Category: 2020

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. 

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.

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 5^th 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.

There is no test for COVID-19.  Instead, testing focuses on detection of SARS-CoV-2, the virus known to cause COVID-19 or the body’s response to infection.  Today we will discuss antibody tests, the blood tests used to detect past infections.

Part of a healthy immune response to infection by any virus is the formation of antibodies.  Antibodies are made in plasma cells, a special type of lymphocyte, in response to an assault by a foreign pathogen such as a virus.  The immune response is amazing.  Once plasma cells “learn” how to identify the virus, they crank out millions of these little molecules which coat the surface of the virus, flagging them as “enemy”, and directing other cells of the immune system to isolate and eliminate them.  Once the infection is cleared, the plasma cells “remember” the code for that virus so they can be quickly recruited to make more antibody if the same infection occurs in the future.  This memory eliminates the time-consuming “learning” step.  This simple process explains why most people only get chickenpox once and explains how vaccines can protect children from mumps and measles. 

The first antibodies produced after infection are known as IgM Antibodies.  These are large pentamers, basically 5 antibody units brought together like a snowflake.  IgM antibody production is replaced with IgG antibody production generally after about a week, but the time varies by individual and virus.  IgG antibodies are produced for weeks to years after infection, again depending on the individual and the virus.  Other antibodies are produced by the immune system, but IgM and IgG are most useful in viral serology.  These antibodies are found in the blood stream, so a simple blood test can detect a variety of antibodies, including antibodies to SARS-CoV-2.  It is thought that antibodies to SARS-CoV-2 is what makes convalescent plasma an effective treatment for severe COVID-19.

There are several facts to keep in mind when interpreting antibody test results.  First, antibody tests tell us about past infections, not active infections.  Second, the antibody form tells us whether the infection was recent or distant.  IgM antibodies are made first but go away, so detection of IgM antibodies means the infection was recent.  IgG antibodies are made last but stay around for a long time.  Detection of IgG without IgM means that the infection occurred in the more distant past, at least three weeks ago, and detection of both IgG and IgM means the infection occurred in the transition period.

Antibody tests use an immunoassay methodology, which basically uses antibodies to detect antibodies.  Many of these tests have good specificity and sensitivity, but they are not perfect.  Cross reactivity and interfering substances can cause false positive and false negative results in the best of circumstances.  But we are not in the best of circumstances.  All SARS-CoV-2 antibody tests are available in the U.S. by an emergency use agreement (EUA) with the FDA.  Rigorous studies demanded by the FDA approval process have not yet occurred.

So, if you are positive for SARS-CoV-2 antibody, will you always be?  Don’t know.  If you are positive for SARS-CoV-2 antibody are you immune to COVID?  Don’t know.  It is simply too soon to define the body’s usual response to infection and its implication for future infection.  

What can we learn from antibody tests?  If your antibody test is positive, you probably had a SARS-CoV-2 infection in the past, even if you do not remember being sick.  If you do not have symptoms, and you have not been around someone with COVID-19, then you are not likely to have a current infection.  Continue normal activities, but with vigilant precautions.  Wear a mask and social distance.  These precautions reduce the spread of the disease.

Elon Musk recently tweeted that he was tested four times in the same day.  Two tests were positive, and two tests were negative.  How can this be? 

Mr. Musk was tested with the BD Veritor Plus rapid antigen test for SARS-CoV-2.  BD Veritor is one of several SARS-CoV-2 antigen tests made available in the United States by an Emergency Use Authorization (EUA) with the FDA.  While PCR tests have some limitations, antigen tests are fraught with many more challenges that bring their results into question.  

First the good news.  Antigen tests are cheap, plentiful, and rapid, usually providing results in 15 minutes or less.  And, with one exception, all antigen tests can be performed in laboratories operating under a CLIA Certificate of Waiver, meaning that they can be performed by personnel with very little education in laboratory science.

So what’s the bad news?  I see three major problems with antigen tests: the test process, the lack of amplification, and poor sensitivity.

The antigen tests from different vendors all follow, with minor variations, the same process.  A sample is collected on a swab, usually from the back of the nose (nasopharynx), and the swab is placed in an incubation well on the test device.  A few drops of reagent containing antibodies against the target (in this case, the SARS-CoV-2 virus capsule) are added.  If the antibodies bind to the target, a signal is sent to the test system.  This signal is usually a color change.  The whole process is very much like a home urine pregnancy test.  

Well, what could go wrong with that?  Strong lines are easy to see, but what about faint lines?  Where is the cut-off between positive and negative?  Some vendors include a reader calibrated to take the guesswork out of reading results, but you begin to see the problem.  The test system introduces an element of subjectivity and operator technique that varies from tester to tester, and these variations impact test results.  Recall that most of these tests are intended to be performed by personnel with very little training in laboratory medicine.  

This process lacks the amplification step of PCR.  That means when the swab is scraped against the back of the nose, what rubs off is all that you have for the test.  If you happened to not scrap off enough virus in an infected person, too bad—the test will be negative.

And that brings me to the final problem with antigen tests: low sensitivity.  According to the FDA submissions by BD, the antigen test used on Mr. Musk has a sensitivity that may be as low as 67%.  What does that mean?  Sensitivity of 67% means that one out of every three infected patients tests negative with the system. That’s right: wrong answers one-third of the time! And that is in the best of circumstances, using data that the manufacturer chose to submit to the FDA. These tests are not always used in the best of circumstances; remember, the test is approved for use by personnel with very little education in laboratory science.

BD makes the following statement in its submission to the FDA: “Negative test results do not preclude infection and should not be used as the sole basis for treatment or other patient management decisions, including infection control decisions, particularly in the presence of clinical signs and symptoms consistent with COVID-19, or in those who have been in contact with the virus. It is recommended that these results be confirmed by a molecular testing method, if necessary, for patient management.” Mr. Musk’s experience is not surprising.

My colleague says she has a Magic 8–Ball on her desk that is a lot like an antigen test: it’s cheap, plentiful and rapid. And, she says, it gives about as many correct answers. I agree.