which uses a new method of processing saliva samples.  Yale researchers partnered with the National Basketball Association, whose players and staff have routinely taken the saliva test before and during isolation in Florida, as part of a COVID-19 testing study.   Providing this type of flexibility for processing saliva samples to test for COVID-19 infection is groundbreaking in terms of efficiency and avoiding shortages of crucial test components like reagents,” said FDA Commissioner Dr. Stephen Hahn, referencing the Yale saliva test.

Yale intends to provide the SalivaDirect protocol to interested laboratories as an “open source” protocol, meaning that designated laboratories could follow the protocol to obtain the required components and perform the test in their lab according to Yale’s instructions for use. Because this test does not rely on any proprietary equipment from Yale and can use a variety of commercially available testing components, it can be assembled and used in high-complexity labs throughout the country, provided they comply with the conditions of authorization in the EUA.
A few days later, the FDA gave the EUA blessing to another saliva test, this one developed by the University of Illinois for use on its campuses by faculty and students who are returning for in-person instruction.

Dr. Martin Burke, an associate dean at the Carle Illinois College of Medicine, said he was given the task in March of creating a team to strategically deploy scalable COVID-19 testing.   Dr Burke said,  “The standard process is too slow. It’s too expensive, and it has too many supply chain bottlenecks in order to be able to do fast and frequent testing on scale.”   The evidence is growing that “this is the medium that matters,” Burke said of saliva-based testing.   “We spread COVID-19 through saliva droplets, primarily, so you’re testing the exact medium in which that infectiousness is likely to occur.”   The results are usually available within three to six hours.   Approval for the U. of I. test came after a “bridging study” found it performs at least as well as the test developed by Yale University.

Several other saliva-based tests have received FDA emergency use authorization.

  • On May 8, EUA was granted to a test developed by Rutgers University in collaboration with Spectrum Solutions.
  • Then, on May 9, EUA was granted to Quidel Corporation for a saliva test using the Sofia testing instrument for detection of a nucleocapsid protein from the coronavirus.
  • Not long after, on June 6, saliva-based antigen tests developed by Becton, Dickinson were granted EUA status.   Becton, Dickinson’s test will use BD’s Veritor instrument, 25,000 of which are already in use in the US, to evaluate the tests.    BD projects being able to process 2 million tests per week by September.
  • On August 1, an antigen test developed by Clinical Reference Laboratory in Lenexa, Kansas, received emergency use approval.   Clinical Reference Laboratory will ramp up their testing capability to 50,000 tests per day.

Dr Mina mentioned several potential rapid and cheap tests for SARS-Cov-2.   One, already in existence, comes from a small outfit in Cambridge called E25Bio, which has recently received $4.14 million from the Bill & Melinda Gates Foundation and $1.68 million from NIH’s Small Business Innovation and Research program, specifically to develop tests for the coronavirus and arboviruses.   E25Bio has developed a rapid test for dengue, which has been approved for use in Colombia, and they have tests for the Zika and chikungunya viruses.

E25Bio’s test for the coronavirus is under development, and has been field-tested in hospitals.   Irene Bosch, E25Bio’s founder and chief technology officer says:

“What we learned is that the test is able to be very efficient for people who have a lot of virus.   It’s nowhere near as good at detecting low levels of virus.  But you can have the most sensitive test in the world and if you only test people once a month, that test, too, will miss a lot of people who are infected.   These are very simple strips.   They’re like miniaturized pregnancy tests.   So, you can imagine you can’t find anything more simple than this.”

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Another small outfit, spun out of Harvard’s Wyss Institute for Biologically Inspired Engineering and the Broad Institute is called Sherlock Biosciences.   Sherlock is currently working on the first CRISPR-based test for SARS-Cov-2 which would be highly accurate and valuable for research purposes.   However, for cheap and rapid testing, Sherlock has in the works another, very fast test.   MIT Professor Jim Collins, who is Sherlock’s co-founder, predicts rapid progress with this test, called “INSPECTR,” which would use synthetic biology to make a test on a simple paper strip.   The focus is on developing a testing device about the size of a Coke can, which would enable people to do a quick test every day for a very low cost.
The tests from E25Bio and Sherlock Biosciences have as yet not been subject to any regulatory scrutiny.   There are serious questions as to whether these tests (or similar quick, cheap tests) would receive FDA approval, based on their lower ability to detect small quantities of the virus, which would translate into a possibly unacceptable percentage of false negatives.   Which is to say, that individuals who test negative on these rapid tests may not at the time of testing have developed sufficient viral load for a positive response to the test.   But, as pointed out earlier, the virus multiplies extremely quickly, so if the testing is repeated often enough, the individual would be positive on the next test, hopefully early enough to prevent much transmission of the virus, which is a principal purpose of the test.
Dr Mina and other scientists have expressed the hope that ways could be found to approve such rapid tests for public health purposes even if they do not meet the standards needed for FDA approval.

It certainly looks as though infection with the coronavirus results in lasting immunity

This optimistic bit of news has been confirmed by several studies.   I say “optimistic” because it points with some degree of confidence toward increasing herd immunity, which by now is generally agreed to be our best chance for getting over this pandemic, whether it comes about through widespread vaccination or as the population of potential spreaders of the disease declines.   Or both.

A study led by Dr Deepta Bhattacharya, an immunologist at the University of Arizona, found that despite the decline in short-lived antibody cells, longer-lived antibody-secreting plasma cells progressively emerge, conferring longer-lasting immunity.   The study concludes that the decay in antibody production after infection or vaccination is not linear and cannot be extrapolated from early timepoints.   Short-term antibody production alone would be without precedent following acute coronavirus infections, which, according to the study, typically induce immunity for at least a year.   Immunity to the previous coronavirus, SARS-CoV-1, typically lasted at least a year, and often for much longer.

Dr Marion Pepper, an immunologist at the University of Washington, commented that although much of the conversation about immunity has focused on antibodies, these represent one cohort of an army of immune soldiers, each of which have their own weapons to attack invaders such as viruses.   Antibodies attack viruses when they enter the human host, but once the viruses have invaded the host’s cells, they are shielded from antibodies.   However, killer T cells have the capacity to recognize human cells that have been invaded by viruses, and they can force those infected cells to self-destruct.   And another group of T cells, called helper T cells, instruct B cells to manufacture more antibodies.

Antibodies do not last very long.   Not being cells, but inanimate proteins, they cannot reproduce.   Most of the B cells that make the early antibodies perish soon after the first wave of free viruses diminish – that is, viruses that have not invaded host cells.   But the body still retains a squadron of longer-lived B cells that can release another wave of virus-fighting antibodies.   Some of these B cells lodge in bone marrow, generating antibodies that are sometimes detectable years, and sometimes decades, after an infection has passed.

Dr Bhattacharya said, “The antibodies decline, but they settle in what looks like a stable nadir, which is observable about three months after symptoms start.   The response looks perfectly durable.”   The study was based on multiple serological tests on 5882 self-recruited subjects (Bhattacharya https://doi.org/ 10.1101/2020.08 .14.20174490).   The study concluded that although tests early in the course of the infection were likely to show that antibodies to the coronavirus diminished very quickly, and thus that immunity to the virus was short lived, further serologic tests told a markedly different story.   To quote from the paper:

“These differences in interpretation are reminiscent of studies on the length of SARS-CoV-1 immunity. Early reports suggested that immunity was transient, but more recent studies have demonstrated that SARS-CoV-1 neutralizing antibodies can still be detected 12-17 years afterwards. Given these lessons, conclusions about the rapid loss of immunity to SARS-CoV-2 are premature and inconsistent with the data we presented here.”

Neither Dr Bhattacharya nor Dr Pepper are saying that immunity to the coronavirus that causes Covid 19 will definitely last several years.   What they are saying is that the evidence so far supports the view that the immunity will last well beyond the first few months in which that first wave of antibodies has assaulted the virus.   There is more immunity in reserve.

The story about the Hong Kong man who was reinfected with the coronavirus six months after first having had Covid 19 bears out the persistence of immunity.   Despite the fact that on being retested for SARS-CoV-2, the virus was present in his system, the man developed no symptoms at all.   Evidently, he had sufficient persistent immunity to defeat the invader.   Interestingly, the second coronavirus infecting this man was the European strain, not the Hong Kong strain, suggesting that immunity offers protection from both strains.

Can artificial intelligence make a meaningful contribution to diabetes care?

Stating this subject as a question is a world apart from the boldly assertive title of a paper in The American Journal of Medicine: “Artificial Intelligence: The Future for Diabetes Care” (Ellahham S. Am J Med 2020;133:895-900).   The author, Dr Samer  Ellahham at the Cleveland Clinic in Abu Dhabi, is clearly a fervent partisan of AI in all possible guises and applications.   He does acknowledge that “AI can pose a risk of deskilling physicians by introducing dependence.   This may introduce a cycle of inadequate accuracy because AI itself requires periodic refinement by experts.”   He also acknowledges that the rapidly growing of numbers apps and devices presents a considerable challenge, which he labels “inoperability.”   In other words, the user is swamped and nothing works.   And he also refers to a paucity of supporting data and concerns about security.   Nonetheless, he proposes the use of AI not only by health professionals, but by patients and by entire health-care systems.

By now you have detected that Doc Gumshoe is somewhat skeptical about artificial intelligence.   However, there are aspects of diabetes and diabetes care that might be especially suited to what AI can actually and effectively do.   First, the prevalence of diabetes is exceedingly high.   According to the International Diabetes Federation, almost 10% of the global population has diabetes.   Half of these persons do not know they have diabetes.   And, in addition, about 7.5% of the population has impaired glucose tolerance, a condition that will lead to diabetes if left unaddressed.

The reason that such a large share of persons with diabetes are unaware of that fact is that diabetes by itself has no obvious symptoms.   The high blood glucose levels associated with diabetes does cause a number of conditions that can lead to severe harm, most of which are associated with problems with blood circulation.

One of these is significant damage to the retina, potentially leading to loss of eyesight.   Diabetic retinopathy, as it is termed, can be detected in images of the retina.   The FDA has approved IDx-DR, a device that uses artificial intelligence to analyze these digital images of the retina, and can detect the earliest signs of diabetic retinopathy as well as of macular edema.   Employing the AI empowered device greatly speeds detection and can help in getting diabetic patients to the required specialized care more rapidly, potentially preventing blindness.

Another condition that causes severe harm in diabetics is the development of diabetic foot and leg ulcers due to poor arterial circulation.   Diabetes happens to be the single principal cause of lower limb amputation.   Digital examination of images of lower legs in diabetic patients can identify patients at risk for losing a limb due to diabetic foot ulcers at a sufficiently early stage to prevent the most severe consequence.

Substitution of AI-enabled devices for examination by skilled human physicians assumes, realistically, that many persons with diabetes receive minimal medical attention, especially examinations and highly specialized treatment.   Community health groups could institute regular assessment of a number of potential signs of the progression from impaired glucose tolerance to the stage where serious threats to health and life become urgent.   The 4 Diabetes Support System is an example of what is termed case-based reasoning, which aims to automatically detect problems in control of blood glucose, propose solutions to these problems, and keep track of whether these solutions are effective for individual patients.

Of course, for several years now many persons with insulin-dependent diabetes have implanted devices that continually monitor their blood glucose levels and administer just the necessary amounts of insulin.   That includes not only those with type 1 diabetes, but some patients with type 2 diabetes for whom oral medications are no longer sufficient.   Whether such devices come under the category of artificial intelligence, I don’t know.   I tend to put them in the same class as thermostats that turn your furnace or air conditioner on and off depending on the temperature in your house.   Is that artificial intelligence?

In spite of my general hesitation to go with the AI trend, I do think it is necessary to recognize the acute shortage of competent health-care at the ground level, which affects millions of people in the US and, even more so, globally.   Any way of alleviating that deficit is worth a try.

A large decline in lung cancer deaths is likely due to improved treatment

The kind of lung cancer we’re discussing here is non-small-cell lung cancer (NSCLC), which accounts for about 84% of all lung cancers.   Small cell lung cancer is much more lethal, and the specific advances in treatment that we’re referring to is unfortunately for NSCLC alone.

Lung cancer is by far the most lethal cancer in men, with a five-year survival rate of about 18%.   Usually, improvements in cancer death rates are attributed largely to changes in life-style, particularly declines in cigarette smoking.   However, since 2013 NSCLC mortality has declined in men by 3.2% annually from 2006 to 2013.   The decline increased to 6.3% per year from 2013 to 2016.   In both periods, the decline in mortality was greater than the decline in the number of new cases.   This implies that at least some of the decline was due to improved treatment in patients who had already developed the disease and been diagnosed, and not to factors like cigarette smoking.   Two-year survival increased from 26% for men diagnosed in 2001 to 35% in 2014.

This information comes from a study published in The New England Journal of Medicine about two weeks ago.   (Howlader N. “The Effects of Advances in Lung Cancer Treatment on Population Mortality.” N Engl J Med 2020:383;640-649)

The authors examined data from SEER (Surveillance, Epidemiology, and End Results), which is part of NIH.   The author’s conclusions were:

“Population-level mortality from NSCLC in the United States fell sharply from 2013 to 2016, and survival after diagnosis improved substantially. Our analysis suggests that a reduction in incidence along with treatment advances — particularly approvals for and use of targeted therapies — is likely to explain the reduction in mortality observed in this population.”

The new drugs introduced during that period included in particular two targeted therapies: erlotinib (marketed as Tarceva by Roche), a tyrosine kinase inhibitor that targets the epidermal growth factor (EGFR) mutation, and crizotinib, that targets the ALK inhibitor.   EGFR normally lives on the surface of cells and helps them to grow and divide.   A mutation in EGFR causes it to remain in the “on” position such that cells, including cancerous cells, continue to divide and multiply.

Anaplastic lymphoma kinase (ALK) is a genetic mutation in lung cell DNA causing these cells to grow, multiply, and potentially spread to other parts of the body.   Crizotinib, marketed as Xalkori by Pfizer, targets the ALK mutation.

Only about 15% of non-small-cell lung cancer patients have the EGFR mutation, and only 5% have the ALK mutation.   However, since the introduction of drug treatments that specifically target those mutations, the survival of NSCLC patients with those mutations is measured in years, not months, whereas the survival of NSCLC patients limited to treatment with chemotherapy seldom exceeds months after diagnosis.

Other drugs known as checkpoint inhibitors, which essentially liberate the body’s immune system after it has been taken over by cancer, were first approved in 2015 and probably had little effect on the mortality data for the period covered by the study, which ended in 2016.   We will see those effects in future studies.

The increase in the rate of decline in NSCLC mortality attributed to the introduction of new treatments amounts to a bit over 3% per year.   For persons with that kind of lung cancer, that amounts to a hugely improved chance for life.

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Doc Gumshoe needs to own up to an error.  In my previous piece in which I referred to the U. S. Preventive Services Task Force (USPFTS) release of guidelines recommending pre-exposure prophylaxis (PrEP) in adults at high risk of acquiring HIV through sexual activity or injected narcotics use, I identified the agent as tenofovir/emtricitabine, marketed as Biktarvy, from Gilead.   That was incorrect.   Yes, it’s tenofovir/emtricitabine, but it’s not Biktarvy, which contains a third ingredient.    My thanks go to the astute reader who caught that goof and told me about it.

Thanks to all for reading and all comments (and corrections if appropriate).   Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed. note: Michael Jorrin is a longtime medical writer (not a doctor), who I dubbed “Doc Gumshoe” many years ago — he writes health and medicine-focused columns for our readers a couple times a month, and though he does not generally cover investment ideas he has agreed to our trading restrictions. You can find his past columns here.]