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Data based news and discussion

Tag: antibody

Covid 19. Schools reopen? Yes or No?

Posted on by stephenliphd

One of the greatest points of disagreement in the media, politics and at home is over the reopening of schools.  On one side of the discussion is that school is critical to the development and well being of children.  Schools provide instruction in important subjects, develop social and emotional skills, safety, reliable nutrition, mental health therapy, physical activity and also allows parents to go to work.  The other side of the discussion is if reopening of schools is safe for the children, teachers and general public.

There are many countries that have reopened their schools and their methods and results should be lessons for the US. https://www.usnews.com/news/best-countries/articles/2020-07-22/how-countries-reopened-schools-amid-the-coronavirus-pandemic

In summary, many countries have demonstrated that it is possible to open schools without causing spikes in cases and more importantly without causing spikes in deaths.  Children are 8 X more likely to die from fly/pneumonia than covid 19.

Denmark was one of the first countries to reopen schools after they shut them down.  Denmark reopened their schools on April 15 for children 2-12.  The measures they implemented appear to be successful as there has been NO increase in covid 19 cases and no serious outbreaks in schools.  On May 18 those aged 12-16 were allowed to return to using the same protocols.

Similarly, schools in Germany, Finland and Norway have reopened without significant spikes in the number of new cases and more importantly, no increases in deaths.

South Korea and Israel are examples of countries that reopened, closed and reopened  In both cases, there was a general increase in the number of covid cases that coincided with the reopening of schools.  However, in neither country was in shown that it was the reopening of schools that caused the general increase in covid.  In both counties other restrictions to the public were also lifted at the same time schools was reopened.  For instance, in Israel, groups of upto 250 were allowed to meet at the same schools reopened.  Schools are now open in both of these countries.

The big question everyuone is asking is “is it safe for children to return to school?’  Often this question is  addressed by the number of children who may become infected.  Although, no one wants any child to get sick, the facts are that people (and children) under the age of 26 have a significantly higher risk of dying from flu than dying from covid 19.

From 2007-2017, 172 million people died from flu and pneumonia.  This is an average fatality rate of 60,000/year.  However, the real detail is in the age of the people effected.  By the numbers, children between 5 and 14 have a 1 in 200,000 chance of dying from fly/pneumonia but a 1 in 1.5 million chance of dying from covid 19.

The following shows the relative risk of death from covid 19 vs pneumonia/flu.  Note that those under the age of 15 have 4 to 9 times higher risk of dying from flu/pneumonia than covid.

Evidence is mounting that children are less susceptible to Covid 19 and are less likely to transmit the virus to others.  When children under 15 test positive for covid 19, almost 40% have no symptoms and majority develop fevers and fatigue but recover. https://pediatrics.aappublications.org/content/145/6/e20200702

The data from around the world is consistent in showing that children are at lower risk from covid than from the flu.  However, there are still concerns about the risk to teachers, staff and student families.  It is likely teachers and staff will be the sources of infection, not the victims.  The results from many countries who have reopened their schools since April and May clearly show that there are ways to reopen schools without causing an increase in the number of cases or the number of deaths due to covid 19.

The current CDC estimate is that the overall fatality rate of covid is .65%.  However, this number is dominated by the fact that the fatiality rate of people over 65 is 5.6%.  The fatality rate of those under 64 is lower than that or flu/pneumonia.

The fatality rate of children who tested positive for covid is .03%.  Or, 99.7% of children who get covid 19 will recover.  This fatality number is much lower than many other diseases and causes for children.

As a last calibration, it is interesting to note that even in this year of the global pandemic, there are still more deaths attributed to pneumonia/flu than covid 19.  Covid 19 is to be respected and avoided but our overall understanding of the disease, use of social distancing, masks, testing and improving treatments have lowered the fatality rates down to levels of other diseases that we have learned to endure without shutting down our society. https://freopp.org/estimating-the-risk-of-death-from-covid-19-vs-influenza-or-pneumonia-by-age-630aea3ae5a9

Covid 19 Testing. The good, bad and unknown.

Posted on by stephenliphd

One of the most talked about issues around Covid 19 is testing.  Everyone seems to want a test.  However, little is said about the details of the tests, such as kinds of tests, good/bad tests and what do you do with the results.  The answers to these questions will help answer the questions about how important the tests are to reopening of businesses of keeping a business open.

A reliable, fast diagnostic needs to be established and available to manage the reopening of businesses.  The ability to identify infections before they become clusters, or clusters before they become outbreaks will be significant in how successful we will be in reopening businesses.

The tests.  There are two kinds of tests being talked about in the news and the reporting does not always make it clear which test they are talking about.  In most cases, they are talking about a DIAGNOSTIC test.  A diagnostic test will determine whether or not the Covid 19 virus is present at the time of the test.  The other kind of test is generally termed a serology (blood) test.  The serology tests determine the presence of antibodies that are created if the patient had been been previously infected with Covid 19.

Diagnostic Testing.  Most diagnostic tests use a method abbreviated RT-PCR (Reverse Transcription-Polymerase Chain Reaction) that will detect the presence of the DNA from the virus.  There are several manufacturers of these tests around and THEY ARE NOT THE SAME in reliability.  The difference in testing methods and reliability should be remembered when analyzing data from different sources.

In most cases, the testing being discussed are the results of diagnostic testing.  That is, diagnostic methods are used  when the daily number of confirmed cases is provided.  For instance, diagnostic tests were used to report the 1,391,316 confirmed cases of Covid 19 in the US (5/12/20).

A diagnostic test will determine if a virus is present at the time of testing.  It can not tell if the person was infected and then recovered nor is it predictive of if the patient will get the disease tomorrow or any time in the future.    If you are showing severe symptoms, you should go get medical attention whether or not you have been tested.  If you are feeling ill in any way, you should stay-at-home regardless of whether or not you are tested.  If you test negative, there are also uncertainties.  You may have been infected just before the test and the virus has not spread enough to be detected, or you could get infected tomorrow.  If you have no symptoms but are positive in a diagnostic test, you are among the 80% of infected people who have no or minor symptoms.

Serology – Antibody Testing

Serology tests are blood-based tests that can be used to identify whether people have been exposed to Covid 19 by looking for specific antibodies.  The mechanisms for antibodies was topic of an earlier blog regarding vaccines.  Covid 19 Vaccine. Where are we in the process? How will they work? What’s taking so long? The presence of antibodies would indicate that the patient had been infected with Covid 19.  As mentioned above, because the vast majority of people who are infected have no or minor symptoms, antibody testing is the only way to determine how many people are actually infected.  Earlier blogs have indicated that the actual number of people infected as determined from antibody testing is up to 20x higher than the number of infections detected with diagnostic testing.New York: Nearly 3 million infections – not 276,000

It is important to know:

  1. It is not known if the presence of antibodies makes the patient immune from further infection.
  2. If the patient does become immune to Covid 19, it is not known how long the immunity will last.
  3. The immediate benefit from antibody testing will be to determine how many people were infected.

Specificity and Sensitivity.  These are KEY factors in the reliability of tests but are seldom discussed in the news.   Specificity is a measure of how reliable the test is.  In other words,  if the test indicates you have the disease, do you really have the disease?  Or is the test somewhat unreliable because it can provide a positive result when you don’t have the disease.  This is termed a false positive result.    Specificity is a measure of how many false positives a test will give.  A test with a specificity of 80% means that only 80% of those who tested positive actually are positive.  20% show an incorrect positive result.

Sensitivity is a measure of how reliable the test is, if the test says that you are negative.  It is a measure of the false negatives.  A test with a sensitivity of 90% means that 90% of the people who test negative, truly do not have the disease but 10% of the negatives are really positives and have the disease.  Some of the reports from South Korea suggests their test had a sensitivity of 80-85%.

Each test should be evaluated for both it’s specificity and sensitivity.  It is possible for a test to have a high specificity but a low sensitivity.

These seem like details, but a 5% false negative means that if 1,000,000 people test negative, there are really 50,000 people who are actually infected.  Labs, doctors and patients should be very aware of the specificity and sensitivity of the tests they are administering.  There are over 20 different tests being conducted around the world, each with it’s own, sometime unknown specificity and sensitivity.  This makes comparative data very difficult.

As the choice of what test to run is determined locally (state, county, hospital), differences in specificity and sensitivity between tests likely exist.

There is an old joke in testing labs about what level of service a client can request. For each test, you can choose how fast you get the results back, how accurate the results are and the cost of the test.  Unfortunately, you can only choose two of the three choices.  This is true for Covid 19 testing as well.

Test Approval Process.

It would normally take more than a year or more to get a diagnostic test to get FDA approval.  This is because of the number of patients and time in clinical trials that are required to demonstrate sensitivity and specificity.  Under the FDA Emergency Use Authorization guidelines, manufacturers only need to test 30 laboratory samples and demonstrate 95% specificity (positives) and 100% sensitivity (negatives).  That means that the test must detect 95% of the samples that contain the virus.  A 100% sensitivity means that there can be no false negatives.  I am unaware of any test whose accuracy has been evaluated by an independent organization (eg not the company who manufacturers the test).

For diagnostic tests, it is important to know that the virus used in these laboratory tests are not from patients but from lab sources.  It is also not clear that all labs are using the same concentration of virus in all of their tests.  Last, the tests are conducted under laboratory conditions without issues of sample collection and other factors present when testing patients.  There is no requirement that any clinical data from patients be part of the Emergency Use Authorization approval process.  This does not mean that the tests are unreliable, it just means the tests have not been as fully evaluated as they would have in an non-emergency environment and we don’t know the number of false positives and negatives we are getting (other than the data supplied by the manufacturer).

There are also factors not related to the actual diagnostic test that can effect the test results.

  1. When the patient was infected.  If the patient was infected very recently, there may not be enough of the virus to detect.
  2. Where the virus is. Most tests are from nasal swabs.  However, as the disease progresses, the virus moves into the lungs, so the viral load in the nasal passages goes down.
  3. Incorrect sample collection. If the nasal swab is too superficial (not deep enough) then the virus may not be detected.
  4. Rapid testing after collection. The tests usually must be run within 8 hours, unless it is refrigerated in which case it much be tested within 72 hours.  Testing outside the windon decreases the chance of detection.

More attention must be paid to determine the specificity and sensitivity of all tests.  Too many false negatives will release infected people into the population and too many false positives can overwork or overload the health care system.  The situation is made more difficult with the increasing number of new tests being introduced in the US and around the world.

The same specificity and sensitivity issues apply to the Serology-antibody tests.  Again, there are over 20 different tests of this type being run around the world.  Like the diagnostic tests, they are being approved for use under emergency use authorization so specificity and sensitivity values are being supplied the manufacturer who makes the tests under laboratory conditions.  This does not make the tests unreliability and I am not criticizing the manufacturers, but independent evaluation under normal clinical evaluation guidelines should be done.

It is a difficult time as development and distribution speed is now prioritized over normal safety and effectiveness procedures.  This undoubtedly has allowed the use of some tests that would not have been approved under more normal conditions.

There are two examples of what can happen if specificity and sensitivity are not well established.  In May, the United Kingdom reported that it had purchased 2 million antibody test kits from China for $20 million (₤16 million).  However, the purchase was apparently made before independent UK analysis was done.  When the kits were received, independent tests showed both too many false positive and too many false negatives.  The 2 million kits are useless. https://www.bloomberg.com/news/articles/2020-04-07/new-test-hopes-dashed-as-u-k-finds-antibody-kits-don-t-deliver

The city of Laredo, Texas also bought 20,000 antibody test kits from China for $500,000.  These kits were not approved by the FDA in any way.  The city took a risk to secure antibody testing.  Once received, the tests, like the ones purchase in the UK, turned out to be unreliable and useless.  The kits were, nonetheless, seized by the FDA.

It is not my intention to criticize the incredible speed at which these highly complex tests are being developed. I have not discussed the actual technology, but it is quite incredible.  We usually just see a box or a device without knowing the complex test that is going on inside.   The balance of speed of development and reliability is a point the world is trying to find.  The purpose of this blog is to discuss the factors involved in testing that have not been often discussed and to provide some background to the daily news regarding testing.

 

 

 

 

 

 

 

Covid 19 vs Flu: Granular Data Analysis

Posted on by stephenliphd

There has been much contention when Covid 19 is compared to the seasonal flu.  One view is that it is much worse than the flu and the opposite view is that it no worse than a bad flu season.  Here is a granular look at the numbers.

By definition, flu is defined as a contagious viral infection of the upper or lower respiratory track.  Deaths caused by flu are similar to Covid 19 caused deaths in that it they induce fatal respiratory failure.  Flu is caused by more than one type of virus.  This definition is broad and Covid 19 could be considered a flu by this definition.  However, is really isn’t important if Covid 19 is classified or considered a flu or not.

A more important question is “Does Covid 19 have a higher fatality rate than the flu?”

The CDC tracks the number of flu infections and deaths each year and the data is available online.  The flu season generally occurs between November and February of each year.  Since 2010, the number of deaths attributed to the flu have varied from a low of 9000 in the 2011-12 season to a high of 61,099 in the 2017-2018 flu season. There was an estimated 45-60 million people infected with the flu in 2017-18. Since 2010, there have been an average of over 37,000 deaths per flu season.  This is an important benchmark because the country did not shut down under these conditions.  It serves also serves as a benchmark for comparison to Covid 19 to answer the fatality question.

The flu is more fatal to those over 65.  In the 2017-18 season,  50,903 of 61,009 (85%) flu deaths were in people over the age of 65.  Again, there were not programs to especially protect this older segment of the population.  It is also interesting to note that 80% of the deaths caused by Covid 19 are also in the over 65 age group.

On May 4, 2020, there were 69198 confirmed Covid 19 deaths in the US.  These deaths occurred between February and May (3+ months), a bit shorter than the November-February flu season.  This is also higher than the 61,099 flu deaths from the 2017-18 season.  The number of Covid 19 deaths is still rising so there it is clear that Covid 19 has caused more fatalities than the 2017-18 flu.  The final number of Covid 19 deaths has yet to be determined.

However, a more granular look at the data provides a further perspective.  Specifically, comparing the number of flu deaths in 2017-18 with Covid 19 deaths, by state.

In a previous blog, it was clear that the distribution of Covid 19 deaths was not uniform across the US.  In fact, New York and New Jersey account for 48% of all Covid 19 deaths while only having 9% of US population.  That is, 32,800 of the Covid 19 deaths were from New York and New Jersey.  The rest of the country had 36,584 deaths.  This is significantly lower than the 61,099 flu deaths in 2017-2018.   In  other words, the statistics from New York and New Jersey make Covid 19 more deadly than the flu.  However, if you do not live in New York, or New Jersey, Connecticut and Massachusetts, there will likely be more flu deaths than Covid 19 deaths. Granular Covid 19 data. How NY and New Jersey effect US Covid 19 statistics and why it matters.

Only 12 states have more Covid 19 deaths than  they did in the 2017-18 flu season. https://www.cdc.gov/nchs/pressroom/sosmap/flu_pneumonia_mortality/flu_pneumonia.htm

 

The following graphs show the 5 states with highest numbers  Covid 19 fatalities and the number of flu fatalities.  The Covid 19 deaths (red) far surpass the number of flu deaths (blue).

In the other 38 states, more people died from the flu than Covid 19. 

In 29 of these 38 states, there were 2-37 times more flu fatalities than Covid 19.

The following graphs shows a graph of several of the larger of the 38 states states that show the number of 2017-18 flu deaths far surpasses the number of Covid 19 deaths.  These include Georgia, Texas and Florida which have begun to reopen business.  Some highlights: California (2215 Covid 19 deaths vs 6340 flu deaths).  Florida (1399 Covid 19 deaths vs 3057 flu deaths).  North Carolina (442 Covid 19 deaths vs 2076 flu deaths).

This make answering the question of whether Covid 19 is more ‘deadly’ than the seasonal flu more difficult to answer in an absolute sense.

There are other differences between the diseases.

There is little doubt that Covid 19 is more contagious in that one Covid 19 patient infects more patients than one flu patient.  However, the magnitude of this difference depends on the assumptions used to do the calculation.

It appears that up to 80% of those infected with Covid 19 have no or minor symptoms.

It also appears that respiratory failure, if it comes, can come faster with Covid 19 than the flu.

The actual number of people who have been infected with Covid 19 is still being determined.  This value will come from continued antibody testing of the general population. However, the preliminary numbers indicate that the number of people infected with Covid 19 will be less than the 45-60 million who can get infected with the flu.

Last, it must be remembered that the flu mortalities are with the use of a flu vaccine.  As the flu vaccine is highly variable in its effectiveness (15-50%), it is probable that the flu fatalities could be higher than Covid 19 (including NY and New Jersey) if there were no vaccine.  However, with each antibody study, the number of people who have been infected with Covid 19 seems to increase.  This drives the overall fatality rate down.  From the antibody data available, the fatality rate is area dependent but is clearly well under 1%.  This is significantly lower than the 10-15% rates being discussed in February.New York: Nearly 3 million infections – not 276,000

The flu comes back every year and tens of thousands die.  The ‘herd immunity’ effect has not taken effect despite having over 50 million people a year being infected and the use of a vaccine.

The answer to the question ‘does Covid 19 have a higher fatality rate’ does not have a simple answer.  The current best answer is that it depends on where you live.  If you live in New York or New Jersey, Covid 19 clearly has a higher fatality rate.  However, in most of the other states, there were many more flu fatalities in 2017-18 (even with a vaccine) than there are Covid 19 deaths.

As more and more restrictions are removed, it is very likely that the results will vary depending on location.  As you read about the numbers, remember they are not the same everywhere, so beware of conclusions based on national numbers being applied to everyone, everywhere.

As more and more data is gathered, it appears that in states other than New York and New Jersey and perhaps one or two other states, the seasonal flu can be just as deadly if not more deadly than Covid 19.

These numbers are encouraging.  We have lived with the ravages of the seasonal flu every year and it appears that we are on our way to making Covid 19 behave similarly, except for perhaps the New England states.

Covid 19 Vaccine. Where are we in the process? How will they work? What’s taking so long?

Posted on by stephenliphd

As the US passes 60,000 Covid 19 deaths and we begin to selectively reopen parts of the country, the race for Covid 19 vaccine is at full speed.  However, questions regarding how vaccines work, how they are made, how well they work and the approval proess are generally not known. Knowing this information will help set expectations for development speed and possible effectiveness.

Recent History.  In the last 10 years, several epidemics have caused rapid research and development of vaccines for SARS (Severe Acute Respiratory Syndrome), H1N1 influenza (Swine Flu), Ebola, Zika, and now SARS-CoV-2 (Covid 19).  In each case a vaccine was ultimately developed.  However, the SARS and Zika epidemics ended on their own before vaccine development was completed and the Ebola vaccine was made available around the time the Ebola epidemic was winding down on its own.

A separate discussion will be provided in another blog regarding the vaccines for seasonal flu.  For now, know that the seasonal flu, with a vaccine, comes back every year and causes 25,000-60,000 deaths each season.  Due to changes in the flu and the corresponding vaccine, the effectiveness of the flu vaccine has been as low as 15% for season and averages around 40% effective overall. https://www.cdc.gov/flu/vaccines-work/vaccineeffect.htm

History.  A vaccine is something that is introduced into the body that causes the body’s immune system to fight off infection by producing specific antibodies.   The first ‘modern’ vaccine was developed by a British physician, Dr. Edward Jenner in 1796.  He discovered that if he infected people with the related but much less deadly cow pox virus, these patients would develop an immunity to the very deadly small pox.  It is a long and difficult process to make a vaccine.  At the start of the 20th century, yellow fever and polio killed and infected millions.  However, diseases such as these diseases, small pox and measles are virtually eliminated from the developed world (where the vaccines are available).

What are vaccines and how do they work?  The human body has amazing ability to generate specific ways to kill harmful bacteria and viruses.  These harmful bacteria and viruses are often termed as pathogens.    Specifically, the body can make special proteins called antibodies which are made specifically to fight off a specific pathogen.  That is, the body makes a different antibody to fight off each kind of pathogen.

Antigens are characteristic molecular structures on the surface of pathogens.  It is the antigen on the virus that attacks and infects healthy cells causing the disease.  Fortunately, we have a type of white blood cell, called a B Cell Lymphocyte that can not only recognize antigens but also produces a specific antibody that binds to the specific molecular structure of the antigen.  Once the antigen is bound by an antibody, the antigen can no longer infect another cell.  Another feature of this system is that once antibodies are produced, the body will recognize these antigens if they appear again and immediately makes more antibodies to fight off the infection.  This is how we get immunity.  This simplified process description is depicted in the figure below.  A part of the virus (pathogen) is seen at the bottom of the photo.  On the surface of the pathogen are the antigens.  A cell is shown carrying antibodies (the purple Y shaped structures).  You can see that the one end of the antibody matches the shape of an antigen and binds to it.  This inactivates that antigen.  The B cell is then seen bursting releasing antibodies that can seek out and bind to other antigens.

There are three general approaches to make vaccines:

Weakened Virus.  In this method, viruses are weakened so they reproduce very poorly inside the body and will not cause illness.  However, they reproduce enough to produce antibodies.   The vaccines for measles, mumps, German measles (rubella), rotavirus, oral polio (not used in the U.S.), chickenpox (varicella), and influenza (intranasal version) vaccines are made this way.   Vaccines made in this way cannot be used on people that already have weakened immune systems like cancer and HIV patients.

Inactivate (dead) Virus In this method, the viruses are killed (usually chemically) and introduced into a healthy patient.  The dead virus can not cause infection but the antigens are still on the surface and antibodies are made. The inactivated polio, hepatitis A, influenza (shot), and rabies are vaccines made from inactive viruses.  Vaccines produced in this manner can be given to those who are immunocompromised.  The limitation of this approach is that it requires the handling of large amounts of live virus and typically requires several doses to achieve immunity.

Use Part of the Virus. In this method, just one part of the virus containing the antigen is removed and used as a vaccine. These ‘parts’ can be DNA, RNA, recombinant DNA and protein units, to name a few.  The hepatitis B, one shingles vaccine (Shingrix®) and the human papillomavirus (HPV) vaccines are made this way.  This strategy can be used when an immune response to one (known) part of the virus is responsible for production of the antibody.  These vaccines can be given to people with weakened immunity and appear to induce long-lived immunity after two doses.  Most of the candidates in Phase I testing use this strategy (although in very different ways).

AN IMPORTANT CAVEAT.  This is a very, very simplified discussion of vaccines.  The actual mechanisms of action, chemistry, biochemistry and molecular biology are quite complex and well beyond the scope of this blog.  If you are interested, there are many references to the details on line.

Development of a Covid 19 Vaccine

On April 8, there were 115 Covid 19 possible vaccine candidates know/discussed.  However, only 78 of these are known to have become actual development projects.  It is unclear how many of these projects are still on going. Only 7 candidates have entered the first phase of human testing somewhere in the world. https://www.nature.com/articles/d41573-020-00073-5

There are several barriers to development of this vaccine.

It is not clear exactly how to prepare the vaccine.  Optimizing the antigen is difficult as it is not yet clear how much (or what part) of the full antigen protein is needed to illicit the appropriate antibody production.  Of the 7 vaccines in Phase I trials, no two use the same antigen preparation method.

There is always concern about causing side effects.  Preclinical trials during the SARS vaccine development raised concerns over exacerbating lung diseases.  As Covid 19 kills through a respiratory mechanism, this is an important concern.

It is not known how much of the vaccine (assuming you have the right one) is needed and if you need to use more than one dose to achieve immunity.

If you achieve immunity, it is not known how long the immunity will last.

Typically, vaccine development is a lengthy (10 year) expensive process.  As the manufacturing method is dependent on the actual way the antigen is prepared, manufacturers generally wait until they are fairly certain they have a successful vaccine before they invest the costly development and construction of manufacturing facilities and distribution plans.  There have been reports that some companies are taking a large risk by starting to develop manufacturing before they are even out of phase I trials in order to get the vaccine out as fast as possible.  It is quite a financial risk to do this as they may construct a facility that does suit their actual final product.

There are 3 Phases required for Vaccine Approval.

Phase 1.  A human trial with a small group (typically less that 100) of HEALTHY patients.  This is to insure that there are no ill effects of the vaccine and to see if any patients develop Covid 19 infections.   This phase usually takes a few months.

Phase 2.  This will involve a larger group of patients followed for a longer period of time.  The results from Phase I will help determine the number of patients and the length of the study.  Typically, this Phase involves hundreds of patients and can take 1-2 years.  However, due to the urgent need for the vaccine, shorter evaluations may be possible with the right study design and accepting higher risks.

Phase 3.  In this Phase thousands of patients will be vaccinated and the patients should be representative of the total population in terms of age, gender, ethnicity etc.  This will provide information on the effectiveness of the vaccine.  Again, the results of Phase 2 will dictate the exact number of patients and study time needed.

FDA Review.  At the end of Phase 3, the FDA will evaluate the results and provide approval, assuming safety and efficacy and patient protocols are demonstrated..

Phase 4.  The vaccine producer is generally required to continue clinical trials to look for additional side effects and study the longer term effects of the vaccine.

The global vaccine R&D effort is unprecedented in terms of scale, speed and diversity of candidates. Given the worldwide urgency, the most optimistic estimates are that vaccines could be available under ‘emergency use’ in the first half of 2021. This would represent an incredible change from the traditional vaccine development pathway time of over 10 years.  Introduction at this speed will require new development requirements, testing criteria and regulatory flexibility.   There is not substitute for letting nature act on its own time scale.  As the saying goes, ‘you can’t get 9 women and have a baby in a month’.

We should not forget that we do not want to sacrifice safety and efficacy for speed.

It is amazing that such a complex problem can have so many possible solutions being pursued simultaneously.  We truly live in amazing time in history.

Next: how well should we expect the vaccine to work?  The current antibody testing of larger number of patients has indicated that actual fatality rate is well under 1% and may be in the range of the seasonal flu.  This is very good news as the seasonal flu numbers include the use of a flu vaccine.  For Covid 19 to the same fatality rate without a vaccine provides some reason for optimism that with a covid 19 vaccine, it will be less deadly than the seasonal flu.New York: Nearly 3 million infections – not 276,000

The Japan Experience: No mass shutdown. No mass isolation. Fewer cases and fatalities. What can we learn?

Posted on by stephenliphd

The big question that is on everyone’s mind is what is going to happen when America ‘gets back to business’ and people have the freedom to move about as they please.  It may take awhile before we get back to the freedom to work and live like we did just 3 months ago, but I am confident we will get there.  In the mean time, what can expect we in the next few weeks?  Of course, it’s impossible to know for sure, but examining how different states and countries have handled the infection may provide some insight into at least the breadth of things that might occur and provide some concepts we could use.s

I believe that looking at places where there have been less restrictions placed on the people AND where people have been less impacted (number of covid 19 cases and fatalities per million people) show us that we can live with open businesses where Covid 19 is no worse than the seasonal flu.  I believe that Japan provides an example.  I know we can’t mimic Japan in many ways, but there are experiences which we could learn from.  It is a story of how a different approach, mind set and cultural behaviors combine to give a final result.

Relatively little has been said about Covid 19 in Japan with its population of 126.7 million.  Most businesses have remained open, yet the Covid 19 infection and fatality rates are much, much lower than in the US (in the range of seasonal flu).  Some estimates are that less than 20% of Japanese businesses have been closed.

As of March 28, 2020, the Covid 19 stats for Japan vs the US are shown below. It is important to note that the US has done far more testing than Japan, but neither country has done much antibody testing, so the true infection rate is not known for either country.  Nonetheless, the statistics for Japan are very good. Covid 19. How many people are actually infected? Santa Clara County

JapanUS
Population (millions)126.7340
Covid 19 cases136141,031,437
cases/million1083033
Cvoid 19 deaths38558705
deaths/million3177
tests150,6925,838,849
tests/million118917143

The difference in number of deaths/million people is dramatically lower in Japan than the US.

They used a ‘cluster-based approach’ to manage Covid 19..  The principal of this approach is that infection is spread from certain people being more contagious than others.  This concept was used to explain why many passengers on cruise ships are not infected despite having close contact with infected persons.

These more highly contagious people form clusters of infected people which go on to infect others.  Under this cluster based approach, each cluster of infections is identified and tracked to the original infection source(s) and these highly contagious people (and those they infected) are isolated.  This approach requires rapid targeted testing.  The government has a dedicated  department which does this monitoring.

This cluster-based approach is conditioned on clusters of infection get detected at an early stage.  In February 2020, a cluster based approach was used when an outbreak was identified in Hokkaido, Japan..  The source was located, containment measures employed (like closing all travel on/off the island, specific quarantine)  and the outbreak was rapidly contained.

It is noteworthy that South Korea used their version of the cluster based approach to contain their Covid 19 outbreak where they found 1 woman who infected over 1000 others and 60% of the cases in South Korea could be traced back to two churches.  Again, targeted testing and quick identification of clusters of infections were keys to success. South Korea: Covid 19 Containment vs Privacy

The Japan version of social distancing is called avoiding‘the three C’s’ : Closed spaces with poor ventilation; Crowded places and Close Contact places.  This is somewhat opposite to US instructions where we have been told to socially isolate but have closed parks, playgrounds and beaches.  Most, but not all Japanese elementary and high schools have closed, but the closures are only planned for 2-4 weeks depending on the local government.  It is not clear, school closures have (or will) influenced infections of fatalities given the relative low numbers of both.

There are also cultural practices that helped Japan limit the spread of the virus.  Large numbers of Japanese were already in the habit of wearing masks before Covid 19.  Western behaviors such as shaking hands, hugging, kissing and other forms of physical contact are not part of Japanese social behavior.  It is also interesting to note that on the famously crowded public Japanese transit systems, talking is considered to be poor etiquette so again, transmission methods are greatly reduced when no one is speaking and they are wearing masks.

Another cultural consequence of covid 19 isolation policy is suicide.  In Japan, the suicide rate has always been proportional to the unemployment rate.  Suicide rates have already increased in Japan even though the increased unemployment rate is still low compared to the US.  There is a real fear that Japanese suicide rates will increase dramatically if there is a US type of business shutdown.  Given the small number of Covid 19 deaths in Japan, it remains to be seen if the lives saved by sheltering in place are offset by lives lost due to suicide.

It is true  there has been an increase in the number of cases and deaths the past few days, but the numbers would have increase dramatically to reach the numbers of cases (108/million vs 2116/million) and fatalities in the US.  Due to these increases, this week, Prime Minister Abe declared a ‘state of emergency’ granting local governments power to make their own decisions about restrictions,  but there have been few nationwide mandatory shutdowns and only an appeal to ‘stay home’.  The state of emergency has also been set to be only 2 weeks long.  The Prime Minister’s opponents are calling for a larger shutdown but so far Abe has resisted.  Although the number of cases and deaths are increasing, Japan is still doing very well compared with most other countries it’s size.

Recent days have seen reports that some Japanese hospitals in major cities are running short of personal protective equipment. However, this may be a failure of poor planning and procedures rather than a failure of the cluster based approach.  The early success of the cluster based approach may have lulled the government into complacency and they failed to procure equipment and supplies when they could.  They are now playing ‘catch up’ to get supplies when they could have done so earlier.  Japan has far fewer ICU beds/100,000 people than the US and they are concerned about needing more ICU beds than they have, but they are not at that point yet.  The US has demonstrated that large numbers of hospital beds can be erected in short periods of time should they become needed.

The Japan model is based on geographic and social conditions which could be difficult to apply here.   However, I think there are clear experiences we can benefit from.

My summary is:

  1. You can limit the effect of the virus without mass shutting down businesses and sheltering in place as long as you have the ability to immediately identify outbreaks and identify and isolate the source of the cluster.
  2. Infections can be minimized by avoiding the ‘three c’s’: Closed in Spaces, Crowded Spaces and Close contact with other. Their version of social distancing.
  3. Infections can be minimized by reducing physical social greetings, kissing, hugging and handshakes.
  4. Mass transit can still be used if other behavioral changes are made.
  5. If you feel sick, stay away from others
  6. If you feel sick, do not go to work.

Japan is an example where people can live in an environment where Covid 19 is no worse than the seasonal flu (bad as that is) without a shutdown of the economy and staying indoors.  There’s always a chance of an outbreak in a closely packed country of 127 million people, but they have done well so far. Only time will tell if Japan’s approach was successful, but I am hopeful.

I am encouraging on our scientists and politicians to include the Japan experience in their thought and decision making process as they develop and implement plans to reopen America.

 

Reopen Businesses – What should the new ‘normal’ be?

Posted on by stephenliphd

Returning to normal…but what’s normal?

As the nation and the world turns toward reopening the world to business, there has been a lot discussion of whether we could ‘return to normal’, but what does that mean exactly and how do we know when get back to normal?  We have lived with numerous causes of death that are higher in number than we are seeing for Covid, yet we did not shut down our country for any of these other causes.  In other words, we accepted as ‘life’ that there are many things cause death but we continue to go through life without stopping.

We should not have to complete end or stop Covid 19 before we ‘return to normal’. ‘Norma’l includes yearly deaths many times that caused by Covid 19.

We get daily briefings and headlines about Covid new cases and new deaths from the US and around the world.  To date (April 27, 2020) there have been 1,004,942 Covid 19 cases and 56,527 deaths.  However, the view of the number of actual cases has drastically changed in the last week.  The availability of antibody tests, which can determine if someone has been infected, has resulted in several reports that the actual number of people that were infected may be somewhere between 16 to 80X higher than this value (up to 21% of the population).  This means the actual number of Covid 19 cases may in the range of 16,000,000 to 80,000,000.  This makes the fatality rate between .34 and .07%.  This is in the range of the seasonal flu. New York: Nearly 3 million infections – not 276,000

The early concern over Covid 19, which caused the nationwide lockdown were basically two concerns. The first was the seemingly high fatality rate which was generally reported to be between 5 and 10% back in March.  The second was the concern that the number of infected patients would overwhelm our health and hospital systems, and whether we could treat everyone who needed help.

As it turns out now, fortunately, neither of those concerns happened.  The fatality rate is most likely be well under 1% and may be in the range of the seasonal flu.  There was not one city, including the hottest spot, New York where there was a shortage of beds, intensive care units or ventilators.

The shelter in place and closing of businesses undoubtedly helped to slow the spread of the virus, but perhaps not as much as we previously thought.  Before antibody testing, we were operating under the fact the 1 million people had been infected.  In a country of 370 million, this would seem to say that the lockdown was very effective.  However, the antibody testing now suggests that the number of people infected may be as much as 80 million!  This means that the lockdown was not nearly effective as we thought.  It also means that the vast majority of those who were infected did not need hospital care and had no or minor symptoms.

As plans are being considered to how reopen America’s business, the question is what state of health are we going to return to or accept?

To try and answer this question, it is useful to examine the top 10 causes of death in the US in 2018.  The CDC reports:

CauseDeathsDeaths/100,000
Accidents1671,2748
Alzheimer's122,01931
Cancer599,274149
Diabetes8494621
Heart Disease655,381164
Kidney52,38613
Lower Respiratory (COPD)159,48640
Seasonal Flu5912015
Suicide48,3449
Covid 19 4/27/202056,527*15*
  • Covid 19 Numbers still increasing, but rate of increase has slowed

Note that as a society, we did not shut down our businesses or go into lockdown over these numbers.  In particular, it interesting to note that in the 2018 season, flu claimed more lives than Covid 19 has caused to date (although Covid 19 is sure to increase further).  We also did not stop driving cars even though over 100,000 per year die from car accidents.

It would seem reasonable that if Covid 19 statistics could be brought into line with these other causes of death that we would be back to ‘normal’.

A key factor to consider is that Covid was much more fatal to those over 65.  Currently 79% of the Covid 19 deaths were in people over the age of 65.  The 65 and older group represents just 16% of the population.  The data strongly suggests that those over 65 may suffer more fatalities.  The younger you are, the less likely that Covid will be fatal, even if you get infected.

When businesses open up, both businesses and individuals may have different behaviors depending on the age of the people involved.

Although, there has been a long and strong voicing that Covid 19 is not the flu, it acts more and more like a flu the more we study it.  It has been thought that Covid 19 was more contagious than the flu, but the recent finding that the number of infections known may be off by many millions, it is not clear how much more contagious it is.  As I always state, comparing Covid 19 to the flu is NOT downplaying the seriousness of Covid 19 – instead it is a reminder that the seasonal flu has always been deadly (25,000-60000 fatalities a season and up to 60 million infections) and will continue to be so.

I will discuss vaccines in an upcoming blog, but it is critical to note that the data regarding the seasonal flu is WITH an annual vaccine.  There is no current vaccine for Covid 19, so Covid 19 statistics should look much better once a vaccine is found.  However, it is very important to know that the seasonal flu vaccine does NOT always work well.  The effective of the seasonal flu vaccine has varied from 10 to 50% depending on the year.  Hopefully, the Covid 19 vaccine will perform much better.

Covid 19 Tests: What we can and can’t say.

Miami Dade: 165000 cases, not 10,000. More Good News

Posted on by stephenliphd

More good news.  It seems that each day, the results of another study of the actual extent of Covid 19 infection show that the actual number of people infected is much greater than we expected.

As always, this is good news.

Until now, Miami-Dade county in Florida has reported 10,600 cases of Covid 19.  However today, a University of Miami reported on a study designed to determine the actual extent of infection by selecting a wide range of patients with and without symptoms for antibody testing.

They found that 6% of those tested were positive for the antibody.  Assuming that their study group was representative of the Miami Dade county, this would mean that 165,000 were infected with Covid 19 instead of the 10,600 reported.  About 50% of the people tested reported having no symptoms for 14 days before being tested.

This data is consistent with the data reported for Santa Clara (2-5 %) and Los Angeles County (4%) in California and New York (up to 21%) as well as testing in Robbi Italy (10%) and Gangelt Germany (14%).  Although each study tested only a few thousand representative people, in all cases, the number of people tested ranged from 4 to 21% of the population- representing 10 to 80X the number of cases that have been reported.

This means that the ‘curve’ that we have been trying to flatten is NOT representative of the actual number of infections that have occurred.  Taking an average of 5% infection for discussion sake, this would mean that in the US alone, there have been 18,750,00 infections, not 953,851.  This would also make the fatality rate .28%.  If it turns out that 10% of the population was infected, the fatality rate would be .14%.  Recall that New York city reported an infection rate of 21%.

Caveat:  All of these studies represent cross sections of different areas of the US, Italy and Germany.  More data is necessary from many more places with wider demographic of study subjects until the actual infection rate is known.

However, even as we watch the daily count of new cases increase, it is certainly the case that the cases being measured are 10 to 80 times less than the actual number of people being infected.  Again, this is good news.  It means that 50-80% of the people who get infected have no or minor symptoms and that the fatality rate gets closer and closer to the values we associate with seasonal flu.  This is especially good news as the seasonal flu numbers are WITH a flu vaccine.  To date, there is no proven vaccine for Covid 19.  The numbers for Covid 19 can only improve with more antibody testing and the introduction of a vaccine.

This also has implications on reopening businesses as sheltering in place may have been effective, but perhaps not nearly as effective as it was thought to be.

New York: Nearly 3 million infections – not 276,000

Posted on by stephenliphd

New York: Infection rate 10x higher than previously thought.  This is good news.

New York reported their first results in larger scale antibody testing to see how many people may have had actually had a Covid 19 infection.  43% of the tests were conducted in New York City while 32.8% of the test were taken out of the city.  The presence of the antibody means the person had and recovered from Covid 19 infection.  In most cases, the person was unaware they were infected.  This is GOOD NEWS.  It means that most people who get infected have no or minor symptoms and it makes the fataility rate (the % of people who die after getting infected) much, much lower.  See my earlier blog on antibody testing. Covid 19 Tests: What we can and can’t say.

The results reflected large differences between different areas of the state.  The number of people who tested positive for the antibody was:

New York City: 21%

Long Island: 16.7%

Westchester 11.7%

Rest of New York 3.6%

This corresponds to 1.7 million people in New York City and more than 2.6 million statewide who have been infected.  These number are much, much higher than the 275,000 confirmed cases that his reported today.

The tests show that the spread of covid 19 was not very different for different age groups:

  • 45-54 age: 16.7%
  • 65-74 age: 11.9%
  • Over 75 age: 13%
  • Less than 45 ranged from 8 to 15%

It is reminded here that this is percentage in each age group that had the antibody – they are the survivors.  The fatality rate among the groups is very different, with those over 65 accounting for 40% of the deaths.  The fatality rates will be discussed in a future blog.

Black, latino and multiracial New Yorkers had a 22% average positive tests while White accounted for 9.1% of the positive results.  Although it is clear there is a racial component to the infection rate, strict comparison of the numbers should be done carefully, as most of the testing was done New York City which has more minorities.

Importantly, this make the fatality rate around .5%, 10x lower than what was known just a couple of weeks ago.

This does not negate the severe impact the disease has had on the public but it does provide more insight into the disease.

The results here are consistent with other immunity tests reports in Santa Clara County, Los Angeles County, Robbi, Italy and Gangelt Germany and continues to indicate that the fatality rate of Covid 19 is likely to be significantly under 1%. Covid 19. How many people are actually infected? Santa Clara County 

Caveat:  This study and others should be considered preliminary studies.  They clearly show a high number of infections but only in limited locales.  Much more data from more locations and wider demographic inclusion will be necessary before the actual numbers of infections are known.  The results may also vary from country to country or county to county.  However, all indications so far are that the number of infections  determined by antibody testing is far higher than the number of confirmed cases being reported.

 

Texas and Georgia Hair Salons Opening: Would you go?

Posted on by stephenliphd

This week, several states like Georgia and Texas are beginning to cautiously allow the opening of selected businesses.  They are doing this in the wake of the Federal Guidelines for reopening their businesses which provides guidelines for reopening but allows local governors to make final specific decisions. I’m going use the opening of Hair Salons as my discussion focus because it is controversial but brings out all the complexities of reopening a business.

In the past month, grocery stores, pharmacies, big box stores and Home Depot have opened without starting any outbreaks – this suggests that other businesses may find ways to reopen and stay safe as well.  It is hopeful that gyms, schools and other places can find ways to open and operate safely.

It should be emphasized that within a state the infection rate of Covid 19 can be very different. This means that you should know the situation around where you live.  Some areas have much higher rate of infection and people should behave accordingly.

Texas.  For instance, in the last 14 days 155 of the 255 counties of Texas have not reported any cases of Covid 19.  Another 19 counties have reported less than 10 new cases of Covid 19.  This is in contrast to the largest county, Harris and Dallas counties which reported 754 and 556 cases respectively in the same time period.  Just 10 counties account for 72% of the Covid 19 cases in Texas.  However, on percentage basis, on average 1.2% of the population of each county has been infected.  Keep in mind that this is a lower percentage that catches the seasonal flu.  Your risk of getting the disease is highly variable in Texas (and everywhere else).

Similarly the 10.6 million people of Georgia live in one of 158 counties.  The top 10 counties account for over 55% of cases.  It is a much different environment in Dekalb County (1600 cases including Atlanta) than in Montgomery County (2 total cases).

The reopening of businesses is not only economically crucial but also crucial to the health of the general population.  Over 50% (some higher) of the people live paycheck to paycheck and lines for food banks are enormously long.  Also, ‘elective’ surgeries and medical treatments have been stopped but the long term health implications of these stoppages are not yet known.  For instance, cancer screening stopped so there are people who may have been able to be diagnosed with cancer and start treatment have been waiting over a month just to get the diagnosis.  People with chronic pain are also not being cared for during this time.  A topic for another blog will be the costs involved.  BEFORE the over 5 trillion dollars recently allocated by congress, the national debt was 18 trillion dollars which translates into an interest payment of approximately $500 Billion each year.  That is $500 billion that could be spent on other things like education, homes, health care etc….the new spending will send our interest payments to over $600 Billion/year – over 10% of the US budget.

On the other hand, no one wants to ‘reignite’ the infection of Covid 19 after working so hard and making so many sacrifices to get the disease under some management so it will be balance to get back to work and stay safe.  I’m sure there will be some good decisions and some bad decisions in the coming weeks. Choices have to made on imperfect and incomplete data and the interpretation of the data we do have can often be interpreted in different ways.

It is important to emphasize that in these states that are beginning to allow businesses to open – it is NOT business as usual.  Social distancing guidelines remain in effect and there are many more procedures that must be followed in order to reopen and stay open.

One of the big controversies is the opening of hair salons.  It seems that this puts two people closer than social distance guidelines.  Is this a good idea?  The first answer is, that we don’t know how this will work – especially if they follow the guidelines.  This may be too much detail, but it illustrates the details that have to be taken for ANY business to reopen.  Here are the Georgia Guidelines for Hair Salons.  Also, consider that everyone should use some common sense along with government guidelines.

If you feel sick – don’t go out. 

If you’ve been in close contact who has been sick, don’t go out. 

If you feel sick – don’t go to work.

If you have been in close contact who has been sick don’t go to work.

Be mindful of exposing others to risk.  Most recent data suggests that 80-90% of infected people have few or no symptoms but can transmit the disease to others.  So even if you are feeling good, be mindful of who you come into contact or close proximity with.

Also, getting testing for Covid 19 just tells you if you have been infected on that day.  If you were recently infected, you may not have had the time for the infection to become detectable.  The test also will not tell you if you get the virus the next day or anytime in the future.  If you feel like you might be sick – stay away from others (test or no test).

Look the hair salon guide over, consider where you live and decide if you would go to hair salon if you were in need of a hair appointment.  I know this is only a small segment of life, but the same decisions will have to be made for every business that opens and every business you frequent.

Salon Guidelines – Georgia

  • Salon/shop employees will be required to wear masks at all times. Salons may want to consider providing masks to clients. Clients should wear face masks to the extent possible while receiving services.
  • Salons/shops should also make use of face shields, gloves, disposable or re-washable capes, smocks, neck strips, etc.
  • These items should be disinfected or disposed of between each client. Employees should should arrive at the salon/shop showered and wearing clean clothing and change clothes before leaving the salon/shop each day.
  • Hand washing with soap and warm water, for a minimum of 20 seconds will be required by employees between every client service.
  • All salons/shops should be thoroughly cleaned and disinfected prior to reopening. Disinfect all surfaces, tools, and linens, even if they were cleaned before the salon/shop was closed.
  • Salons/shops should maintain regular disinfection of all tools, shampoo bowls, pedicure bowls, workstations, treatment rooms, and restrooms.
  • Additionally, salons/shops should remove all unnecessary items (magazines, newspapers, service menus, and any other unnecessary paper products/decor) from reception areas and ensure that these areas and regularly touched surfaces are consistently wiped down, disinfected, and that hand sanitizer is readily available to clients and staff.
  • Avoiding the exchange of cash can help in preventing the spread of the virus, but if this is unavoidable, be sure to wash and sanitize hands well after each transaction.
  • The use of credit/debit transactions is preferred, using touch/swipe/no signature technology.
  • Employees who are sick will be expected to stay home.
  • Salon/shop owners/managers should provide training, educational materials, and reinforcement on proper sanitation, hand washing, cough and sneeze etiquette, use of PPE, and other protective behaviors.
  • Ensure break rooms are thoroughly cleaned and sanitized and not used for congregating by employees.
  • Be flexible with work schedules/salon hours to reduce the number of people (employees and clients) in salons/shops at all times in order to maintain social distancing.