SARS-COV-2

Unpacking Mortality from COVID-19

The severity of any disease, especially a new pathogen like SARS-COV-2 is important to measure, especially it’s ability to cause death, which is the ultimate measure of severity. There are two ways to measure mortality from any infection.

Fatility Infection Ratio (IFR)

The proportion of deaths among all infected individuals. To measure IFR one has to know accurately the total number of infections as well as all deaths caused by, the disease. In the midst of a pandemic, with testing variably available and deaths often occurring at home it is impossible to accurately measure IFR.

Case Fatality Rate (CFR)

The proportion of deaths among identified cases. In the early stages of the pandemic, most cases are identified by surveillance and often only the most severe cases are tested. This leads to wide variation in estimates of CFR ranging from 0.1% to as much as 25%.

In fact, it is only possible to accurately measure either one of these fatality rates in retrospect, long after the initial stages of the epidemic. The number of deaths attributed to COVID-19 is almost certainly an underestimate. On the other hand, the number of people who have been infected is also certainly an underestimate. People with mild or asymptomatic infection are unlikely to get tested.

Another problem is that fatality rates from COVID19 are not uniform. Certain groups of people have an increased risk of mortality from COVID-19, so mortality is not uniform across people who are infected.

Excess Mortality

One way to deal with the first problem is to look at excess total mortality rates compared to historical mortality rates. It is very likely that excess mortality during the pandemic reflects the impact on mortality of COVID-19. Even if all of these deaths are not directly attributable to COVID-19, some may reflect unavailability of care at hospitals overwhelmed by COVID patients.

Excess mortality statistics are available through the first 30 months of 2020, which takes us through July 25 of this year. Because of the delay in reporting of death certificates, data for August and September are incomplete. For the US as a whole, there were 207,000 excess deaths for the first 30 months of 2020. This figure suggests that we passed 200,000 deaths from COVID-19 by the end of July whereas the number of reported deaths from COVID-19 at the end of July was 150,000. This was clearly an underestimate. It is also clear from these excess mortality numbers that the mortality from COVID-19 is much higher than from influenza.

Here is a graph of weekly recorded deaths from all causes for the first 30 weeks of 2020. The dark line represent excess mortality for 2020. The gray lines underneath are death rates from the previous 5 years. The spike in the beginning of the top gray line represents the H1N1 influenza epidemic. You can clearly see that even this spike is dwarfed by the excess mortality for the first 30 months of 2020. Here is a link to the website which has these data

Mortality by race/ethnicity

Another way to look at mortality data is to look at mortality by race and ethnicity. The mortality rate for african americans from COVID-19 is twice as high as for non hispanic whites. For native americans the death rate is 1.4 times as high and for hispanics the death rate is 1.1 times as high. These increased death rates by race and ethnicity have nothing to do with genetics. People of color have all sorts of socioeconomic factors that increase their risk of underlying conditions as well as living in crowded housing that make social distancing difficult or impossible. Many have low wage jobs that increase risk of contact with multiple people.

Mortality by age

Risk of dying from COVID-19 increases dramatically with age. Taking age 18-29 as the reference group, here are data from the CDC.

30-39 Risk of death four times higher

40-49 Risk of death ten times higher

50-64 Risk of death thirty times higher

65-74 Risk of death 90 times higher

75-84 Risk of death 220 times higher

85+ Risk of death 630 times higher

Mortality by underlying condition

According to the CDC, 94% of COVID-19 deaths had at least one underlying health condition. These include obesity, chronic lung disease, diabetes, poorly controlled high blood pressure, asthma as well as conditions or medicines that suppress the immune system.

Bottom Line

Mortality from COVID-19 is complicated. Traditional measures of mortality are impossible to obtain in the midst of the pandemic. Excess mortality is the best way to assess the impact of COVID-19 on death rates. Measurements of mortality are also not uniform and are markedly increased in older people, people of color, and those with underlying conditions. Excess mortality statistics clearly demonstrate that the death rate caused directly or indirectly by COVID-19 far exceeds influenza epidemics in recent years. The only pandemic that had similar or worse mortality was the 1918 influenza epidemic.

Basic Epidemiology II: How Superspreading Events Work

In a previous post I talked about R, the reproduction number for an infectious agent such as SARS-COV2. R is the average number of other people a person with infection infects. The basic idea is that if R is less than one, the infection dies out. This works for infections like influenza which spreads pretty much evenly in susceptible populations.

There is another epidemiologic number called k, which is the dispersion factor. The math is somewhat technical, but if k is substantially less than one that means that the infection is spread primarily by a small number of superspreader events. It is estimated that k for SARS-COV2 is about 0.1

As we learn more about how this virus spreads, we have discovered that about 80% of people who are infected are unlikely to infect anyone else. The virus is spread primarily by “superspreader events” where one infected person is responsible for as many to as 50 or 100 infections. In other words, about 20% of infected people are responsible for the majority of the spread of the pandemic.

Superspreader events are relatively rare, so if we could focus on preventing the conditions that lead to super spreader events, then we could get the pandemic under much better control without having to shut down the whole economy.

There are some well known superspreader events. The Biogen leadership conference in Boston led to infection of 99 people in Massachusetts alone. A funeral in Albany Georgia led to infection of more than 100 people. Infection in a single person in a choir practice in Washington state led to 52 infected people, two of whom died. In Arkansas an infected pastor and his wife infected 30 church member at services over several days. Three of them died. An additional 26 people were infected from church members, one of whom died.

There are common factors in each of these events. They all happened in large groups of people who were close together, mostly in poorly ventilated indoor spaces. They involved people who were talking, often loudly, or singing or eating (you can’t wear a mask while you are eating or drinking). Talking or singing produces lots of particles and are likely to aerosolize (tiny droplets hanging in the air) the virus and make it much more likely to spread. It also turns out that exercising vigorously in a closed space, such as a gym also can cause superspreader events. For example fitness dance classes in South Korea with up to 22 people in a room led to 65 new cases. On the other hand, yoga classes were not associated with new cases.

So how do we prevent superspreader events? Obviously by avoiding situations where large groups are close together in enclosed spaces eating talking or singing. That means no indoor dining in most restaurants, no exercising in gyms in groups larger than 5-10 people, and no church services indoors. It also means avoiding indoor bars. Alcohol disinhibits people and makes them less careful. It means prohibiting crowds of spectators at sporting events or concerts.

Large indoor retail spaces where it is possible to keep social distancing and wear masks are unlikely sources of super spreading events. Time of contact is important too. If you are in contact with an infected person for less than 5 minutes, you are unlikely to become infected. That means passing people briefly indoors or out is unlikely to create a superspreader event.

People have also worried about using public bathrooms. Although it is true that public bathrooms are for the most part poorly ventilated enclosed spaces, no one stays there very long. Even though flushing a toilet creates a plume of particles, they don’t hang in the air very long. As far as we know, there has been no documented case of infection due to using a public bathroom.

An excellent article that goes into more detail about super spreading events and their importance can be found in an article in Scientific American. It is written in non technical language and is easy to understand. Here is a link to that article.

Bottom Line

COVID-19 infections are primarily transmitted by superspreader events. Eighty percent of infected people do not infect others. The vast majority of infections that maintain the spread of infection are produced by twenty percent of infected people. Superspreader events are associated with large groups of people in closed indoor spaces where talking, singing, eating and drinking, and vigorous exercise are occurring.

SARS-COV-2 Vaccines: Hype vs Reality

There have been predictions by the Trump administration and by some news media as well that it may be possible to have an effective preventive vaccine for the SARS-COV-2 virus by this fall. Every even slightly positive report of phase 1 and phase 2 trials have been breathlessly reported in the media. The purpose of this post is to give some reasonable estimates of when and if there could be an effective and safe vaccine for prevention of SARS-COV-2.

How vaccines are tested and developed

Exploratory stage

In this stage academic and federally funded scientists identify antigens (molecules that stimulate the immune system) that might help or prevent a disease such as COVID-19. This stage normally takes two to four years, but because of the tremendous financial resources and number of scientists involved in the exploratory stage, there are many potential vaccine antigen candidates already identified. In fact there are currently 165 vaccine candidates who have completed the exploratory phase.

Animal Trials

Vaccine candidates are often tested in animal models. If the vaccine protects animals from infection then it is more likely to lead to human trials. Vaccine protection in animals though, does not mean the vaccine will work or will be safe in humans. The two coronavirus vaccines that are farthest along in development, the one by Moderna and the one by Oxford have shown protection from pneumonia in mice and monkeys, but the noses of the animals showed just as much virus as monkeys that were not vaccinated.

Phase 1 Trials

In phase 1 trials, a small group of people are given a vaccine to see if the vaccine induces antibodies and if there are any adverse reactions. These involve only 15-20 people. The production of antibodies does not prove the vaccine will be effecting in preventing or reducing severity of infection. Twenty eight coronavirus vaccines have completed phase 1 trials.

Phase 2 Trials

In phase 2 trials the vaccine is given to hundreds of healthy people in different age and risk groups to see if the vaccine acts differently in different groups of people. Phase 2 trials provide more information about antibody production, but do not provide evidence about the effectiveness of the vaccine in the real world. Fifteen vaccines have completed or are currently in phase 2 trials.

Phase 3 Trials

In phase 3 trials, the vaccine is given to thousands of people. Half the people get a placebo injection while the other half get the vaccine injection. Both groups are followed over time to see how many in each group get infection and how severe the infection is. Each group is also monitored for side effects. A vaccine that is safe and effective will show decreased infection in the vaccine group compared to the control group and side effects in the vaccine group should be minimal and not serious. To count as effective, a vaccine would need to be at least as effective as the flu vaccine, which usually has about 50% protection. Nine vaccine candidates are in phase 3 trials. There are no shortcuts for phase 3 trials. Depending on the prevalence of the virus in the population being tested, phase 3 trials are likely to last from 1 to 4 years.

Chances of success

The success rate for vaccines that make it to phase 3 trials is low, around 30%. The good news is that there are a very large number of vaccines in various stages of testing. It is likely that at least two or three of these will turn out to be safe and effective. There is no guarantee that any of the vaccine currently in phase 3 trials will turn out to be safe and effective, and most will likely fail. Although it is possible that we will have a safe and effective vaccine by early in 2021, it is very unlikely.

Risks of emergency approval of vaccines

Russia and China have given emergency approval of vaccines that have not yet completed phase 3 trials. This is very dangerous. The bar for safety for giving a vaccine to millions of healthy people is very high. Short cutting the phase 3 trials has the potential to harm thousands of people with a vaccine that we don’t even know will be effective.

Hopefully the U.S. will not follow suit and the FDA will not approve a vaccine until phase 3 trials are completed and a vaccine is shown to be safe and effective.

Testing for SARS-COV-2

Many people want to be tested for the SARS-COV-2 virus, not because they are sick, but to make sure they are not infectious. This is important for people to know in certain work situations where they may be at higher risk of infection, to know if it is safe to visit their grandchildren, grandparents or any other person who might be vulnerable to severe disease from COVID-19. It also may be important for young people returning to in person education in school or college settings.

In this post  I will outline the tests that are available now as well as some that may be available soon. I will discuss how sensitive and specific each one is as well as how many days after infection a test is a reliable indicator of the presence of infection with COVID-19.

Incubation Period

Incubation period is the time from exposure to the virus to development of symptoms. This ranges from two to fourteen days, but the median (middle) is 4-5 days. Because of this variable incubation period, it is difficult to predict how soon a test for the virus will be positive. It could be as soon as one or two days after exposure, or as much as 7 days after exposure. People shed the most virus and are therefore most infectious 48 to 72 hours before they get symptoms.

What does a negative test for SARS-COV-2 mean?

A negative test for the virus could mean one of two things:

  1. You are not infected with the virus
  2. You are infected with the virus but are still in the incubation period, so your test is not yet positive.

If you know the date you were exposed, then a negative test 7 days later is good evidence that you are not infected. If you don’t know whether you have been exposed, then one negative test does not distinguish between 1 and 2. In order to be sure that you are not infected, you would have to have a second negative test a week later. If you are having symptoms of COVID-19 and have a negative test, that is good evidence that your symptoms are not due to COVID-19.

PCR Tests

PCR stands for polymerase chain reaction. These tests use a tiny amount of virus recovered from a swab and make millions of copies of part of the viral RNA, which  is then enough to measure. This is the most sensitive test for detecting SARS-COV-2. False negatives and false positives are rare (as long as you are not still in the incubation period).

The standard PCR test requires a nasopharyngeal swab. This means that a swab is put in the nose and pushed all the way to the top of the throat. Not only is this not very pleasant, but it has to be collected by someone wearing full PPE (personal protective equipment) because obtaining the swab can induce coughing and therefore has the potential to release coronavirus particles into the air. The testing is done by large machines at reference labs like Quest and Labcorp. These machines can run multiple samples at a time and give results in about an hour. The commercial labs have been overwhelmed by the huge number of swabs they have received from places like Arizona, Texas and Florida. Delay in obtaining test results is common and can be up to 10-14 days in some instances.

Point of Care PCR Tests

Abbot ID Now. It has received emergency approval from FDA. The machine is about the size of a toaster and is small enough to use in doctor’s offices and pharmacies. It works with nasal or throat swabs which can be obtained by the patient, and thus does not require a technician wearing full PPE. This is the machine that is used for testing president Trump and the people around him. Results are available in about 5 minutes for a positive test and about 13 minutes for a negative test. This is a PCR test.

Mesa Biotech Accula. It has also received emergency approval from FDA, This is a very small machine that fits in the palm of your hand. It is too complicated to use as an at-home test, but would be suitable for clinics, pharmacies and perhaps schools. Test results are available in about 30 minutes. This is also a PCR test.  This test uses just a nasal swab. This can be done by the person being tested, so does not require PPE.

Point of Care Antigen Tests

Antigen tests are used to test for the presence of proteins from SARS-COV-2. This is the same technology used for the rapid strep test and for rapid flu tests. These are rapid tests, with results in a few minutes. This is a much less sensitive method than tests that use PCR. Antigen tests miss up to 20% of infected people, that is, there are a high number of false negatives. False positive antigen tests are rare, so a positive result means a high likelihood of current infection. If you have symptoms that might be due to COVID-19 and an antigen test is negative, that negative should be confirmed with a PCR test.

You cannot safely use a negative antigen test as proof that you are not infected and are safe to interact with other people, especially vulnerable people who are older or who have underling conditions.

At Home Tests

The holy grail of COVID-19 testing would be a test that people could do at home. Lots of companies are working on such a test, which would be similar to a home pregnancy test. It should work with a simple nasal swab or a saliva sample. No such test has yet received emergency approval from the FDA, but stay tuned. It is likely that such a test will soon be available.

At present there are some tests that use saliva or a nasal swab collected at home, but the sample than has to be mailed to a commercial lab. That does not really count as a home test., although it does mean that no one wearing full PPE has to collect the sample. That is definitely a plus.

Antibody Tests

As I reported in a previous post, antibody tests are used to detect previous exposure to SARS-COV-2.  Unless the population being tested has had a high percentage of people infected, positives with this test are likely to be false positives. Antibody tests are therefore not of much use to individuals and are mostly used by epidemiologists to estimate the percentage of a population that has been infected with SARS-COV-2.

Bottom Line

Lets say you want to visit your grandchildren or your elderly parents and you want to be sure that you do not have COVID-19. In that case, you would need two negative PCR tests a week apart.

Antigen tests are much faster and cheaper. If you get a positive test, you are very likely infected. If you get a negative test, it does not tell you much.

Home tests are not yet available, but likely will be reasonably soon.

 

 

 

Why We Should be Worried About Recent COVID-19 Spikes in Young People

Recent spikes in COVID-19 cases in the south and west have primarily involved people in their 20’s and 30’s. The governors of those states have stated that such spikes are of less concern because they are predominantly among young people. Younger people have a much lower risk of hospitalization and death than people over 65 or those with underlying conditions. Although hospitalizations have risen in most of these states, hospital capacity has not been exceeded. Governors and health departments have admonished young people to be more careful about mask wearing and social distancing, but see no reason to not continue relaxing restrictions. Not to worry, right?

I don’t think so. It is very likely that this pattern of infection among younger people went on for weeks in places like New York City and New Jersey. We did not detect this pattern there because the shortage of tests at the beginning of the pandemic meant that we were only able to test people sick enough to be hospitalized.

There is no way to know for sure if this pattern among younger people preceded the terrible illness and death rate in New York City and New Jersey, but what we now know about how SARS-COV-2 spreads makes this very likely. Antibody testing in New York City suggested that as much as 20% of the population had been infected with SARS-COV-2.

It is clear that community spread was happening silently for weeks or months before people started coming to emergency departments in the northeast. We now know that from 30% to 50% of people who have COVID-19 have no symptoms, but can spread the virus to others.

As the people with no or mild symptoms interacted with the more vulnerable populations, hospitalizations, ICU admissions and deaths went through the roof. New York City hospitals just barely managed to avoid the situation that is now happening in India, where the health system and hospitals are completely overwhelmed and turning sick people away because there are no ICU beds or ventilators.

Could this happen in states like Florida, Texas, Arkansas, Mississippi and California? Unfortunately, I think the answer is yes. All of these states have large vulnerable populations. Many of these live in rural areas with small hospitals that would be overwhelmed by only a few very sick COVID-19 patients.

There are two things that might mitigate or prevent this impending disaster. It is probably too late to do one of them, but the other is still possible.

  1. Contact tracing for cases with isolation of cases and contacts. This is doable if the number of new cases is reasonably small. The maximum number of new cases where this will be feasible is 1-500 per month. In places like Florida, Arizona and Texas where new cases are exceeding 1000 per day, this approach will not be feasible.
  2. Universal mask wearing in public and maintaining at least 6 feet social distancing. We know this works to limit community transmission. Unfortunately, there is growing resistance to these measures.

People are emotionally and economically traumatized by the initial draconian measures that were necessary to get virus community transmission down to a manageable level. They just want to forget about the virus and get back to normal life.

Unfortunately, SARS-COV-2 has gone nowhere. It is still among us and will reproduce itself in any human host where it gains access through mouth, nose or eyes.

People who are upset and angry about not being able to return to normal life should listen to an old Rolling Stones song. The lyrics go “You can’t always get what you want. You can’t always get what you want. But if you try, sometimes you get what you need.”

What we need is to learn to live with mask wearing and social distancing for a long time to come. We also have to learn to live without sports, concerts or any other venue that requires large gatherings of people indoors. Outdoor gatherings may be possible, but only with mask wearing and social distancing.

We may have an effective vaccine that will provide long enough immunity that we can return to Pre-COVID life. There is no guarantee of that and if it does happen it is very likely to be next summer or later.

That’s all the good news I have for today! Hopefully my next post can be more upbeat. It would be especially wonderful if my predictions are wrong.