The Daily Digest, 16Apr2021

Georgia COVID-19 Updates

The Johnson and Johnson vaccine

I wrote about some initial thoughts and observations regarding the Johnson and Johnson vaccine pause by CDC and FDA on Wednesday. That was also the day that the Advisory Committee on Immunization Practices (ACIP) met to discuss some of the findings that led to the pause and consider next steps. They ultimately decided to continue the pause until their next meeting, scheduled for a week from today. Today, I’d like to show you some of the things they talked about so that we have a better sense of why the pause is happening.

Blood clotting

I’m going to give a very brief and simplified explanation of why blood clotting is important and what platelets are. Understand that this is a really complex process. My explanation is for educational purposes only and should not be considered medical advice. Please consult with your physician for any health concerns.

The primary purpose of your circulatory system is carry oxygen and nutrients to the cells of your body in blood and remove waste. It is intimately tied to the gas exchange (carbon dioxide for oxygen) in your lungs. Without oxygen, your cells can’t perform the chemical reactions needed to process nutrients and provide energy for cell functions. If cells are starved of oxygen long enough, they die. Your blood contains a number of different cell types. The ones that carry oxygen are the red blood cells (look like red donuts in the image below) and another type are platelets, also known as thrombocytes (purple star-shaped cells in image below). These cells are important for forming blood clots. It’s a complicated set of reactions, but platelets are able to sense when there is damage to a blood vessel wall. If that damage isn’t dealt with quickly, you could lose blood volume and that would mean less ability to carry blood (and precious oxygen) to the cells of your body. The vessel will constrict to limit the amount of blood that can be lost. Then platelets gather up at the site of damage and form a platelet plug to stop blood loss. Eventually a mesh-like scab is formed called a fibrin clot (also known as a thrombus). Similarly to how your skin heals starting with a scab, the blood vessel wall can also be repaired. The important thing is that this clot stays local to the site of injury.

But sometimes clotting can go awry and that can have really dangerous consequences. This danger is why the clotting process is so tightly controlled in the body, with multiple reactions needed and multiple confirmation points along the way for things to proceed. If you’re not clotting enough, this can result conditions like hemophilia. If you’re clotting too much or inappropriately, you can have clots that travel along with the non-clotted blood and get stuck somewhere (called an embolus). If the clot gets stuck in the eye, it can lead to sudden blindness. If it gets stuck in the brain, it can cause a stroke. Why is this dangerous? Blood flows like a river, in one direction. What happens when you install a dam in a river? Water pools upstream of the dam and the landscape dries up downstream of the dam. If a clot gets stuck and blocks blood flow, the blood can’t backfill upstream from elsewhere in the body, the same as a river. So what happens to the cells downstream of the blockage? They run out of oxygen, run out of nutrients. Your cells don’t take down time. They are constantly performing biochemical reactions to harvest energy from nutrients (this requires oxygen) to power the reactions that cost energy in the cells, to keep cross-membrane traffic moving, and other critical functions. Without that oxygen, you don’t harvest energy. So you don’t have the energy needed to build things inside the cell, to perform certain chemical reactions and to maintain a healthy cell. In effect, the cell is starving. As they starve, the cells begin to die. The longer the cells are deprived of oxygen, the higher the cellular death count. So keeping blood flowing as it should is really, really important.

This music video by They Might Be Giants is part of a larger album on science for children, called Here Comes Science. I highly recommend it.

The ACIP meeting revealed more details about the clotting disorder that triggered the pause on the Johnson and Johnson vaccine. The people impacted have developed what’s called Cerebral Venous Sinus Thrombosis (CVST) with Thrombocytopenia. Let’s define these words. Cerebral = brain. Venous = blood vessels that return oxygen-deficient blood back to the heart to get more oxygen from the lungs. Sinus = open space. Thrombosis = clot. So a blood clot that got stuck in a pocket of the brain. And blood continues to flow toward that clot which adds pressure to the surrounding tissue, kind of like water pooling upstream of a dam. Downstream of the clot, the cells are deprived of oxygen. The thrombocytopenia thing is interesting. Remember that another word for platelet (the clot or thrombus-forming cells) is thrombocyte. Thrombocytopenia means that they have a shortage of platelets. So it’s this weird situation where you have clotted inappropriately to form this thrombus, but you’re also dangerously low on platelets. And it’s not common to see these things in combination. Typically, strokes are treated with blood thinners to break down the clot and restore blood flow. But if you did that with the folks with CVST + thrombocytopenia, the precious few platelets these people have couldn’t form a clot in the event of another injury. So this was one reason for the pause - to make healthcare providers aware of this complication and the ways that it impacts treatment.

On their own, CVSTs are rare, estimated to cause 0.5 - 1% of all strokes according to slides presented at the ACIP meeting. They typically happen among younger people, with a median age of 37 years and happen more often in women (3:1 ratio compared to men). And some of the risk factors include using oral contraceptives (also known as the birth control pill), pregnancy and post-partum recovery, among other conditions. The slide below shows how many CVST events have been reported following vaccination for COVID-19. It’s important to remember that there’s a big difference between something happening after vaccination versus something happening due to vaccination. We’ll talk about why the Johnson and Johnson numbers stand out and merit a closer look.

So far, there have been 6 reports of this unique condition of CVST + thrombocytopenia out of 6.86 million doses of the Johnson and Johnson vaccine administered, as of 12Apr. It’s occurring at a rate that is less than one in a million. The time between vaccination and onset for the 6 women was 6-13 days. However, it’s possible that additional cases will be reported for at least two reasons: (1) CVST tends to happen in younger individuals and vaccine eligibility only recently expanded to younger population, around April 1 for most states. (2) Another presentation at the ACIP meeting indicated that 52% of the Johnson and Johnson doses have been administered since 30Mar. This is one of the reasons why the ACIP ultimately decided to continue the pause until more time could elapse and they could get a better handle on how significant the problem was.

I want you to also notice that there have been ZERO cases of CVST reported among Pfizer-BioNTech vaccine recipients. There have been three CVST reports among Moderna vaccine recipients out of 84.7 million doses administered. However, this was the more typical form of CVST without the thrombocytopenia. And because so many more doses of Moderna have been administered than the Johnson and Johnson vaccine, the frequency of this event with Moderna is within expected incidence and is more likely to be coincidental. Earlier I said that just because one thing happens after a vaccine does not mean that the vaccine caused it. For example, let’s say that you have a grilled cheese sandwich for lunch today. Later today, you trip off of a sidewalk and sprain your ankle. That doesn’t mean that the grilled cheese caused your injury. Some things are coincidence. But one way to discern whether something is likely coincidence versus a cause for further scrutiny is to compare how common an event is compared to what we would expect under normal conditions. If the event is more frequent than we would expect, it might warrant a closer look. That’s what this table below does - calculate the expected and observed frequency of CVST.

The estimated annual incidence (or frequency) of CVST is 0.5 - 2 per 100,000 people. And it should be noted that this is just for CVST, not the CVST + thrombocytopenia that the 6 women experienced, making the event we’re talking about even more rare. But the 0.5-2 per 100,000 means that the rate of infection among women aged 20 - 50 years of age would range from 0.39 - 1.5 (middle column). In the third column they calculated how the 6 cases differ from what we would expect among the 1.4 million women aged 20 - 50 who had been dosed with the Johnson and Johnson vaccine. For the women vaccinated, the frequency of CVST was 3.8 - 15.2 times greater than expected. This is the safety signal that led FDA and CDC to pause Johnson and Johnson vaccinations and convene the ACIP for an emergency meeting. It should also be noted that the Johnson and Johnson vaccine is very similar to the AstraZeneca vaccine that has also had problems with CVST. Both are adenovirus vector DNA vaccines. Johnson and Johnson hasn’t seen any CVST + thrombocytopenia in their clinical trials for adenovirus vector vaccines for Ebola and RSV.

The ACIP then weighed some different options including limiting use to certain age groups or to men only. But given how few cases have been identified so far, they opted not to do this yet. They also discussed the practical advantages of the Johnson and Johnson vaccine that are being lost during the (extended) pause, specifically that its easy storage requirements and single dose make it a helpful tool in protecting vulnerable populations that can be hard to follow up for second doses. But one member pointed out that the same people who are well-served by the J&J vaccine are also the ones that are most likely to struggle to reach medical care in a timely manner if a complication should arise. The committee also identified that even though the ACIP makes recommendations on US vaccine policy, its decisions have a global impact. A decision to not recommend or limit the recommendation to particular groups could impact ongoing clinical trials and hamper vaccination efforts in other countries. However, the Johnson and Johnson vaccine isn’t the only vaccine available and makes up less than 5% of the US vaccine doses administered so far. At one point, the Hippocratic oath was invoked, “Do no harm.” The public could hear them weighing and agonizing over the decision - it clearly wasn’t an easy decision to come by. What they ultimately decided was that they didn’t have enough data to make a policy recommendation. They needed more information on the background frequency of CVST + thrombocytopenia. And they wanted to see how many additional cases came up since there was now increased awareness and more than half of the doses administered were in the most recent two weeks, during the window in which this complication might occur. As they wait for that additional information, there are two safe and effective alternative vaccines. They’re scheduled to meet again next Friday and hopefully we get a decision then.

Again, so far the complication appears to be very rare. However, it’s quite serious for those who have it.


Georgia updates

Testing

Today there were 21,194 newly reported PCR tests and 5.7% were positive. Test positivity seems to be ticking up this week so we’ll see if we’re still under 5% for the week on Sunday. Today there were 7777 newly reported antigen tests and 7.3% were positive.

Cases

Today Georgia reported a net increase of 1650 newly reported COVID-19 cases (1151 by PCR, 499 by antigen testing). The state 7-day case rate has risen 20% in the past week. Not only that, case rates are rising once again for young adults as you can see in the graph below. Previous surges have begun with this age group, so this is a concerning development. You can explore this graph and other state wide data in the School Aged Surveillance Data Report, released on Fridays.

Hospitalizations

Today there was a net increase of 112 new COVID-19 hospital admissions and 15 admissions to the ICU. The 7-day averages for daily admissions to the hospital in general and to the ICU are both trending upward.

Something weird is going on between the data that the state reports on currently hospitalized COVID-19 patients and what the HHS reports daily. I’ve been downloading and graphing the HHS data daily since the Georgia GIO hub went offline in December. I’ve provided a graph below on the right from the NY Times that also uses HHS data because it has the complete HHS data set whereas I’ve only been graphing the data since December. The HHS data clearly shows that COVID-19 patient census has been rising (about 20%) in the past two weeks. The data provided by the state on the left show a flat line, that probably wouldn’t be cause for concern. I should note that the two graphs do use roughly the same y-axis. HHS typically reports higher numbers day-to-day than Georgia and that may indicate that they have the more complete data set (i.e. including pediatric populations, etc). But the trends have always been about the same up until the last two weeks.

As of today, patient census is rising in eight of the fourteen hospital regions in Georgia. Cases and COVID-19 patient census are rising. Only 17.9% of the Georgia population is fully vaccinated. Please, please make good choices.

Deaths

Today there was a net increase of 58 newly reported confirmed COVID-19 deaths and 4 probable deaths.


References

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04/03-COVID-Shimabukuro-508.pdf

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04/05-COVID-Oliver-508.pdf

https://dph.georgia.gov/school-aged-covid-19-surveillance-data

https://dph.georgia.gov/covid-19-daily-status-report

https://covid-gagio.hub.arcgis.com/

https://www.nytimes.com/interactive/2021/us/georgia-covid-cases.html?action=click&module=covid_tracking&pgtype=Interactive&region=TableRowLink


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My Ph.D. is in Medical Microbiology and Immunology. I've worked at places like Creighton University, the Centers for Disease Control & Prevention and Mercer University School of Medicine. All thoughts are my professional opinion and should not be considered medical advice.