Author: Kevin Homer, MD

Kevin Homer has practiced anatomic and clinical pathology at a community hospital in Texas since 1994.

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2021 COVID-19 Testing

Where’s the Flu?

Since October, all rapid SARS-CoV-2 PCR tests performed at the hospital laboratories where I work have included a PCR test for flu.  But of the thousands of tests performed, not one positive flu has been detected.  Has COVID cured flu?

No, I don’t believe that COVID has cured the flu, but I believe that masks have dramatically reduced the prevalence of flu in the community.  Flu is a respiratory infection, passed from person to person by the same transmission mode as COVID, mainly inhaled droplets from an infected person.  Standard face coverings reduce flu transmission in two ways.  First, droplets from an infected person are less likely to be spread into the surrounding air; instead, they hit the mask and fall.  Second, the mask helps filter the air of droplets that may contain viral particles.  The result is a reduction, but not an elimination, of respiratory viral transmission.

So why haven’t masks cured COVID?  SARS-CoV-2 is more infectious than flu, meaning that compared to flu, far fewer SARS-CoV-2 viral particles are needed to cause infection.  Masks reduce the number of viral particles in the air, but they don’t eliminate them.  Some virus leaks out from the masks of infected persons, and some virus can be inhaled by masked individuals nearby.  It’s a matter of how much virus gets inhaled.  It takes much more flu to cause infection than SARS-CoV-2.  Masks slow the spread of COVID-19, but do not eliminate disease the way masks have flu.

We may use this COVID/Flu comparison to make some predictions about the B.1.1.7 variant, the “variant of concern” now reported in at least 70 countries.  This variant is reported to be much more infectious than the standard SARS-CoV-2 virus, about fifty percent more, with the consequence that masks may not be enough to slow its spread through the community.  Tighter, less permeable, and more uncomfortable masks may be necessary to protect against this variant as it spreads across our nation.  The higher transmission rate also predicts that this variant will soon be the dominant form of the SARS-CoV-2 virus in the U.S.

If standard face coverings may soon become less effective protection against COVID-19, maybe now is the time to learn about different types of masks.  We will do that next time.

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2021 COVID-19 Testing

New Information about Variants and Tests

On January 8, the FDA released a warning that certain PCR tests for SARS-CoV-2 available by EUA may have seriously reduced sensitivity for the SARS-CoV-2 Variant of Concern (VOC, also known as 20I/501Y.V1, VOC 202012/01, or B.1.1.7), resulting in false negative test results.  The tests mentioned in this advisory are the Accula SARS-Cov-2 Test by Mesa Biotech, the TaqPath COVID-19 Combo Kit by Thermo Fisher Scientific, and the Linea COVID-19 Assay Kit by Applied DNA Sciences.  How will this development impact testing?

The SARS-CoV-2 virus mutates regularly with new strains emerging once every two weeks.  Mutations occur in the genetic material of the virus, the very material that molecular test methods like PCR use to detect the virus.  Until recently, none of these mutations has been associated with different clinical characteristics, such as more severe disease or increased rate of transmission.  However, a variant of concern (VOC) recently emerged in the UK.  As far as we know, this is still the one and only VOC.  Since this VOC has a much higher rate of infectivity than standard SARS-CoV-2 virus, we can expect it to spread quickly. It will probably soon become the predominant form of the virus in the United States.  

PCR tests look for a match in a region of viral RNA.  The target sequence is like a computer password:  any mistake causes the password to fail, even if the entry is off by only one letter.  Therefore, when a mutation occurs in the target region of a PCR test, the test will be unable to detect the virus.  This is why the tests mentioned in the FDA warning may not detect all forms of the virus.

Most PCR tests look for a match in more than one target sequence of RNA.  Generally, the more targets in a particular test system, the less likely a mutation will impact test results.  But beware: negative results should be evaluated in combination with history and symptoms.  If COVID-19 is still suspected after a negative test, consider repeat testing with a different test—one with different targets.

How do you know which test you received?  Look closely in the fine print of the results—the test used is probably referenced there.  If not, ask. 

Although most commercially available tests will continue to detect the VOC, these tests do not identify whether the virus is the variant or standard form.  They will only identify that a SARS-CoV-2 virus is present.  Furthermore, there is no assurance that a variant will not emerge that evades detection.  

Obviously, this is a situation we will continue to follow closely.

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2021 COVID-19 Science

The FDA and Its EUAs

We have learned that science is a method, not a product.  Science begins with an educated guess which is proven true by a series of experiments designed to show that the guess is false.  If the hypothesis cannot be proven false, it is accepted as true by the community of scientists.  Now that we’ve waded up to our armpits in philosophy of science, let’s move back into shallow waters and consider the process by which our FDA approves new drugs, medical devices, and laboratory tests in the United States.

First, I am going to reveal a personal bias.  I believe that the United States has the safest healthcare system in the world for individual patients.  Notice I did not say most efficient, cost effective, or optimized for populations.  But if I am sick or injured, I want my healthcare delivered by U.S. trained doctors in U.S. hospitals using drugs, devices and tests approved by the U.S. FDA.   

The FDA has been disparaged for being too slow to approve new therapies and methods. True enough, the FDA’s priority is not speed.  Instead, the FDA’s mandate is safety.  The FDA conducts a thorough, time-consuming review of all details of science supporting an application for approval, granting approval only after all questions have been answered satisfactorily.  The FDA conducts post-market surveillance of approved drugs, devices and tests, mandating reporting of adverse outcomes.  The FDA’s slow, methodical pace keeps Americans safe.

The FDA does not conduct science.  Rather, the FDA performs quality control for science, validating the logic, analytics and data supporting the claims of products submitted for approval.  Therefore, FDA approval implies a level of trustworthiness akin to science.  But like science, FDA approval takes time.  Time is something we do not have in a pandemic.

Enter the Emergency Use Authorization, known as EUA.  When time is short, the FDA may allow unapproved medical products to be used to diagnose, treat, or prevent serious or life-threatening diseases or conditions when there are no adequate, approved, and available alternatives.  All SARS-CoV-2 tests have been made available by EUA.   Convalescent plasma is transfused under EUA.  Antibody treatments for COVID-19 are prescribed under EUA.  Remdesivir, Baricitinib and the their combination are first line treatments for severe COVID-19, available for use by EUA.  And COVID-19 vaccines released by Pfizer and Moderna have been made available by EUA.  None have been approved by the FDA.  The trust conferred by FDA approval should not be transferred to the tests, treatments, or vaccines we are using in the fight against COVID-19.

Are there reasons to believe that the vaccines are safe and effective?  Yes, and good ones too.  But as with any experimental treatment or product, risks of adverse outcomes are elevated.  Individuals must evaluate whether the risks–both known and unknown–are outweighed by the potential benefits of the vaccine. In a recent article published in the New England Journal of Medicine, Dr. Mariana Castells and Dr. Elizabeth Phillips articulately summarize the outstanding questions about the vaccines currently available:

“In the world of Covid-19 and vaccines, many questions remain. What are the correlates of protective immunity after natural infection or vaccination? How long will immunity last? Will widespread immunity limit the spread of the virus in the population? Which component of the vaccine is responsible for allergic reactions? Are some vaccines less likely than others to cause IgE- and non-IgE–mediated reactions? Careful vaccine-safety surveillance over time, paired with elucidation of mechanisms of adverse events across different SARS-CoV-2 vaccine platforms, will be needed to inform a strategic and systematic approach to vaccine safety.”

Some may criticize me for suggesting that the vaccine is not risk-free and that it may be better for some to wait before receiving their shot.  However, honesty is one of the foundational characteristics of science.  We must be willing to follow the data where it leads, even if it leads to a place we do not want to go.  It is dishonest to say that any COVID-19 vaccine has FDA approval; to say that possible adverse effects—short term and long term–have been fully evaluated by the scientific method; to say that the protective immunity imparted by vaccine has been fully studied scientifically; to say that vaccine will alter the course of the pandemic or any infected person’s disease.  I am not saying the vaccines will cause harm, but likewise we cannot say the vaccines will not cause harm.  

The vaccines available now are associated with the risks of the unknown.  For some that risk is worth taking; for others it is not.  Whether you decide to take the vaccine or to wait, keep doing what we know slows the spread of disease: mask up, keep apart, and isolate when exposed.

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2021 COVID-19 Science Vaccine

The Science of COVID

Spoiler alert: This essay contains an unpopular conclusion, and you may disagree.  It’s okay if you do, because you’ll probably be in the company of many of my colleagues who disagree with me too.  Today I’m going to talk about when we can trust science.  To do that, I’m going to pretend to be a scientist and a philosopher.  This is dangerous because, as I have said before, I am neither a scientist nor a philosopher.  Instead, I am a practitioner, applying science to the problems of diagnostic medicine.  As a practitioner, I must know when science is applicable and when it is not.  I know just enough about science and philosophy to be dangerous.

Our experience tells us to trust science, and the explosion of technology during our lifetimes tells us we can.  But science is a process, not a product.  Not everything labelled as science is science.  To understand the difference, let’s consider how science works.

The scientific method begins with a hypothesis.  A hypothesis is just an educated guess about some aspect of reality.  It is proposed by a scientist as a fact of the world, something that can be relied on to be always true within certain conditions.  If the conditions are true, the hypothesis can be used to predict the future and tell us about the past.  

Once formed, the hypothesis is communicated to other scientists, who test the hypothesis by experiment.  The objective of an experiment is not to prove the hypothesis true; rather, the objective of an experiment is to prove the hypothesis false.  If successfully proven false, the hypothesis is rejected.  This is the fate of most hypotheses.  The path of science is littered by the half-truths of discarded hypotheses.  On the other hand, if the hypothesis survives the challenges of repeated experimentation, it becomes elevated by the community of scientists to the status of theory, and its predictions become part of scientific knowledge.  This is a relatively rare phenomenon.  

The falsification objective of the scientific method is a commonly misunderstood aspect of the process, but it is fundamentally important.  It gives science its power over other means of understanding reality, but it also gives science its pace.  It takes time to test hypotheses.  The proof of a hypothesis can be shortened by increasing the number of simultaneous experiments, but only to a point.  Science, like fine wine, requires adequate aging.  

For all its power, the elevation of hypothesis to theory illustrates another weakness of the method: theories are created by scientists.  Scientists are people, and people make mistakes. Scientists have made many.  We can review examples of the most spectacular blunders of scientists later.  The point is that the mistakes of science are the mistakes of people, not fallacies in the method.

So why do we trust science?  Because, despite its flaws and weaknesses, science has increased our understanding of the world exponentially.  But can we be misled by science?  Of course we can, and we are most vulnerable when products labeled as science are not developed with strict adherence to the scientific method.

This brings us to the controversial part.  Most of everything we have learned and developed in the war against COVID-19, including the tests, the treatments, and the vaccines, should not be trusted as science.  In the middle of this emergency, there has not been enough time to fully study the virus and the disease by the scientific method.  Rather, what we have so far are merely hypotheses: the best guesses of the smartest and brightest people in the land.  To be sure, these hypotheses are our best hope in this fight against pandemic, but they should not be labeled science.  There has not been strict adherence to the scientific method.  So, what should we trust, what should we view skeptically, and how can we tell the difference?  We will address these questions next time.

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2020 COVID-19 Testing

Spread and Detection of Variants

Last time we learned that a new strain of the SARS-CoV-2 virus has emerged in London and southeast England.  This variant strain, called “VOC 202012/01” or “B.1.1.7” is more infectious than the standard SARS-CoV-2.  It has quickly spread to other parts of Europe, and its presence is now reported in Canada and the United States.  At least two other distinct variants are reported in South Africa and Nigeria.  How do we keep track of these variants, and what does their rapid spread mean?

The variants are named by adding suffixes of letters and numbers to help keep the many cataloged mutations straight.  Two different systems may be used.  For example, the South African variant is labeled “501Y.V2”, but it is also known as “B.1.351”.  The Nigerian variant is called as “B.1.207”.  Neither of these has been labeled a “variant of concern”.  

A “variant of concern” is a strain is associated with differing clinical features such as greater disease severity or faster spread.  “Variants of concern” will have the letters “VOC” in their name.  So far, the first and only “variant of concern” is VOC 202012/01, the variant identified in London which has now spread into Europe, Canada, and the United States.  

While none of the variants identified so far seem to evade detection by the PCR tests generally available to the public, these tests will not tell you whether a detected virus is one of the variants.  Specialized sequencing is required to identify a virus as a variant.  This testing is conducted on a regular but limited basis by the CDC, state and local health departments, and various universities.  

The CDC is watching the evolution of variants closely.  The concern is that increasing numbers of variants may change the way the virus spreads, may reduce detection by current tests, may create resistance to drugs such as monoclonal antibodies, or may produce a strain that evades immunity caused by vaccine or previous infection.  We will watch too.  As the “variant of concern” spreads into the United States, remember what keeps us safe: mask up, keep apart, and isolate when exposed. 

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2020 COVID-19 Testing

Viral Variant

A new variant of the SARS-CoV-2 virus is emerging in Great Britain, becoming the dominate form of the virus that causes COVID-19 in London and southeast England.  What are the implications of this new variant?

The new variant has been officially named “SARS-CoV-2 VOC 202012/01.”  You may also see it referred to as “B.1.1.7”, or “SARS-CoV-2 Variant” in both the popular and scientific press.  This variant has a mutation in one of the spike proteins which binds the virus to human cells during the infection process.  So far, this variant has not been reported in the United States.

Viral mutations are common.  In fact, many different strains of the SARS-CoV-2 virus are likely to exist in the United States right now.  But so far, none of these mutations has caused a significant difference in the binding capacity of the virus to human cells.  At least none that we know of.  Our understanding of SARS-CoV-2 continues to evolve rapidly.

The variant identified in England seems to spread more quickly in humans.  The thought is that the change in spike binding protein makes it more likely for the virus to stick to human cells.  

Why does increased stickiness of virus affect the virus’ ability to spread?  After the virus sticks to the cells lining the inside of the nose and upper airways, the virus injects its genetic material into the human cell.  This genetic material is programmed to take over the machinery of the cell, causing it to abandon its usual functions and become a virus producing factory, spewing out hundreds of new copies of the virus.  These new viral copies infect other cells, either in the same body, or in bodies nearby.  This accounts for the waxing of disease within a sick, infected person, and the spread of virus from person-to-person.  If the virus is stickier, more human cells are taken over, and more copies of the virus are produced, making it easier for the virus to go, well, viral!

Will tests detect this new virus strain?  Yes, PCR tests will, at least for now.  Because PCR tests use two or three different detection targets, the change in this variant’s genetic code is not enough to evade detection by PCR tests.  However, as the genetic code of the virus continues to evolve, it is conceivable that a mutation will arise that is not detected by tests currently in use, even PCR tests.  Antigen tests, which already have low sensitivity, do not share the multi-targeted feature of PCR tests; therefore, even more false negative antigen test results can be expected when the variant becomes more prevalent.

Will the variant reduce the effectiveness of vaccine?  The honest answer is that we really don’t know.  Theoretically, this variant will not, since the vaccines released in the U.S. are polyclonal, causing the formation of antibodies to several different parts of the virus’ spike proteins.  The theory is that even if one part of the spike protein changes, the antibodies will still be effective against the other parts that have not changed.  But theory and reality are not the same thing.  We won’t know for sure until vaccine effectiveness has been studied in populations infected by the variant.  

This brings us to one final point about this viral variant.  This variant is undoubtedly the first of many variants to come, and the answers for these yet-to-be-seen variants may be different than the answers for this one.  Viruses want to survive.  Just as the use of antibiotics causes the emergence of antibiotic resistance in bacteria, the use of vaccine will favor viral mutations that evade vaccine-induced immunity.   Variants will emerge that are unaffected by vaccine.

The pandemic is a war, both metaphorically and really.  Our best defense is the practice of what we know reduces spread: mask up, keep apart, and isolate when exposed.  We will prevail.  But it’s still too early to celebrate victory.

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2020 COVID-19

Mask Up!

Individuals exposed to someone infected by SARS-CoV-2 should be quarantined to slow the spread of COVID-19 and keep our loved ones safe.  However, being quarantined is a lot like being in jail.  How can we avoid drawing this card?

We have learned a lot about the spread of SARS-CoV-2 in the last ten months.  Those exposed to individuals infected by the virus are at risk of becoming infected themselves.  According to the CDC, an exposure is an encounter of less than 6 feet apart and more than 15 minutes long when one or both individuals are not wearing face masks.  By this definition, wearing a mask and keeping your distance from those not wearing masks prevents exposure to SARS-CoV-2.  

Does that mean that you will never get SARS-CoV-2 if you wear a mask?  No, wearing a mask cannot prevent all SARS-CoV-2 infections, but it will dramatically reduce your risk of infection and your risk of being dragged into quarantine jail.

How do we know that masks work?  The CDC has published evidence for the effectiveness of masks.  To this list, I add two observations from my own experience.

In the hospitals where I work, all physicians, staff, patients, and visitors are required to wear masks.  Although some individuals have become infected with SARS-CoV-2 during the pandemic, contact tracing demonstrates that individuals were infected outside of work.  I have not observed “hot-spots” of infection in clinical areas where these precautions are practiced.  This, despite treatment of hundreds of patients with COVID-19 at these hospitals.

The second point is the absence of flu in Texas this December.  By this time of the year, flu season is generally in full swing.  In mid-December, the laboratories where I work have usually detected many positive flu samples.  However, this year these same laboratories have yet to see their first positive flu test.  This is not for lack of testing for flu.  Since October, every rapid PCR test for SARS-CoV-2 has included a test for flu.  

Why is this observation relevant?  Flu is a respiratory illness transmitted in much the same way as SARS-CoV-2.  What prevents spread of coronavirus also prevents the spread of influenza virus.  With masking orders in place, the spread of flu has dramatically reduced. 

If masking has effectively stopped the spread of flu, why is COVID-19 surging?  Coronavirus is much more infectious than flu.  The point is that masking reduces all disease that spread by the airborne route.  Imagine what the surge would be like without masking?

In Texas, we love to wear our boots and hats.  This year, we’ve learned to love our masks, worn all the way up, covering the nose and mouth. Be safe during the coming holidays.  Mask up, y’all!

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2020 COVID-19 Testing

Quarantine

In guidance updated December 2, 2020, the CDC adjusted quarantine period for asymptomatic individuals.  Today we consider these latest quarantine recommendations.

Before we do, we must first discuss what it means to quarantine and the conditions that trigger a quarantine.  Quarantine separates an individual who may have been exposed to SARS-CoV-2, the virus that causes COVID-19, from others to prevent further spread of the virus.  Simply stated, quarantine means stay home and stay away from others.  If you live with other people, keep to a separate room.  If you must be in the same room with someone else, stay 6 feet away, wear a mask and make sure everyone else does too.  Generally, if one person in a household is quarantined, all persons in that household should also quarantine.

You must quarantine when (1) you have COVID-19, (2) you first positive test for SARS-CoV-2, or (3) you are exposed to someone infected by SARS-CoV-2.  An exposure is an encounter of less than 6 feet apart and more than 15 minutes long when one or both individuals are not wearing face masks.  

The standard quarantine period for asymptomatic individuals is 14 days.  This recommendation comes from the maximum observed time between exposure and development of symptoms, known as the incubation period.  The incubation period is less than 14 days for most infected individuals, with 5-7 days being average.

The new CDC guidance lists two situations when the quarantine period can be shortened to less than 14 days. If no symptoms develop, the quarantine can be ended after 10 days without testing for SARS-CoV-2.  But if the person tests negatively for SARS-CoV-2 on or after the 5th day of quarantine, and if the person never develops symptoms, then the quarantine period can be ended after day 7.  For the purposes of counting days, the exposure day is considered day 0.  

Immediate testing at the time of exposure is not recommended.  Testing prior to 5 days after exposure does not shorten the recommended quarantine period and could lead to a false perception that the exposure did not lead to infection, perhaps promoting risky behavior. 

The quarantine period is different if you have symptoms.  For persons with mild illness, the quarantine period is 10 days from the onset of symptoms or 24 hours since the last fever without use of fever-reducing medicines such as Tylenol, whichever is longer.  Generally, a mild illness is one that does not require hospitalization.  If hospitalization is required, the quarantine period may be 20 days or more, depending on the advice of your doctor. 

Following these updated quarantine guidelines slows the spread of the disease and keeps your loved ones safe.  However, wearing a mask and staying away from people who are not wearing masks minimizes the risk of exposure in everyday encounters.  More on masks next time.

Categories
2020 Statistics Testing

Accuracy, Precision and Predictive Value

We want accurate tests, don’t we?  By that, don’t we mean that we want precise test results?  Well, not exactly.  Before we leave the subject of laboratory statistics, there are a few more words we need to learn.

Accuracy is the ability of a test to aim for the target.  Visually, accuracy looks like this:

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Even though none of the shots hits the bullseye, we can tell where the shooter is aiming.

Precision is the ability of a test to get the same answer repeatedly, illustrated like this:

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Even though none of the shots hits the bullseye, all of the shots go to the same spot.

Putting these terms together, we can describe different aspects test performance.  Poor accuracy and poor precision look like this:

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The shots are not centered on the bullseye, and they do not hit the same spot.  Together, favorable accuracy and precision can be illustrated like this:

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All the shots hit the bullseye, repeatedly.  This is what an accurate and precise test looks like, too.  Accuracy and precision are both desirable but different aspects of test systems.

But are accuracy, precision, sensitivity and specificity enough to interpret tests?  Consider the case where these aspects of a test system are optimized.  In other words, the test is highly accurate, precise, sensitive and specific.  But what if the condition being tested for is not prevalent in the tested population.  Prevalence is the percentage of people in a given population who have the condition of a positive test.  Consider a test is 99.99% specific.  That means that for every 10,000 results, there is only 1 false positive.  But let’s say that the condition exists in the population at a rate of only 1 per 10,000 individuals.  In other words, out of 10,000 results, there is only one true positive result.  But we’ve already said that out of 10,000 tests, there will be one false positive result.  Therefore, if we get a positive result, there a 50% chance it’s the false positive, not the true positive.  That is what is meant by the term positive predictive value.   

Both positive and negative predictive values can be measured.  These are expressed mathematically as PPV = TP / (TP + FP) and NPV = TN / (TN + FN), respectively.  It’s okay to skip the math; just remember that predictive values are dependent on the prevalence of the condition; sensitivity and specificity are not.

Predictive value is important for test interpretation but should not be used for test selection.  Instead, sensitivity, specificity, accuracy and precision should be used to guide appropriate test selection.  These are the terms by which test systems are judged, and the key aspects of test performance analyzed by the FDA before tests are approved for use in the United States.

Categories
2020 Statistics Testing

Sensitivity and Specificity

We want tests that are highly sensitive and highly specific for the condition being tested, but that is not always possible.  Often, we must sacrifice one for the other.  Simply stated, negative results can be trusted when there is high sensitivity, and positive results can be trusted when there is high specificity.  So, we have to ask: is it better not to miss negatives or positives?  

There is not usually a neat separation between healthy patients and patients with disease.  Instead, patient populations exist in overlapping distributions, which can be illustrated as follows:

The vertical blue line represents the cutoff between positive and negative test results.  In this illustration, the cutoff is placed in a compromise position between the two populations, creating a group of false negatives (FN) and false positives (FP).  

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If a test is highly sensitive, the cutoff is shifted to the left, eliminating false negative results, but increasing the number of false positive results.

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If a test is highly specific, the cutoff is shifted to the right, eliminating false positive results, but increasing the number of false negatives.  As we have discussed previously, this is the situation with antigen tests for SARS-CoV-2. 

When screening large populations for disease, it is important not to miss possible positives, so we choose a test that highly sensitive.  We do not want any false negatives.  False positives can be sorted out later; this is just a screen after all.  On the other hand, it is important that confirmatory tests have high specificity.  When we are confirming disease in a population selected by a screen, we want to eliminate false positives.

If the goal of testing for SARS-CoV-2 is to avoid false negative results, favor sensitivity over specificity.  But this trade-off is not necessary with all test systems.  PCR tests increase sensitivity by amplification and increase specificity with detection probes unique to the virus.  The result is a separation between populations, increasing specificity and sensitivity at the same time:

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Are sensitivity and specificity the only considerations when evaluating a test?  No, it is more complicated, but I am sure you guessed that.  We will talk about other measures of test systems and the results they produce next time.