Digital PharmD

Informatics in Pharmacy

Dr. G, PharmD

Johnson and Johnson Coronavirus EUA Vaccine FAQ

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Does this Vaccine use Genetic Material Too?‘

Unlike the mRNA vaccines by Pfizer and Moderna, the Johnson and Johnson (J&J) vaccine uses DNA to tell our bodies to make the spike protein. The J&J vaccine is an adenovirus based vaccine. That means that scientists took a human adenovirus, Adenovirus 26, modified it, and added a gene for the spike protein to it. Adenoviruses are pretty common, and cause things like colds or flu-like illnesses. This one has been modified so it can’t replicate or cause human illness, but it can make the coronaviruses spike protein.

Viruses are like little machines and their job is usually to get into cells and use the cell’s machinery to make copies of themselves. That’s their only job: cell entry and reproducing themselves. For a vectored vaccine, scientists use this against another virus. Viruses already know how to get into a cell, but scientists modify can modify certain viruses to reproduce an antigen, like the spike protein, instead of themselves. So, the virus infects your cells, as viruses do, and instead of reproducing itself, it has your cells make spike protein. Just as in the Moderna and Pfizer vaccines, your cells are making the spike protein. The virus vector just helps the DNA get in.

Once the spike protein is made, your body reacts to it much like the two other EUA coronavirus vaccines do. The immune system sees the spike protein, makes antibodies and immune cells to fight it, and the adenovirus gets taken away by them too. The mRNA virus FAQ has more on the immune system and the spike protein. The Johnson & Johnson vaccine uses double-stranded DNA to code for the spike protein, so it does skip the translation step. It also has a virus to help it into the cell, so it doesn’t need complexing agents than the Moderna and Pfizer vaccines do. The PEG in the Moderna vaccine, its complexing agent, is one possible allergen.

Adenoviruses are actual ideal vectors. They are easy to manipulate. They are capable of infecting many types of cells. They can induce both CD4+ T cell- and CD8+ T cell-mediated immune responses. There is also a chimp adenovirus vaccine in the pipeline, but the J&J one is human. Scientists have been working on adenovirus vectored vaccines since the 1970s.

Johnson and Johnson Experience

J&J has a lot of experience with adenovirus vectored vaccines. They have been researching them for decades and released one in July of 2020 for ebola. Prior to approval, there were actually two adenovirus Ebola vaccines used in a couple hundred thousand people in the ebola outbreaks in West Africa and the Democratic Republic of Congo. They have trials on adenovirus vectored vaccines for HIV and Zika Virus as well.

Why Can it Be Refrigerated and the Others Need to be Frozen?

mRNA is pretty fragile. That’s why those vaccines have to be frozen and handled with care. J&J uses DNA, which is more resilient. The adenovirus helps protect it too. It still needs to be handled with care, but it can stand up to higher temperatures and a bit rougher handling.

What Happens to the Adenovirus?

The adenovirus has been crippled. It can’t reproduce itself. Your immune system will react to it like it does to any other new virus and remove it from your system. It won’t stay around forever and you won’t produce spike protein forever.

What if I’ve Been Exposed to an Adenovirus Before?

Most of us have been exposed to an adenovirus before. If you’ve been exposed Ad26 or one that looks too close to it, your immune system may destroy the vaccine before it has a chance to work. Ad26 antibodies are uncommon in Europe and the US, but more common in some other countries.

There is some concern that being exposed to the vector once would ruin a boosted dose, and AstraZeneca’s chimp adenovirus vaccine had some controversy. They accidentally gave some participants half a vaccine dose for one shot. Those patients did better than the people who had two full doses. There was some concern that maybe the first dose canceled the second because the immune system destroyed the vector before it entered the cell.

Russia’s Sputnik vaccine actually had this very concern and used two different adenovirus. They used one virus for the original shot, and a different one for the booster dose. J&J’s Zabdeno, the ebola virus vaccine, is actually 2 doses that use a different vector too.

Johnson and Johnson claims that one reason they chose Ad26 is that it’s not as immunogenic as other adenovirus vectors (like Ad5). That means you won’t have a large immune response when you’re exposed to Ad26 again. That could lower vaccine efficiency, but it could mean that a boosted dose is possible. They are doing trials to see if a 2 dose regimen is better. We should have a better answer after those trials.

Is That Why This is a One Dose Only Shot?

Partially. The real reason is that is the way the trial was designed. They could have just as easily designed the trial with a booster dose. However, one shot is a marketing advantage of the J&J vaccine, and a real world advantage to rural populations, the homeless, and other patients you have a hard time getting into your office for even one shot. If one shot can give pretty good and long lasting immunity, that’s great.

The data seems to say it’s “good” immunity. The vaccine is really efficient at preventing serious disease. It looks like it prevents some transmission too, however, like most vaccines it doesn’t appear to be sterilizing (see the discussion on the mRNA vaccine FAQ). We’ll see how long lasting the protection is and how good it is at protecting against variants as time goes on.

*I haven’t thoroughly reviewed the FDA data yet, I’ll update this in a few days when I have had a chance to do it with more info.

COVID-19 mRNA EUA Vaccine FAQs

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There have been a lot of questions about the COVID-19 mRNA vaccines. I thought I would put together an easy FAQ with some referenced answers. I’ll keep adding to it as I get more questions. I have a FAQ about the Johnson and Johnson vaccine too.

Is it Going to Alter my DNA?

If you remember your basic science classes, you remember that genes on DNA are transcribed to mRNA. mRNA is read by the ribosomes in cells and translated into proteins. Proteins do a lot of the work in our bodies. Enzymes, carrier proteins, hormones, cell structures, and more are all made of proteins. Antibodies are too.

mRNA is basically just a recipe card on how to make these proteins. It doesn’t change our DNA at all, it just says “make this.” This is a basic course with some nice diagrams. My explanation is pretty simplified.

Pfizer, please show this to my B-cells, thanks!

The two EUA COVID-19 mRNA vaccines produced by Pfizer and Moderna have a piece of mRNA that tells our cells to build part of a protein called the spike protein that’s found on the surface of SARS-CoV-2. Why would we want to do that?

Our immune system sees foreign invaders, like viruses, and activates to get rid of them. However, for a new invader, it usually takes some time before the immune system recognizes it. It’s like when a stranger moves in down the street. You don’t even really notice him much until he crashes a car through your fence or throws a huge party and invites all his friends to your pool.

Viruses and bacteria have all kinds of ways they can lay low to get around the immune system. Once the immune system ramps up, there are sometimes too many bad guys to fight. It would be nice if we could give the immune system a heads up. When we meet “bad guys,” our immune system makes antibodies, B-cells, T-cells, and other immune cells that are ready to get rid of them if they ever show up again. What we want to do is supply our immune system with a “Most Wanted” poster with the virus’s likeness so it knows that this guy is bad before he settles in. We want it to have a head start to make those cells that are ready to get rid of the bad guys if they show up. This article from Nature has a nice graphic about immune cells and SARS-CoV-2.

The mRNA vaccines tell our bodies to produce parts of a protein found on the surface of SARS-CoV-2 as kind of a wanted poster. They’re saying “See this protein? We don’t want it around.” If we ever get infected, we know right away that this guy is bad news and we’ll be ready for him when he comes into town. We only need the poster. We don’t need to get in a fight with him first. We can get ready for him without all the nasty side effects of getting exposed to the real disease. Our immune cells see the protein, recognize that it’s bad, and get ready to fight if it ever shows up.

The spike protein is, as far as we know, perfectly safe for us, unlike the virus itself. It’s just a protein. It doesn’t really do anything on its own, but it’s unique to SARS-CoV-2.

How Does it Know When to Stop?

This is a question that I’ve been getting a lot. If I get this vaccine, will the mRNA be telling my cells to produce this spike protein forever? If so, what are the long term effects of that?

mRNA is relatively fragile. It doesn’t last long. This mRNA doesn’t replicate and, as mentioned above, it doesn’t integrate into the DNA. It’s just a recipe. That recipe card will disappear within days (usually around 72 hours). Here’s a decent paper about the stability and development of mRNA vaccines. Once it’s gone, the cells won’t remember how to make the spike protein anymore. We don’t need the cells to keep making spike anyway. Remember, we just want our immune to see it and recognize it.

We think mRNA vaccines are probably going to be safer than our standard vaccines because they don’t need traditional adjuvants, they aren’t made in eggs or anything like that, and they don’t contain many of the preservatives that might cause a reaction. They’re also really flexible because almost any protein can be encoded on mRNA.

That being said, they usually require some sort of complexing agent, which might be the reason some people have strong allergic reactions to them (scientists don’t think it is just yet, but it’s worth pointing out). In order to work, the mRNA has to get inside the cell. These agents help enhance the uptake of the mRNA into cells so the mRNA can be translated.

There’s a rumor that the spike protein is the same protein and syncytin-1, found in the placenta. It is not. They share a few amino acids, but they are different proteins. This is a pretty good debunking of that. If that were true, however, we would expect natural infection with coronavirus to be devasting to fertility too, because you’re going to make antibodies to spike once you’re naturally infected.

Can I Get COVID From the Vaccine or Will I Test Positive on a COVID Test?

Since this vaccine just uses a tiny piece of mRNA that encodes for a protein, you cannot get the virus from the vaccine nor will you test positive on a RT-PCR or a rapid antigen test. This vaccine only encodes for a small portion of the spike protein. It doesn’t even contain the virus. The virus has lots of other proteins and antigens and those are what these rapid tests and PCRs look for, not just this tiny spike region. You will not test positive on a COVID test as your body has never seen these other antigens.

If a test was using spike as a marker, you would test positive, but none of the commercial SARS-CoV-2 assays use the spike protein as a marker (in the USA at least, I didn’t look at the international ones, but I haven’t heard of one).

That being said, the incubation period of SARS-CoV-2 is about 7-14 days and it takes about 14 days for the vaccines to confer any protection. You can be exposed and get sick before your vaccine kicks in. You could be exposed 13 days before you get your vaccine and get sick the next day, or you could have been exposed the day before you got your vaccine and get sick 10 days after. That’s unfortunate timing, but it has happened (and it’s a real risk since community spread is so high).

There are some “flu-like” side effects of the vaccine that are not COVID. They are your body’s immune response. These vaccines seem to produce more of a robust immune response than some traditional vaccines, making some people feel a little down for a day or two. That’s what our immune system does when it’s ramping up. Fever, chills, that nauseous feeling you have: those are all ways our immune system fights the bad guys. You’re not getting that because you have COVID, but because the immune system is activating. For most people, it only lasts a day or two.

Will I Test Positive on an Antibody Test?

You hope that you will test positive on a COVID antibody test. That’s what we want. However, these tests also look for different antibodies. Most of the ones I’ve seen look for antibodies to the spike protein and our hope is that you will test positive on those after vaccination. That means you’re making antibodies to spike. Yay! Your cells listened to the vaccine.

A few commercial tests look for antibodies to the nucleocapsid. You will never test positive on those if you’ve only been vaccinated and not exposed to the original virus. Remember, your body only knows the spike protein. There is a whole lot of virus it’s never seen. That doesn’t mean you’re not covered though. The real virus will have spike protein on it. If you see a negative antibody test and you were vaccinated between 14 and 90 days ago, ask which specific antibodies the test is looking for (you may have to look to the manufacturer, because the test giver may not know). Here’s a list of FDA approved antibody tests and which antibodies they are looking for. Most of the nucleocapsid tests also look for spike, so I don’t think it’s a big concern.

A bigger concern is that these antibodies wane. I tested positive for IgG in January. If I get another test in September, it will likely be negative (maybe not – we’re not sure, but I’m predicting it will be). Should I worry? Not necessarily. My immune memory cells are still on my team. Our hope is that they remember that they know spike and he’s a bad guy, even my antibodies don’t, and they’re ready to make new spike antibodies quickly (see a link above for information on immune memory and SARS-CoV-2).

What Else is in These Vaccines?

These vaccines actually don’t have a lot of ingredients and they can be broken down into three main categories. Aside from the different lipids and buffers, the portion of the spike protein sampled is different in each vaccine.

  • Complexing Agent: Helps the mRNA get into cells. They’re all big words, but they’re just fats.
  • Genetic Material: Our recipe for a portion of the spike protein.
  • Buffer: Helps to make the solution close to the pH of humans so it doesn’t hurt as much.

The Pfizer-BioNTech COVID-19 Vaccine includes the following ingredients:

  • Complexing Agent: lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-Distearoyl-sn-glycero-3- phosphocholine, and cholesterol)
  • Genetic Material: mRNA
  • Buffer: potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose.

The Moderna COVID-19 Vaccine contains the following ingredients:

  • Complexing Agent: lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC])
  • Genetic Material: messenger ribonucleic acid (mRNA)
  • Buffer: tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate, and sucrose

Don’t Vaccines Take Decades to Make? How Was This One So Fast?

It’s true that most vaccines take decades to make, but there are several reasons why this vaccine was quicker.

  • SARS-1 and MERs: Scientists did a lot of work with SARS-1 and MERs before this coronavirus ever erupted. These outbreaks were similar viruses, but not really pandemic potential viruses. Scientists also had researched other coronaviruses before (look at “Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor” from 2013) and knew the spike protein was probably a good target.
  • Previous mRNA Vaccine Study: Vaccinologits have been trying to perfect mRNA vaccines for a while. They’ve found ways to overcome several initial problems. mRNA itself can be very immunogenic upon initial doses, but they’ve fixed most of those issues. Immune cells want to get rid of foreign mRNA just as much as they want to get rid of viruses. They’ve figured that out. They’ve figured out how to get the mRNA into the cells and to turn on translation. All of that was done before we even know about SARS-CoV-2. Several mRNA vaccines have been in human trials for years, but they’ve never reached significance.
  • Worldwide Interest: mRNA vaccines have been in the pipeline for quite a while (Moderna was founded in 2010). If you look at the drug’s in Moderna’s Pipeline and on Clinicaltrials.gov, the biggest problem seems to be sample size. It’s hard to prove something is working if you only have 100 participants. A lot of the diseases that mRNA vaccines have been studied for are things like ebola, zika, and certain cancers. There really isn’t a huge population size for these diseases. There haven’t been safety issues, as much as there have been significance issues. For SARS-CoV-2, the entire world was filled with people who wanted to be in the trail. They recruited tens of thousands of people for both of these trials within months. That’s usually not the case. It’s a lot easier to prove significance in 10,000 people than 100. These vaccines were studied in more people than the Shingrix phase 3 trials (that’s the shingles vaccine).
  • Lots of Dollars: With worldwide significance comes worldwide funding. Many countries pitched in money to help research. Usually, companies have to wait for proof of concept before they get more funding to go on to the next step (here are the steps of drug development). This time, companies and governments (even celebrities) said, “Just do it all.” Instead of having to present data in front of a review board or grant committee to get approval to move from phase to phase, or to start manufacturing, they just did it all at the same time (more or less, there are some things you can’t do at the same time).
  • mRNA Vaccines Are Quick to Produce: It also helps that mRNA vaccines are relatively quick to produce. Vaccines like influenza have to grow. For the egg-based vaccines, they figure out which strains of flu they want to be in the vaccine this year, and inject those into fertilized chicken eggs. Those eggs are incubated for several days to allow the viruses to replicate. The fluid containing virus is harvested from the eggs. Those viruses then have to be inactivated and purified to make the shot. That’s a pretty long process. mRNA can be made in huge batches in a lab. Small changes can be made to the vaccines without much effort or downtime. This is actually revolutionary and will probably change future vaccines.

What About the Long Term Effects

To be honest, we can’t truly say what the long term effects of this vaccine will be. We can say that most vaccine-related reactions happen within 28 days, and we haven’t seen many. We can say that some trial participants got pregnant with no issues. We don’t see why there would be further issues. We can’t say 100% that there won’t be. That’s true at the end of any Phase 3 trial (remember the steps of drug development). We see more adverse reactions when drugs are released to the general population because we’re all different. We all have different immune systems, drugs, chronic conditions, genes, etc. It takes millions of people before you reach a point where you can say you probably have seen every combination of people to really classify the rarity of reactions.

I’ve heard people say that mRNA technology is brand new and just developed for this pandemic. That’s not true. We have had human trials of mRNA vaccines since 2008 and seen no significant signals of safety concerns (I linked some of Moderna’s trials and pipeline drugs previously). That is promising, but these studies have been small, so we could see some adverse effects in a population this large. I don’t think anyone is bold enough to say that’s not a possibility, just that it’s not a probability that there will be widespread harm or serious adverse effects. This is a really good review article about some of the early problems with mRNA vaccines and the history of them, also their safety now that some of those issues have been overcome. The graphic below comes from that article.

To the best of our knowledge, these vaccines appear safe and effective. That’s all we can ever say. I’ve had patients who had severe adverse effects to drugs that have been out forever. We can’t always figure out why or what caused it. We’re all different. This is a novel vaccine delivery system that’s been studied a lot, but never had its prime time moment until now. We can’t know with 100% confidence that they’re absolutely safe.

What we do know are the effects of SARS-CoV-2. Those on the front lines have seen patients with amputations, chronic fatigue, clots, stroke, and continuing joint and back pain. We’ve also seen lots of people die. All of medicine is a benefit vs risk equation. I think for most of us, the benefits outweigh the small risk, but that’s a personal decision between you and your healthcare providers.

I respect if someone wants to wait until next year, as long as you’re also wearing your mask, keeping your distance, isolating, and not hosting parties. However if anyone asks me, I absolutely recommend getting the vaccine and I got one myself, despite being relatively low risk of serious disease.

Why Should I Care About a Disease that 95% of People Recover From

The recovery rate of COVID-19 is often exaggerated because we hear that “only” 5% of die. If we look at just this statistic, the vaccine would have to have killed a lot of people already to be as deadly (it hasn’t killed any*). That being said, death is not the only bad outcome of COVID-19. One in 11 severe patients who recover end up in the hospital multiple times after discharge. Patients have strokes, emboli, amputations, kidney and heart problems, etc.

Even in relatively mild cases, not requiring hospitalization, the CDC reports that 1 in 5 previously healthy adults will have symptoms from headache, fatigue, loss of taste and smell, nausea, fever, chills, congestion, shortness of breath, and chest pain for more than 14 days. That’s a lot of affected people. We aren’t 100% sure of the full impact of those “long COVID” patients the future of our healthcare system or the long-term impact on these patients’ lives. One small study showed that 46% of college athletes had some heart damage after a SARS-CoV-2 infection that did not require hospitalization. The study was only 26 students, but it’s still something to think about for those of us who aren’t young, competitive athletes. Out of 26, 12 had cardiovascular changes consistent with myocardial injury, though we don’t know what that means for their long term health.

The vaccine would have to have some pretty serious long term effects, which we haven’t seen, to make the risks outweigh the benefits.

*Covid Vaccine Deaths? Not really.

There were actually six deaths reported in the Pfizer trial. People die during trials sometimes. Only two of these people were given the vaccine. The other four were given a placebo. They found no causal relationship between the vaccine and the two deaths. One of the vaccine recipients had a cardiac arrest 62 days after a second dose of the two-dose vaccination and died three days later. The other died from arteriosclerosis three days after a first dose of the vaccination. 

I should also mention the 23 nursing home patients that died after they got the vaccine in Norway. That’s the part of the story you see on social media. It doesn’t mention that those patients were frail and elderly, and already sick (many had terminal illnesses.) When you vaccinate a population of frail, elderly people, some will die. Most would have died anyway. Norwegian officials report that 15 nursing patients die each day and these 23 patients don’t represent any excess deaths, but it has caused officials to question whether or not frail patients should get the vaccine.

There is also an Auburn nursing home that has been referenced on social media. They had a COVID outbreak that killed 24 people as they were vaccinating, but social media says “24 COVID deaths after the vaccine was administered.” The nursing home had a COVID-19 case confirmed on December 21 and began vaccinating on December 22. In the next two weeks, 24 residents died of COVID-19. That’s not surprising as COVID spreads fast in nursing homes, the patients had not been vaccinated for long enough to build up immunity, and had only received one shot. It’s unfortunate timing though.

Finally, an MD died of acute immune thrombocytopenia after receiving the COVID-19 vaccine. Acute immune thrombocytopenia is extremely rare and is usually either of unknown origin or triggered by an infection, but it can theoretically be a reaction to any vaccine. It’s most common in MMR and only 1 in 25,000 children are affected. It’s usually mild, goes away on its own, and treatable if it does not. It was not treatable in Dr. Micheals’s case, which is really unfortunate, but it’s hard to say definitively the vaccine was the cause. It’s hard to say it’s not. This is something to look out for as the population vaccinated increases. So far, it’s one out over 16 million people vaccinated.

Once I Get the Vaccine, Can I Take Off My Mask

No.

I wrote about sterilizing immunity (which is immunity from being infected and spreading infection) in an earlier post. Neither of these vaccines seems to provide it. They provide excellent protection against getting sick. That means you could still get infected and still spread it. That’s pretty common in vaccines. Many vaccines decreases transmission, but are not 100% sterilizing (Rotavirus, Conjugate Pneumococcal, Pertussis Influenza, etc. do not). The live polio vaccine is actually pretty famous for vaccine-derived poliovirus outbreaks. Sterilizing immunity happens most often in diseases with a longer incubation period (like HPV). That wouldn’t happen here, the SARS-CoV-2 vaccine doesn’t contain virus. What could happen is that a person who is vaccinated gets exposed and infected, but doesn’t feel bad. They go around without their mask. They’re spreading it everywhere without knowing it.

Moderna actually swabbed trial participants after the first dose and it looks like the transmission is blocked a little (not 100%) and they plan to do more studies to see if it actually does block transmission significantly. Even a little bit would help, and that’s why most vaccines, even though they only reduce transmission and don’t stop it completely, are pretty effective at slowing outbreaks.

If the majority of the population is vaccinated, transmission doesn’t matter as much. That won’t happen for a while. It’s also not as important if community spread is lower, because your chances of exposure are lower to begin with. Low community exposure probably won’t happen for a while either.

Another more self-serving point is that vaccines are never 100% effective. Pfizer and Moderna are both reported to be around 95% effective. The problem is that you don’t know if you’ll be in that 5%. With cases so high, it’s not worth the risk to yourself.

We’ll probably be masking until at least mid-2021, maybe longer.

How long will the vaccine last?

We don’t know how long vaccine-mediated immunity will last. We think at least six months, but probably longer. Despite media hyperbole, SARS-CoV-2 doesn’t mutate that quickly in any clinically meaningful way. One of the reasons why coronaviruses are so successful is that they have built-in proofreading that fixes mutations. That being said, mutations that favor spread or infectivity are very possible. It was probably a mutation that caused it to jump to humans afterall. Spike, however, seems to be fairly stable, even with the few point mutations we’ve seen in it so far. That could also change.

It’s often reported that antibodies last for 5-7 months, but memory B and T cells can last for much longer than antibodies. You expect antibodies to fall off after infections, but those other immune cells remember spike too. Will these other immune cells protect us? For how long? We don’t know. We suspect at least a year, probably more.

People also ask about reinfections. We hear about them in the media. Even in infections that typically produce good immunity, you expect that immunity will fail some people. Let’s just pretend a natural infection and a vaccine both produce immunity in 95% of people for three years. That leaves 5% of people who are open to reinfection. From most of the data I’ve seen, we’re not getting a large number of reinfections yet. We can’t say for sure that it’s not just those expected immune failures, especially with community exposure being so high. We may see more reinfections though. It’s only been a year.

It’s expected that vaccine mediated immunity will last longer than natural infection, but again we’re not sure.

Which one should I get?

The data looks so similar for Pfizer and Moderna that I would take either one. I personally took Pfizer, because that is what we had. I think Moderna’s trial design was better, but they got more or less the same results as Pfizer.

Pfizer has more to lose if this goes bad. They are worth $221 billion, while Moderna went from $6.6 billion to $20 billion over the last year. I think I would probably be skeptical that Moderna’s data was so great if Pfizer wasn’t here to back them up. However, the data is so similar, I think they’re both good choices.

One important note is the that the spike portion is different in these vaccines, so if you get the Pfizer vaccine for your shot, you need the Pfizer vaccine for shot 2 and vice versa. With current data, you shouldn’t mix and match.

Why did the government grant Pfizer and Moderna immunity from claims?

The PREP act does give these companies unique immunity against lawsuits for the next four years. That means that for the next four years, these companies “cannot be sued for money damages in court” over injuries related to the administration or use of products to treat or protect against COVID as long as they weren’t acting with “willful ignorance.”

To me, this makes sense. I actually think it should be applied to most drugs. Companies should not be sued for acting within the best interest of the public with the best information they have available and the information required for FDA approval. Companies should absolutely be sued if they hide or refuse to collect and report data that would look bad for them. Some people may disagree, but frivolous drug lawsuits are raising prescription prices in the USA and making care and novel drug development harder. If Pfizer and Moderna had to account for frivolous lawsuits, the cost of vaccination would likely be higher and this public health crisis would likely last a lot longer.

This is purely my opinion, but I think these frivolous lawsuits (not just for vaccines) encourage bad behavior in companies. If I’m a drug company and I notice my newly approved drug is causing some bad side effect in 0.1% of patients, I think I might be more willing to overlook that if I knew I would see it in some drug injury lawyer commercial. If I don’t have any liability, I might be more apt to look into it further, especially if my immunity would disappear if I were guilty of “willful ignorance.” There would be no downside to admitting adverse effects.

In this case, the government asked companies to speed up their process so that they have less trial data to back them up in court. They are afraid that people will bring up frivolous lawsuits against them that they won’t have the data to rebuke. The PREP act also set up a countermeasures compensation program for COVID-19. There are some criticisms of this program, including that it doesn’t pay enough, but it is available.

If this vaccine did hurt people, even without willful ignorance, it would be a PR nightmare for both of these companies. Pfizer would be forever connected to the bad COVID vaccine. No one would trust it’s multi-billion dollar brand again. A doctor prescribes you a new Pfizer product and you’ll say, “Isn’t this that COVID vaccine company? No thanks.” Moderna would likely completely go under.

As I mentioned above, they have a lot to lose. They obviously trust the vaccine or they wouldn’t have associated their name so closely with it. Pfizer has more to lose than to gain in my opinion, but you make your own choice.

I read one shot is 50% effective. What does that mean? Can I just get one shot?

When we talk about “effectiveness” in vaccines, we’re talking about how effective the vaccine is at preventing disease. Vaccine efficacy is the percentage reduction of disease in a vaccinated group of people compared to an unvaccinated group. What it means when we say one dose is 50% effective is that if we vaccinate 100 people, 50 percent fewer people will get the disease than if we didn’t vaccinate. It doesn’t mean that you’re halfway protected with one dose, which is a common thing I see the media saying. Moderna actually did study a single dose in about 2,000 patients and showed it may be almost as effective as a boosted dose (around 80%), but that wasn’t the trial protocol and it was a small sample, so we don’t know for sure. Here is vaccine efficacy is calculated.

So, you may be protected and you may not be if you just get one dose. We don’t know if a single dose will affect the amount of time you’re immune or not either. The second booster usually boosts those immune memory cells we need to mount a quick response to infection, so it could be that a single dose wouldn’t be effective for as long as the boosted doses. Here’s an article from the BBC that discusses immunity after one shot and what that means for long term immunity.

Also note that it takes about 14 days for the vaccine to be effective. Our immune system needs time to circulate that wanted poster around. You can get COVID the day you get your booster, even if you’re mounting an immune response. That’d be pretty bad timing, but it could happen.

There are some public health experts asking if 50% is enough. Would we better off vaccinating 1000 people and having 500 of them develop immunity or 500 people with 475 people developing immunity (that’s not exactly the right figure, but for comparison purposes)? With limited vaccines, 50% might be a better answer. However, we’re not just limited by vaccine doses. There are many doses in the USA right now not being utilized because of logistical issues. Public health officials argue that mRNA vaccines can probably be created as fast as they can be utilized, and we should vaccinate based on the actual study data to make sure they are most effective.

We also have to acknowledge that people aren’t numbers and some people are at higher risk. Would we want to cover 50% of those high-risk patents so we can cover more that are not at as high risk, or would we rather protect 95% of them and let the others wait? These are complicated questions. The FDA has recommended both doses and so have Pfizer and Moderna.

Another complication for me is vaccine acceptance. If this vaccine fails to curb the pandemic because we mess up and give a single dose that doesn’t grant long-lasting immunity, will the public continue to trust vaccines? Vaccines are one of the cheapest and most effective public health interventions we have. If we screw this up, it could have a long-lasting impact on other areas of public health too.

Should I get it if I’m pregnant or lactating?

In short, most experts are recommending you do because you’re at higher risk for ill effects from the virus. Here’s the American College of Obstetricians and Gynecologists’ official statement. That statement has more details about risk groups and timing. This is a decision that should be evaluated individually based on your risks with your obstetrician.

There is a meme going around that the Pfizer package insert (or FDA data, depending on the meme) says that you shouldn’t have unprotected sex for 28 days after receiving the vaccine. There is no such warning on the package insert or in any of the data. Phase 3 trials usually try to exclude pregnant women on the onset. It’s because we want to cause the least harm if something bad does happen. That being said, 12 patients in the Pfizer study arm became pregnant (11 in the placebo group) with no ill effects. There were 13 pregnancies in the Moderna trial, with 6 in the vaccine group. There have been no safety issues in that group so far.

As mentioned above, another rumor has to do with the spike protein itself. The spike protein is not the same protein as syncytin-1, found in the placenta. They share a few amino acids, but they are different proteins. This is a pretty good debunking of that.

Should I get if it I’ve had COVID-19?

Yes. You should wait until your acute infection is over, but since we believe that vaccine-mediated-immunity will be stronger than natural immunity, you should still get the vaccine. The CDC is suggesting it’s safe to wait 90 days between your COVID-19 disease and your vaccine. The ACIP recommends that vaccination should be deferred until you’ve recovered from acute illness and you’ve completed the isolation period. For most people, that’s 10 days after the onset of symptoms, provided there’s been no fever for at least 24 hours.

If you develop COVID-19 between your first and second dose, there are not currently clear recommendations, but based on the above recommendation, you can get the second dose per the ACIP recommendations above (10 days after the onset of symptoms, provided there’s been no fever for at least 24 hours), if it fits your vaccination schedule. If it does not, you can probably get the boost later than scheduled. We don’t really know what the vaccine sweet spot is yet, but usually vaccination later the prescribed does trigger boosted immunity in a smiliar way.

A booster is just a second exposure. If you get infected or exposed between the first and the second, theoretically, you’re doing the same thing that a “booster” dose would do. You’re exposing your immune system to the spike protein again. So, you may not even need a second booster at all. Again, we don’t have data on this scenario, but it’s an argument by some health professionals.

Does the vaccine increase my risk of HIV?

I’ve been seeing this one more and more. The short answer is no, the Pfizer or Moderna vaccine do not.

There are two potential sources for this rumor. An abandoned Australian vaccine used two fragments of a protein found in H.I.V. to form part of a molecular “clamp” for their vaccine. When they saw it was causing false positives on HIV tests, they abandoned the vaccine.

There is also some concern that the adenovirus type-5 (Ad5) vectored vaccines may cause an increased risk for HIV infection. This concern was first published in The Lancet by a group of researchers who evaluated an Ad5 vectored HIV-1 vaccine and found an increased risk of HIV-1 acquisition among vaccinated men. Further studies suggested that Ad5-specific CD4 T cells could be more susceptible to HIV infection. However, they haven’t seen a signal of this with the SARS-CoV-2 adenovirus vaccines. Those are not approved in the US at this time. The mRNA vaccines do not share this concern.

Can I take the vaccine if I’m blood thinners?

The vaccine screening questionnaires often do ask if you’re on blood thinners. This is not because blood thinners are a contraindication of the vaccine. This is because people on blood thinners tend to bleed more when they are given shots of any kind (you probably should be asked this before any vaccine). It’s just to give the health care practitioner administering the vaccine a heads up that you may bleed a bit more after they give you your shot, so they can be prepared.

What about satanic genes, microchips, fetal cells, etc?

Get real. None of these things are in the vaccine.

What Makes a Good Vaccine? (Part 1)

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There has been much discussion about vaccine expectations because of the SARS-CoV-2 pandemic. Many people think that a good vaccine will completely eliminate the disease. That is the lofty goal of vaccination. We eradicated polio because of vaccines. We would love it if all vaccines eliminated the disease entirely, but that’s not the reality for many vaccine-preventable diseases. Take the flu vaccine as an example. It doesn’t always stop infection from the flu. A lot of people use that to claim it’s not a “good” vaccine. That claim is a misunderstanding of what the goals of vaccination are. Eliminating infection, called “sterilizing immunity,” is not the goal of every vaccine.

Most vaccines don’t actually provide sterilizing immunity. Vaccines for diseases that have a long incubation period sometimes do, because the immune system has time to act on the pathogen before it’s infectious, but vaccines for pertussis, rotavirus, conjugate pneumococcal, influenza, etc. do not. They do usually reduce transmission.

So, let’s look at what makes a good vaccine and the goals of vaccination.

Long Lasting Protection

For some pathogens, like the flu, long-term immunity is seemingly impossible to achieve. The flu, which is actually four types of Orthomyxoviridae, changes quite a bit from year to year. We can’t yet design a vaccine to account for the changes. For some other pathogens, immunity wanes over time. Tetanus, diphtheria, pertussis is recommended every 10 years because of waning immunity. The perfect vaccine would offer lifetime protection, but good vaccines are scheduled and designed to boost immunity when needed. That’s why we get boosters and have vaccine schedules.

We aren’t sure what kind of immunity a SARS-CoV-2 vaccine will provide yet, but natural immunity to the virus appears to wane. There have been a few case reports of reinfection. With any pathogen, we expect that immune response within the population will vary. Some people will have a strong immune response. Some will have a weak one. Most will have a response that’s somewhere in the middle. The reinfections could just be those outliers who didn’t mount a good immune response. The majority of us could have a better, longer-lasting, response in the middle. We don’t know.

Even if the majority of us don’t mount a long-lasting natural response, it doesn’t mean that a vaccine won’t offer better immunity than natural infection. They often do. Only time will tell. We may have to have a yearly shot like the flu, or maybe a booster every few years like some other vaccines. It doesn’t mean, as headlines claim, that a vaccine against coronavirus won’t work. It just means we have to design one that works with our immune response.

Protection from Severity of Disease

A criticism I hear about the flu vaccine quite a bit is that “it isn’t very effective.” They usually aren’t talking about the long-term effectiveness I discussed above. They’re talking about the 40-60% of people who get the flu vaccine and still get the flu. Remember: sterilizing immunity isn’t always the goal. The secondary goal of the influenza vaccine is to reduce the incidence of severe disease. Our current flu vaccines are very good at that.

It’s been shown that influenza immunization significantly reduces the risk of bacterial complications associated with influenza and shortens the average hospital stay of those infected by the flu. The majority of people who die “from influenza” don’t actually die from influenza. They die from secondary infections caused by influenza, and sometimes end up with organ damage from the treatment of those infections. It’s theorized that while your immune system is busy fighting influenza, other opportunistic bugs like S. pneumoniae and Pseudomonas move in. If we can eliminate some of those infections, we’ve eliminated a big part of influenza mortality.

Aside from bacterial infections and hospital stay, infection with the flu can cause heart attacks and myocarditis. There’s a significant body of evidence that finds the influenza vaccine prevents up to 45% of heart attacks, which is about the same risk reduction as smoking cessation.

That’s pretty impressive for a vaccine that’s not “good.”

There’s a concern with just preventing serious illness that we should consider in the context of SARS-CoV-2. People who get the flu shot and get infected may be protected, as explained, but their friends and families aren’t. That’s why some experts believe that even with a SARS-CoV-2 vaccine, we may still need to have some restrictions in crowd size and possibly still need to wear masks until the majority of the population is vaccinated. Why?

As a health care worker, I may have the opportunity to get the vaccine early to protect myself. I may decide to drop all my precautions and walk around like it was 2019. I’m vaccinated and safe. However, I may get infected and never know it. Hopefully, I’d be protected from disease and symptoms myself, but I could be interacting with unvaccinated patients or coworkers and spreading coronavirus around. We don’t know enough to know if that’s going to happen, but it’s one possibility. The initial run of vaccines probably won’t be enough to vaccinate everyone who is at high risk. We may need still need to protect them, even if we’re protected ourselves. That still doesn’t make it a bad vaccine. It’s just probably not going to be the perfect vaccine. Welcome to medicine, where nothing is perfect.

Many of our vaccines are unlike the flu vaccine and do provide a immunity that basically prevents infections, or sterlizing immunity.

Few Side Effects

Another thing we want in a good vaccine is for it to have very few side effects. A vaccine that harms more people than the disease isn’t very smart. That’s why a few of the SARS-CoV-2 vaccine candidate trails have been stalled. They want to make sure that these vaccines aren’t causing more harm than good.

Our current vaccines don’t have a large incidence of severe adverse effects. Guillain-Barré is among the most serious, and it’s really similar to the cytokine storm syndrome we’ve been hearing about. It’s basically an overreaction of your immune system.

More common side effects are things like a mild fever or feeling a little sick. For me, my arm always hurts for a few days and I usually feel nauseous after the flu shot. I don’t consider that a big deal. That vague sick feeling is usually just your immune system turning on. It’s really not concerning, especially with a “killed” virus. I’ll write more about vaccine types in part 2.

If you have trouble breathing, wheezing, swelling or hives, that is not normal. Vaccines can rarely cause serious allergic reactions or other problems. We want to avoid vaccination in those severe cases. Luckily, some of our vaccines provide a mostly sterilizing type of immunity, so if Joey Jr. can’t get the pertussis shot but everyone else in his class does, Joey would be protected too. (Note: The pertussis vaccine isn’t sterilizing, meaning it doesn’t completely stop transmission. However, like most vaccines, it reduces transmission. The SARS-CoV-2 vaccine may too).

Easy to Administer and Store

Another thing we really want vaccines to be is easy to store, ship, and administer. That’s a supply chain issue, but it’s important for access.

Some of the SARS-CoV-2 vaccine candidates require unusual cold storage which means only limited clinics and pharmacies will be able to have them. Those clinics and pharmacies probably won’t be in underserved areas. We would prefer a vaccine that either needs normal refrigeration or none at all.

We want vaccines that are easy to administer and have a low barrier to effectiveness. Vaccines like the PPSV23 (for pneumonia) are pretty easy. You usually just need one shot and you’re done. That’s a pretty low barrier to effectiveness. We try to make sure everyone over 65 who is admitted into the hospital for anything gets their shot. They’re usually vaccinated for life after that. Vaccines like the influenza vaccine are more difficult because you have to get them yearly. Many vaccines, like the new shingles vaccine and the hepatitis vaccines, are a series where you have to get a shot and a booster or two for the best immune response. That can be tricky, especially in underserved areas and people with poor transportation and access. It’s common to forget or not have access to the booster.

Most of the SAR-CoV-2 candidates are going to require a booster. I think there’s currently one in phase 2 that is one shot, but chances are one of the boosted ones will be first to market.

For a new vaccine, there’s also a supply and demand issue for clinics and pharmacies. We’ve seen this with the shingles vaccine as well. Do you vaccinate everyone with the first in the series and hope for more stock in a few months (or whatever the time period will be) or do you set stock aside for the repeat dose? Most won’t set stock aside. What happens if you don’t have stock later? How far schedules can be pushed and still ensure a good immune response varies with the vaccine, and I doubt we’ll have that information for SARS-CoV-2 anytime soon.

In part 2, I’ll discuss the different types of vaccines and why would chose, say a vaccine made in chicken eggs over cell-cultured vaccine or a recombinant vectored vaccine.

COPD and Bronchitis

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Chronic obstructive pulmonary disease (COPD) causes a significant amount of morbidity and mortality. It’s the fourth leading cause of death in the world.

COPD produces anatomical changes in the lungs that lead to narrowing of small airways, destruction of lung tissue, overproduction of mucous, reduced ciliary function, and airflow limitation.

Smoking is the most common cause. Other risk factors include pollution, second-hand smoke, occupational exposure, and lead poisoning. Other factors include age, frequent respiratory infections as a child, and genetic factors.

Asthma is a disease of inflammation. COPD is a disease of obstruction. Goblet cells make mucous to get particles out of the lungs, but cilia are paralyzed and can’t move it out. The mucous obstructs the airway. That’s why we use steroids in asthma as the first line to reduce inflammation, but not in COPD. Patients with COPD tend to get worse as the disease progresses.

Diagnosis by pulmonary function testing. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines are the accepted guidelines.

  • Comorbidities: pneumonia, stroke, lung cancer, heart disease 
  • Chronic bronchitis usually degrades to emphysema with age.
  • Use Beta-blockers with caution (carvedilol is preferred)
  • Vaccinate for the flu and pneumonia, consider things like Tamiflu (oseltamivir) in this population
  • Consider smoking cessation.

Severity Scale:

A post-bronchodilator Fev1/FVC ratio of less than 0.7 (70%) confirms COPD. Patients are then classified as below.

  • Gold 1 (mild): Fev1 >=80% of predicted
  • Gold 2 (moderate): Fev1 between 50% and 79% of predicted
  • Gold 3 (severe): Fev1 between 30% and 49% of predicted
  • Gold 4 (very severe): Fev1 less than 30% of predicted

Remember, these are post-bronchodilator.

Assessment Tools:

  • CAT (COPD Assessment Test) is the best test to assess medications.
  • mMRC (Modified Medical Research Council dyspnea scale) is simple and not usually enough information. The scale is from 0 to 4 and assesses breathlessness
  • St George’s Respiratory Questionnaire (SGRQ) is too complex and not feasible in most clinical settings.
  • After assessment, use the ABCD tool to determine treatment
  • History of exacerbations is the most important factor in determining care.

ABCD Assessment:

Exacerbation HistoryPatient Symptoms mMRC 0-1 or CAT <10Patient Symptoms mMRC 2 or CAT >=10
<=1 moderate excerabation (no hospitlization)AB
>= 2 moderate exacerbations or >- 1 leading to hospitilzationCD
COPD Gold ScoreInitial Treatment Choices
AShort-acting bronchodilator (SABA – short-acting beta-agonist or SAMA – short-acting muscarinic-agonist or combo)
BLABA (long-acting beta-agonist) or LAMA (long-acting muscarinic-agonist)
CLAMA or LAMA plus LABA or ICS (inhaled corticosteroid) plus LABA (LAMA is preferred: See POET trial)
DLAMA or LABA (LAMA is preferred here too)
*If CAT score is super high (~20) can start with LAMA + LABA, if eosinophil count is above 300 um, consider LABA + ICS (eosinophils mean inflammatory processes involved)
All patients should have short acting bronchodilator for rescue.

Long-acting bronchodilators should be used in anyone in B or above because they are superior to short-acting bronchodilators. You can use two different classes if you need more control. LAMAs are superior to LABAs in some groups See POET trial. ICS have very little to no benefit in patients without eosinophilia. If blood eosinophilias are less than 100 cells/um, don’t use them.

Unlike asthma, patients need a SABA and/or SAMA for rescue therapy. COPD is obstructive, so you don’t really need to reduce inflammation as you do in asthma (that recommends an ICS + formoterol for rescue). You need to dry secretions and dilate airways. A combo like Combivent is better than either alone.

If the response to initial treatment is appropriate, maintain it. If initial treatment is not appropriate, you need to consider the treatable trait to target. GOLD has two: dyspnea and exacerbations. They are very similar.

Gold considers LABA + LAMA the best combo in most cases. See FLAME trial. LAMA + LABA was superior to LABA + ICS.

Escalation for Dyspnea:

Escalation for Exacerbations:

  • If on single long-acting bronchodilator (LABA or LAMA) and blood eosinophils are >300 cells/um or >100 cells/um and the patient has had at least 2 exacerbations or one hospitalization can change to LABA + ICS OR change to LABA + LAMA if they don’t meet the guidelines for ICS.
  • If on LABA + ICS, add LAMA or change to LABA + LAMA (especially if no indication for ICS)
  • If on LABA + LAMA, consider adding ICS if eosinophil count is >100 OR add roflumilast** if the patient has chronic bronchitis and FEVz <50% and eosinophil count <100 OR consider adding azithromycin if the patient is a former smoker* and eosinophil count <100
  • If on LABA + LAMA + ICS, consider removing ICS (especially if no indication for ICS) OR add roflumilast** if the patient has chronic bronchitis and FEVz <50% or R consider adding azithromycin if the patient is a former smoker*

    *Benefit is the greatest in patients who don’t currently smoke. Former smokers can be colonized with h.influenza, azithromycin has some anti-inflammatory effects too
    **Patients with a history of hospitalizations benefit most from roflumilast. Phosphodiesterase 4 inhibitor. COPD increases cyclic AMP levels. Decreases exacerbations, but no mortality benefit.

Corticosteriods in acute exacerbations only (not long term, bursts or acute).

This chart of medications can be found in the Gold Pocket Guide, Page 18

Acute bronchitis:

  • Usually caused by virus: rhinovirus, coronavirus, influenza virus, RSV
  • Can be caused by bacteria: mycoplasma pneumonia, chlamydia, pneumonia, bordetella, pertussis
  • Treatment:
    • Bedrest, increase fluids
    • APAP, NSAIDS, use cautions with antihistamines and decongestants (they increase the viscosity of secretions), dextromethorphan, codeine, Tessalon, and Tussionex
    • If flu, can give Tamiflu or Relenza (Relenza causes bronchospasm) within 48 hours of symptoms.

Asthma

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Asthma is pretty common. Over 25 million people in the US have it, and over 3500 people died from it in 2017. Hispanics and blacks suffer disproportionately. It’s a disease of chronic airway inflammation causing expiratory limitations including wheezing, chest tightness, shortness of breath, and cough. It can be spontaneous or triggered by exercise, allergens and irritants, or infections. Patients usually have more than one symptom. Isolated cough is usually not asthma. Exercise-related chest pain and shortness of breath need a cardiac workout.

Asthma is a disease of inflammation. COPD is a disease of obstruction. Goblet cells make mucous to get particles out of the lungs, but cilia are paralyzed and can’t move it out. The mucous obstructs the airway. That’s why we use steroids in asthma as the first line to reduce inflammation, but not in COPD.

The “Biodiversity hypothesis” states that exposure to microbes early in life provides protection against allergic and autoimmune diseases like asthma. Decreasing biodiversity is associated with increases in human immune disfunction.

Diagnosis is based on symptoms and pulmonary function tests and is most accurate before controller meds are initiated. Patients who have already been initiated should hold long-acting beta-agonists (LABA) for up to 2 days before PFTs and hold short-acting beta-agonists (SABA) for at least 6 hours. The FEV1/FVC ratio is a measurement of the amount of air you can forcefully exhale from your lungs. FEV1, or forced expiratory volume in one second, is the volume of breath exhaled with effort in that timeframe. FVC, forced vital capacity, is the full amount of air that can be exhaled with effort in a complete breath.

There are several different phenotypes of asthma: allergic asthma, non-allergic asthma, adult-onset asthma, asthma with persistent airflow limitation, and asthma with obesity.

Some guidelines break it into only two types: T-helper cell type 2 asthmas (Th2) and non-Th2. Th2 asthma is associated with poorer outcomes due to elevated immunoglobin. They also tend to have eosinophilia, elevated exhaled nitric oxide (FeNO), and more oral corticosteroid use. FeNo levels relate to eosinophils in the blood, but FeNO can be elevated for other reasons. Check for skin conditions like eczema first.

The Global Initiative for Asthma (GINA) recommends using FeNO >20 ppb as a factor when increasing ICS or considering a biologic. The American Thoracic Society (ATS) recommends using <25 ppb (20 for kids) as a determinant that eosinophilic inflammation is not likely. ICS response is less likely. A value of >50 ppb (30 for kids) means eosinophilic inflammation and ICS response are likely.

Asthma and COPD often overlap. They call this ACOS (asthma-COPD overlap syndrome). Here is a good pocket guide to the stepwise diagnose of all three syndromes.

The GINA guidelines are the most popular guidelines, but EPR-3 Guidelines are also used (I like this EPR-3 Pocket Guide).

GINA VS EPR-3

  • GINA has 2 treatment goals (risk reduction and symptom control), EPR-3 has 4 (reduce impairment, reduce risk of exacerbation, controlling symptoms, and preventing asthma-related death)
  • GINA has 5 treatment steps for 2 age groups (ages 5 and under and 6 and older), EPR-3 has 6 treatment steps for 3 age groups (0-4, 5-11, 12+)
  • GINA has 3 levels of severity, EPR-3 has 4
  • GINA favors formoterol as the long-acting beta-agonist (LABA) and requires lower doses of inhaled corticosteroids (ICS) than EPR-3.
  • In 2019, GINA changed to no longer prefer LABA-only rescue. They now prefer low-dose ICS plus formoterol (a LABA)
Levels of Control in EPR-3
ComponentsWell ControlledNot Well ControlledVery Poorly Controlled
Frequency of Symptoms<2 days/week> 2 days a week,
but less than daily		Multiple times
daily
Nighttime Awakenings<2 times a month1-3 times a week>4 times a week
SABA used<2 days a week> 2 days a weekseveral times
daily
Interferes with Normal Activitiesnoneminorextremely
limited
FeV1 / FVCnormalnormal or reduced <=5%reduced >5%
FeV1 % of normal> 80% normal60-80% normal< 60% of normal
Exacerbation requiring steroids0 or 1/yer>=2 / year >=2 / year
Recommended step of therapyStep 1 or
Maintain current step
Reasses in 1-6 month
Consider Step Down
If controlled for 3 mo		Step 2 or
Step up 1 step
Reassess in 2-6 wks		Step 3 and consider
oral steroids or
Consider oral steroids
step up 1 to 2 steps
Reassess in 2 weeks
Levels of Control in GINA
Well ControlledPartly ControlledUncontrolled
Daytime Asthma symptoms > 2
times per week, any nightime
symptoms, reliever needed
>2 times per week, any limits
on activity		None in past 4 weeks1 or 2 in past 4 weeks3 or 4 in past 4 weeks
Reasses in 2-3 months
Can step down if well
controlled		Step up one step
Reassess in 2-3 months		Step up
Reasses in 2-3 months
unless exacerbation, then
reassess in 1 week.

The preferred rescue inhaler is no longer albuterol with GINA 2019 (I know I already said this, but it flies against everything most of us were taught, so I’ll say it over and over again). An ICS formoterol combination is the rescue. Why formoterol? It takes 3-7 minutes to take affect (similar to albuterol). It’s a LABA (long-acting beta-agonist) that has the onset of a SABA (short-acting beta-agonist). You can’t just use any LABA as a rescue. It was also the studied drug.

Previously, it was believed that PRN LABAs could cause premature patient death. The SMART trial is responsible for this original black box warning. The AUSTRI (adults) and VESTRI (kids) studies showed no increase in asthma-related deaths. LABAs upregulate corticosteroid receptors and ICSes upregulate Beta receptors. They work synergistically (and that helps decrease steroid requirements). LABAs alone may cause Beta receptor downregulation. NO LABAs ALONE FOR ASTHMA.

Step 1:

GINA (Mild Asthma):

  • Low dose PRN inhaled corticosteroid (ICS) plus formoterol PRN or *Previous guidelines have not had PRN use of LABA.
  • Low dose ICS when SABA is taken
  • **You don’t schedule LABA until Step 3*** Controller is the same as rescue inhaler, everything is PRN.

EPR-3 (Intermittent):

  • SABA as needed

Step 2:

GINA (Mild Asthma):

  • Preferred rescue is ICS/formoterol still PLUS
  • Low dose ICS/formoterol PRN (same as step 1) OR
  • Low dose ICS alone OR
  • Leukotriene modifier OR
  • Low dose ICS when SABA is taken

EPR-3 (Mild Persistant):

  • Low dose ICS or
  • Leukotriene modifier
  • Theophylline
  • Cromolyn

Step 3:

GINA (Moderate Asthma)

  • Low dose ICS/LABA OR
  • Medium dose ICS OR
  • Low dose ICS + leukotriene modifier
  • Consider house dust mite sublingual immunotherapy for patients with allergic rhinitis and FEV1 >70% of expected
  • Preferred rescue is ICS/formoterol still, but you can use albuterol.
  • Patient shouldn’t be on two different ICS/LABA combos (ie: if you want to schedule a different LABA/ICS combo than ICS/formoterol, you would change the rescue inhaler to albuterol). You can use ICS/formoterol scheduled and PRN though.

EPR-3 (Moderate Persistant):

  • Low dose ICS + LABA or
  • Medium dose ICS or
  • Leukotriene modifier
  • Theophylline
  • Zileuton

Step 4:

GINA (Severe Asthma):

  • Medium dose ICS/LABA OR
  • High dose ICS (add on tiotropium or leukotriene modifier) *Tiotropium is only LAMA studied in asthma (bronchodilation and dries up secretions so more useful in COPD)
  • Consider house dust mite sublingual immunothearphy for patients with allergic rhinitis and FEV1 >70% of expected
  • Preferred rescue is ICS/formoterol still

EPR-3 (Moderate Persistant):

  • Medium dose ICS + LABA
  • Leukotriene modifier
  • Theophylline
  • Zileuton

Step 5:

GINA (Severe Asthma)

  • High dose ICS/LABA OR
  • Refer for phenotypic assessment (TH2 Asthma)
  • Can add add on tiotropium, anti-IgEm anti IL-5/5R, anti IL-4R
  • Consider low dose oral corticosteriods
  • Preferred rescue is ICS/formoterol still

EPR-3 (Severe Persistant):

  • High dose ICS + LABA
  • Consider omalizumab in patients with allergies

Step 6:

EPR-3 (Severe Persistant):

  • High dose ICS + LABA + oral steriods AND
  • Consider omalizumab in patients with allergies

Considerations when stepping up:

  • Inhaler technique. Is the patient getting their dose? Most MDIs must be shaken before use, pressurized MDIs require deep and steady inhalation, patients may breathe too slow or too fast or forget to hold their breath. Some inhalers are breath activated by they still require slow and steady inhalation. Spacers sometimes help. MDIs are just as effective as updrafts and offer fewer side effects. Watch the patient use the inhaler before stepping up. Consider switching types.
  • Adherence. Are they skipping doses?
  • Comorbidities (see below)
  • Overuse of SABA
  • Mood effects
  • Modifiable risk factors like smoking

Comorbities

  • GERD: some asthma medications (Beta-agonists and theophylline) worsen GERD leading to cough. Patients should be treated with PPI before stepping up.
  • Obesity: obese patients may have harder to control asthma due to lung strain and other comorbidities associated with obesity.
  • Sinusitis: Patients with T2 asthma tend to have sinusitis frequently. Treatment with nasal corticosteroids can help.
  • Pregnancy: Asthma worsens due to hormonal fluctuations during pregnancy. Budesonide is preferred in pregnancy. Pregnancy and asthma: Keeping vitamin D levels above 30 mg/mL decreases asthma risk in the fetus. Breastfeeding mothers should avoid broad-spectrum antibiotics during the first year of life.
  • Exercise-Induced Asthma: Patients should warm-up for 10-15 minutes, breathe through the nose, and use a facemask to create warmth and humidity to breathe.
  • Medications: NSAIDs can make asthma worse
  • Infections: Viruses like influenza can worsen asthma

Acute Asthma Exacerbations:

  • Steroids: no difference in oral vs IV – 80 mg of methylprednisone.
  • Magnesium sulfate if not responding to steroids (IV)
  • Racemic epinephrine either subQ or by nebulizer, use IV is not responding to initial albuterol.
  • Antibiotics are not usually given
  • Non-invasive ventilation with largest tube possible.
  • Step Down – Reduce steroid dose by 50% at 3-month intervals or switch to daily dose if on low dose.
  • Step Up – Increase ICS temporarily or add formoterol.
  • Exercise induced asthma: B-2 agonist, LABA for prevention
  • Use bronchodilator first and then ICS (open the bronchi for steroid)

Step Down

Once patient is controlled for 3 months of more, step down to see the lowest step where they remain control. You can decrease ICS dose by 25-50% every 2 to 3 months until they are back to step 1 or at the best level for the patient.

Medications:

GINA has moved away from SABAs (albuterol and levalbuterol) since SABAs do not reduce airway inflammation.

LABA:

  • formoterol
  • arformoterol
  • indracontrol
  • olodaterol
  • salmeterol

ICS:

You should probably be able to tell if an ICS dose is a low dose (all < 200) or high dose (all > 400) so you can recommend therapy changes.

Oral Corticosteroids: Oral corticosteroids should be the last option. Use 7.5 mg of prednisone equivalent or less for the shortest time possible.

Anticholinergics: Evidence shows that adding tiotripium to a ICS + LABA improves lung function and reduces exacerbations

  • aclindinium
  • glycopyralate
  • tiotropium
  • umeclidium

Leukotriene Modifiers: Useful in patients who can’t tolerate higher doses of ICS (maybe kids) or have allergic rhinitis. They can also help with exercise induced asthma.

  • montelukast sodium – Blackbox warning: suicidal ideations, mood changes.
  • zafirlukast
  • zileuton

Monoclonal Antibodies/Biologics: mostly reserved for patients with T2 Asthma, but can be used in step 4 and 5

  • expensive
  • Anti-IgE mAb for childhood-onset and allergen driven symptoms
  • Anti-IL-5/anti-IL 5R and anti-IL-4R for T2 type asthma
  • If patients don’t meet the criteria for a biologic or can’t afford one, adding tiotropium is an option.
  • Most common side effects are injection site reactions, headache, and antibody development.
  • Mepolizumab, benralizumab, and dupilumab can be given at home.

IgE:

  • Omalizumab (XOLAIR) inhibits IgE binding to receptors on mast cells and basophils.
  • Indicated in patients 6 years and older with moderate to severe asthma (can be used in child-onset).
  • Need a positive skin test to an allergen (looking for a specific IgE antibody and levels) and inadequate control with ICS.
  • Risk of anaphylaxis. It must be given in a health care setting. There is a slight increase in cardiovascular events associated with the drug, so screening is necessary.
  • Given every 2-4 weeks.

IL5/IL5RA:

  • Mepolizumab (NUCALA), reslizumab (CINQAIR), and benralizumab (FASENRA)
  • These target pathways that affect eosinophils, so are indicated only in patients who have elevated eosinophil count. Patients must have had an exacerbation in the past year and eosinophil count 300 per microliter of blood or more. Better responses if eosinophil count is higher or more exacerbations.
  • Better for adult-onset asthma and patients with nasal polyps present.
  • Mepolizumab can reactivate herpes zoster.
  • Benralizumab is only given every 8 weeks after 3 doses (others every 4 weeks)

IL4:

  • Dupilumab (DUPIXENT – also for atopic dermatitis) targets a receptor for two molecules that drive allergic inflammation. 
  • Indicated for moderate to severe uncontrolled asthma.
  • The Liberty Asthma QUEST trial foundThe most benefits was in the patients who needed maintenance oral corticosteroids.
  • They need eosinophil count > 150 ul, a least one exacerbation in the past year.
  • Can cause hypereosinophilia
  • Given every 2 weeks

COVID ONLY Caused 6% of Reported Deaths? That Headline Doesn’t Mean What You Think It Means.

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A few of my friends have been throwing around that the CDC “quietly” updated its statistics in the middle of the night, without telling anyone, to say that only 6% of COVID deaths were real. “All the other reported deaths were caused by PRE-EXISTING CONDITIONS.” I’m sure the CDC was dressed in black surrounded by the Illuminati while doing it. “They” don’t want us to know, so they removed President Trump’s tweet about it.

First of all, that’s not what the updated report says at all (and that’s why the tweet was removed). Secondly, it’s “in the middle of the night” with no press coverage because it’s not news at all. Let’s take a look. Everyone is referring to this passage on this page.

This passage is talking about the CDC comorbidity data. Comorbidities are common in pretty much every disease. It basically means medical conditions that are found together (maybe by coincidence, maybe not). Sometimes they can make things worse. Diabetes and heart disease make many infections worse. That’s pretty common. Here’s what a death certificate usually looks like.

This really is not news. This is how deaths have always been recorded, and how deaths should be recorded. When you die in a hospital, as opposed to at home, it’s unusual for your death certificate to say just one thing. Let’s say you have chronic obstructive pulmonary disease (COPD) and get admitted for the flu. Your flu turns into pneumonia and sepsis, and you end up dying from cardiac arrest. Everyone would concede that COPD was a contributing factor. Sepsis and cardiac arrest killed you. Would you have been alive today if you didn’t have COPD? Maybe so. The underlying condition is a pretty important factor in this case. We don’t want to leave it off. We also don’t want to write that you just died from “COPD.” That would be misleading. The COPD made you more prone to getting a serious infection in your lungs, but you probably would have been fine if you never had the flu. We usually say those people died from influenza pneumonia or sepsis complicated by COPD.

The same goes for HIV. HIV has never killed anyone if we go by the rules of the SocialMediaDocs. HIV doesn’t directly do damage to you. HIV just makes you a lot easier to kill. All of these opportunistic infections just can’t wait to kick you while you’re down. Do you die of HIV or cryptococcal pneumonia? It’s literally both. That cryptococcus (a fungus) could only infect you because you had HIV, but HIV wouldn’t have killed you if cryptococcus hadn’t paid a visit (it’s like a really depressing “Which came first?”). Both of them are really important factors.

And even then. . .

A lot of the “hot takes” I’ve been seeing on this are saying it shows that “healthy people are safe.” They don’t really understand what “underlying conditions” have been reported on death certificates. They think most of what the CDC is reporting are things like diabetes, COPD, hypertension, etc. I think it’s pretty horrible that people are willing to throw all of those people under the bus. However, that’s not what the CDC data is saying at all. The CDC lists the “underlying” conditions pretty plainly.

Let’s look at the top 10 things other than COVID that were listed on the death certificates:

  • Influenza and pneumonia
  • Respiratory failure
  • Hypertensive disease
  • Diabetes
  • Vascular and unspecified dementia
  • Cardiac Arrest
  • Heart failure
  • Renal failure
  • Intentional and unintentional injury, poisoning and other adverse events
  • Other medical conditions

I’ve bolded a few that COVID or treatment for COVID actually can cause (pneumonia and respiratory issues were the number 1 comorbid conditions). I could have probably bolded vascular and unspecified dementia too. There has some been association with COVID induced hypercoagulability and that, but since the connection is a bit tenuous, I didn’t.

When someone is admitted to the hospital for COVID, we usually admit them for “COVID Pneumonia” or respiratory distress. It’s amazing to me that 6% of people died without pneumonia on their death certificate. They usually ultimately die from “cardiac arrest” or “respiratory failure.” These are the outcomes that COVID causes, not underlying conditions (the CDC calls them comorbidities). It’s not “shocking.” The Illuminati can go home. Sorry guys.

I did look up “Intentional and unintentional injury, poisoning and other adverse events” because that one seemed weird. There isn’t a whole lot of data from the CDC, but it’s probably people who were admitted for something like an accident or illness and ended either being positive upon admission or contracting COVID while in the hospital and then progressed to COVID pneumonia. It’s not George who got hit by a truck and somehow gets COVID on his death certificate.

I’m not saying there aren’t some rogue data. I’m sure a George somewhere is reported as having died from COVID (I’ve been shown this article about a million times now). I’m just saying, this is not news. This is nothing to change our behavior. This doesn’t change the severity of COVID at all, even for healthy people.

I’m glad the Facebook-certified infectious disease specialists don’t keep as close an eye on flu data. Flu burden is a wild estimate compared to this. Our data here is pretty solid.

Clostridium/Clostridiodes Difficile

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Clostridiodes difficile
Clostridiodes difficile

Clostridiodes difficile is a pretty big problem, causing quite a bit of morbidity and mortality every year, and it’s becoming more and more common. It can be pretty tricky to treat. C. diff is an anaerobic, spore-forming rod and it makes a toxin that contributes to the severity of the disease. It causes diarrhea and can end up in toxic megacolon/fulminant colitis requiring bowel resection, complete removal of the colon, or causing death. It contributes to tens of thousands of deaths a year.

Risk Factors:

  • Exposure to Antibiotics: This is the biggest risk factor. The ones that cause it the most are CLINDAMYCIN, FLUOROQUINOLONES, CARBAPENEMS, and 3RD or 4th GEN CEPHALOSPORINS. Even one dose in the past 8 weeks seems to increase risk. Exposure to more than 1 antibiotic increases risk.
  • Hospitalization (especially longer stays)
  • Age over 65
  • Cancer
  • IBD
  • Kidney Disease
  • Organ transplant
  • Liver disease
  • Immunodeficiency
  • Exposure to proton pump inhibitors

It’s not recommended to test everyone with diarrhea. You should only test patients with unexplained and new-onset ≥3 unformed stools in 24 hours who have risk factors. If you use screening criteria such as this, a nucleic acid amplification test (NAAT) is fine. Otherwise, you want to a multistep algorithm for testing (ie, GDH plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) rather than a toxin test alone. See the SHEA guidelines for treatment and testing.

C. diff is spread via the fecal oral route. Alcohol based cleaners don’t remove the spores. You need soap and water and a thorough hand cleaning.

Disease Severity:
Non-severe: WBC <= 15,000 and SCr < 1.5
Severe Disease: WBC 15,000-20,000 or more or SCr > 1.5
Fulminant: Presence of shock, hypotension, ileus or megacolon

Treatment Depends on Disease Severity.
It’s important to note that metronidazole used to be first-line therapy. It has fallen out favor in the 2017 guidelines. Vancomycin is considered the drug of choice, with some exceptions, now. Also, treatments used to be recommended for 14 days, however now most are only recommended for 10 days.

  • Discontinue therapy with the inciting antibiotic agent(s) as soon as possible.
  • First Episode:
    • Non-severe
      • vancomycin 125 mg PO four times a day for 10 days OR
      • fidaxomicin 200 mg PO BID for 10 days OR
      • metronidazole 500 mg PO TID for 10 days (only if other two aren’t available)
    • Severe
      • vancomycin 125 mg PO four times a day for 10 days OR
      • fidaxomicin 200 mg PO BID for 10 days
    • Fulminant
      • vancomycin 500 mg PO four times a day AND 500 mg metronidazole IV every 8 hours for 10-14 days
  • First recurrence
    • If previously treated with metronidazole: vancomycin 125 mg PO four times a day for 10 days
    • If previously treated with vancomycin:
      • vancomycin 125 mg PO four times a day for 10 days THEN taper vancomycin 125 mg BID for 7 days then daily for 7 days, vancomycin once every 2-3 days for 2 to 8 weeks OR
      • fidaxomicin 200 mg PO BID for 10 days
    • Consider adding bezlotoxumab 10 mg/kg IV one time dose to any of the above
  • Second or third recurrence
    • vancomycin 125 mg PO four times a day for 10 days THEN taper vancomycin 125 mg BID for 7 days then daily for 7 days, vancomycin once every 2-3 days for 2 to 8 weeks OR
    • vancomycin 125 mg PO four times a day for 10 days THEN rifaximin 400 mg BID for 20 days
    • Consider fidaxomicin if not already given (fidaxomicin 200 mg PO BID for 10 days)
    • Fecal transplant is an option
    • Consider adding bezlotoxumab 10 mg/kg IV one time dose to any of the above

Bezlotoxumab is a newer agent. It’s a monoclonal antibody that neutralizes the toxin produced by C. diff. It can prevent damage to the colon, but it should not be used alone as treatment.

Fecal transplants are only reccomennded for those who have 2 or more reoccurances. Enemas are less effective than capsules or NG administration.

Proton Pump Inhibitors: The SHEA guidelines state: “Although there is an epidemiologic association between proton pump inhibitor (PPI) use and CDI, and unnecessary PPIs should always be discontinued, there is insufficient evidence for discontinuation of PPIs as a measure for preventing CDI.” Histamines receptor antagnoists have less association with C. diff.

Prophylaxis with vancomycin has been recommended in past guidelines, but the 2017 guidelines say there is insufficient evidence to recommend routine prophylaxis.

Dissecting a Study: Is Wearing a Neck Gaiter Worse Than no Mask at All?

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If anything, the 2020 coronavirus pandemic has shown us that we don’t do a good job at interpreting medical literature. I expect news outlets to get the headlines wrong. They always do. Eating chocolate cake for breakfast isn’t going to make you lose weight. Drinking 8 glasses of wine a day won’t make you look younger (it might make you care less about the way you look). The media’s job is to grab your attention with a flashy headline. They’re good at that. They aren’t so good at dissecting studies. It’s often not the scientists’ fault. They weren’t even trying to make the same conclusion as the headlines are.

The latest one is a face mask study from Duke University. The headline claims “Wearing a neck gaiter may be worse than no mask at all, researchers find.” I think it’s a fine study, but it doesn’t say what you might think it says. Let’s go through the steps I usually take when I see a study quoted in a pop-science article.

1. Find the Source

Most of these pop-science articles are based on a real study of some kind. Sometimes the article links the source directly. Often, the sources are tricky to find. Pop-science press often says things like “A study done out of John Hopkins found. . .” They don’t always mention the author’s name or the name of the study. If you’re familiar with PubMed you can usually find it. Sometimes, especially during the pandemic, the “studies” are actually preprints and they can be harder to find (preprints.org, https://www.medrxiv.org/ are two good places to look for health sciences, I’ll list some more at the bottom). Sometimes, I have to bounce around to a few different media takes on the article to get enough information to find it. You can always just email the journalist and ask too. They are usually happy to help (and it’s not always the journalist that writes the headline). In this case, the mask article was published in Science Advances and is free to read: https://advances.sciencemag.org/content/early/2020/08/07/sciadv.abd3083

2. Find the Question the Researchers were Answering

Every study has a thing it’s looking for. Sometimes the researchers find other interesting things along the way, but they all have one thing they set out to find. Those other things are usually not as significant as the main thing they were looking for. Is the thing they are looking for the same thing the headline claims? Let’s look.

The headline claims “Wearing a neck gaiter may be worse than no mask at all, researchers find.” That seems like the question was, “Which face masks are more effective”, “Are neck gaiters effective?” or maybe even “What is the relative efficacy of different face masks.” Let’s see if this study was designed to answer a question like that.

In the introduction, the authors write (emphasis mine):

“While some textiles used for mask fabrication have been characterized, the performance of actual masks in a practical setting needs to be considered. The work we report here describes a measurement method that can be used to improve evaluation in order to guide mask selection and purchase decisions”

“Below we describe the measurement method and demonstrate its capabilities for mask testing. In this application, we do not attempt a comprehensive survey of all possible mask designs or a systematic study of all use cases. We merely demonstrated our method on a variety of commonly available masks and mask alternatives with one speaker, and a subset of these masks were tested with four speakers. Even from these limited demonstration studies, important general characteristics can be extracted by performing a relative comparison between different face masks and their transmission of droplets.”

That doesn’t really sound like the question the headline was answering. It sounds to me like they are testing the testing method, right? Their question seems to be more like, “Is our method a valid method for evaluating masks?” Let’s see what their method and design were. We can see if the study would be adequate to answer the headline question from that.

They had someone wear a face mask and speak into the laser beam in a dark enclosure. They recorded the light scatter from the droplets with a cell phone camera. They tested 14 types of masks. Some masks were tested by only one person. Four masks (a cotton mask, a surgical mask, a bandana, and the control group of no mask) were tested by four speakers.

They don’t compare material weave or fit (but the N95 they used was fit tested). They do discuss that the fleece neck gaiter transmitted a larger number of droplets than the control trial (though not significantly larger). They think gaiters disperse larger droplets into several smaller droplets, therefore increasing the droplet count. That’s where the headline “Wearing a neck gaiter may be worse than no mask at all, researchers find” comes from.

I’m not sure that one speaker and one neck gaiter have me convinced. This study really isn’t designed to tell us that. It tells us maybe we need to do some more tests on that type of mask before we recommend it. That what these other findings usually do. They tell us, “Maybe we should look into that.”

3. Look At the “Power” of the Study

There are things that biostatisticians look at: was this the right study design for the problem, did they pick the appropriate statistical test, are they calculating the right p-value, was there a type-1 or type-2 error. Those are things you should consider if you’re making a medical judgment off the study (see my biostatistics section for some basic tips). However, if you’re just trying to learn about a topic, you can get a good estimation of what we call the study’s power without even knowing what test they should have chosen.

Technically, power is the probability of rejecting the null hypothesis when, in fact, it is false. I know, null what? It’s just asking if your study is good enough to pick up a difference between two groups if there is a real difference between those groups. The biggest tip-off is usually the sample size. If I have 100 people and I give 50 people a Tylenol and 50 people a cube of sugar, I have a better chance of picking up a side effect from the Tylenol than if I had only 10 people and gave 5 people a Tylenol. With 1000 people, I’d have an even better chance. Just because I didn’t pick up a side effect in those 10 people, doesn’t mean that one doesn’t exist. I could miss even a significant side effect if my sample was too small.

The sample size here was four speakers on four masks and one speaker on 14 masks (the gaiter only had one speaker). I’d say it’s a pretty small sample to make any real decisions.

Here’s a fun one to look at to do this quick and dirty estimation of power. This has been highly circulated as “proof” that asymptomatic patients don’t spread coronavirus: A study on infectivity of asymptomatic SARS-CoV-2 carriers. It’s also free to read. So, do we think this study is powerful enough to “prove” that claim?

This one is pretty easy. I saw someone claiming the study had 455 participants. If you just quickly read the abstract, you might think so too. If you read the paper, you’ll see that they followed ONE person. Just one. One asymptomatic person was contacted traced to 455 people (who has that many friends and family? Some of them were at the hospital the patient was at) and didn’t transmit it to any of them. To me, that isn’t even close to adequate enough to say no asymptomatic carriers spread coronavirus (and the study authors don’t claim it is, it’s a case study). Can you find another interesting thing about the study that the headlines leave out?

The patient, and pretty much everyone else, wore a mask when they made contact. That’s neither here nor there, but I’ve seen media report this story and leave that out. Those extra, possibly significant, tidbits are things to look out for too.

4. Is it significant to you?

If this study had 455 participants, we might have had to look a little deeper. I like to look at the study population in that case for a quick and dirty, no maths, check. Are they like my patients? Were they all 20-year old males? Did they have something else in common (like were they all wearing masks)? Sometimes study designs are aimed at a specific population. They may have shown a significant difference to that population, but those results might not apply to everyone. That’s often the cause with conflicting studies. The conclusions are different because the populations were different.

In this particular study, we can look at the way droplets were detected and the characteristics of the one speaker. The one speaker that tested all the masks spread significantly more droplets than the other speakers. Could that impact the data? How does that speaker compare with most of us? Does the average person spread like the speaker who tested all masks or more like the speakers who tested just the four?

As for the measurement, the study only looked at the number (and somewhat size, but not really) of the droplets, and not how far or in what direction they spread. That information is probably important.

5. Is there prior data?

If want to take your search a bit further, you can see if there is prior data to support or detract from this study. A study done in June had data demonstrating that, while bandanas (similar to gaiters) let more droplets through, they spread less than 4 feet, while uncovered faces spread droplets 8 feet. That study has some limitations too, but that’s probably important information to consider.

6. Is there missing data?

What else would we need to make the claim that gaiters were worse than nothing at all? I think you probably need to know more about the fabric. They don’t talk much about the fabric weave tightness or how the various fabrics compare. In order to adequately test a hypothesis that gaiters are worse than nothing at all, you would have to test a wide variety of gaiters of popular fabricks. Gaiters come in all of kinds of weaves. In order to test a hypothesis that the style is worse than other masks, it would be best to try masks with the same fabric type and weight. Maybe the “cotton” style would show worse results when made with the gaiter fleece. We don’t know if it’s the fabric, the style, or the speaker.

7. What do you do?

With all that information, you can now decide what to believe. Do I believe neck gaiters are worse than no mask at all? I think they are probably better than nothing, but they may not be the best protection. We need more data. That’s why places like Disney have banned them for use in the parks. I personally would feel comfortable wearing one in a situation where I thought I would be able to adequately social distance, but thought I might occasionally come in contact with people (like running in the park). I would not wear one in a situation where I thought I would have occasion to come in contact with more people (like in Wal-Mart), but that’s just me. The great thing about actually looking at the data this way is that you can be fully informed to make your own choices.

Preprint Servers

https://preprints.org – general
https://www.medrxiv.org/ – medical
https://therapoid.net/ – life science
https://mindrxiv.org/ – mind and contemplative practices
https://psyarxiv.com/– psychological
https://osf.io/preprints/focusarchive– ultrasound
https://osf.io/preprints/nutrixiv – nutrition
https://www.sportrxiv.org/ – sports and sports medicine
https://www.biorxiv.org/ – general biology
https://arxiv.org/ – mostly physics, computing, etc
https://peerj.com/preprints/ – biomedical sciences
https://figshare.com/ – all sciences

BCPS Notes

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Anything marked BCPS are my BCPS study notes that I try to keep updated (I update a new section every few months).  That being said, some of the data is not up to date and it should not be used for clinical purposes.  I thought I would make it public because it might help someone out!

All of these, with a few referenced exceptions, came from my handwritten notes. I digitized them when I went back to update some of them because updating handwritten notes is hard. I combined and compiled a lot of different sources to get the info I wanted to remember, including guidelines and materials from the ASHP and ACCP. I don’t have the sources for the notes. They are presented as-is with no warranties.

BCPS Study Guide Index

Common Pharmacogenomic SNPs and Interactions

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UM = ultrarapid metabolizer, EM = extensive metabolizer, IM = intermediate metabolizer, PM = poor metabolizer

Drug SNPTypesEffectRaceMisc 
IvacaftorCFTR     
amitriptylineCYP 2C19UM (R), EM, IM, PMPM = increased conc, side effects, UM = decreased concenPM =Common in Asians UM=Common in CaucasionsUM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity score 
citalopramCYP 2C19UM (R), EM, IM, PMPM = increased conc, side effects, UM = decreased concenPM =Common in Asians UM=Common in CaucasionsUM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity score 
escitalopramCYP 2C19UM (R), EM, IM, PMPM = increased conc, side effects, UM = decreased concenPM =Common in Asians UM=Common in CaucasionsUM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity score 
PlavixCYP2C19UM (R), EM, IM, PMProdrug – PM have decreased levels, UM have increased drug levelsPM =Common in Asians UM=Common in CaucasionsIM and PM should use alternative. Prasugrel is a prorug, but not CYP related.  Ticagrelor is not prodrug. 
SSRIsCYP2C19UM (R), EM, IM, PMPM = increased conc, side effects, UM = decreased concenPM =Common in Asians UM=Common in CaucasionsUM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity scoresee specific drugs
TricylicsCYP2C19UM (R), EM, IM, PMPM = increased conc, side effects, UM = decreased concenPM =Common in Asians UM=Common in CaucasionsUM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity scoresee specific drugs
PPICYP2C19UM (R), EM, IM, PM PM =Common in Asians UM=Common in Caucasions  
voriconazoleCYP2C19UM (R), EM, IM, PM New Terms: Plasma 3-4 times higher in PMS compared to Ems.  UM may have sub-thera levels (not as clear)PM =Common in Asians UM=Common in Caucasions2C19 polymorphism explains 50% of the variability. Adult specific and peditric specifif tables for this one.  NTI. Exposure can cause hepatotoxity, visual distburances, neurological side effects, etc.Also 2C9 and 3A4.  (Ultra rapid, Rapid (this has been split into two groups now, one is homozygous and one is not), Normal Metabolizer, Intermediate Metabolizer, Poor Metabolizer).  must still monitor drugs.
WarfarinCYP2C9EM, IM, PMIM and PM associated with lower dosesSome variants more common in AAdosage calculators available 
PhenytoinCYP2C9EM, IM, PMIM, decrease dose, PM decreased morePM= Mostly caucasiun Phenytoin needs 2 tests.  EM as usualy, IM decrease by 25%, PM decrease by 50%.   
PhenytoinCYP2C9EM, IM, PMEM as normal, IM = 25% of dose, PM 50% of dose Phenytoin needs 2 tests 
NSAIDsCYP2C9EM, IM, PM    
GlyburideCYP2C9EM, IM, PM    
SSRIsCYP2D6UM, EM, IM, PMUM =decreased concentrations, PM = increased concentrationsPM= Mostly caucasiun UM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity scorewatch for 2d6 inhibitors, see specific drugs
TricylicsCYP2D6UM, EM, IM, PMUM =decreased concentrations, PM = increased concentrationsPM= Mostly caucasiun UM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity scorewatch for 2d6 inhibitors, see specific drugs
nortriptylineCYP2D6UM, EM, IM, PMUM =decreased concentrations, PM = increased concentrationsPM= Mostly caucasiun UM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity scorewatch for 2d6 inhibitors
amitriptylineCYP2D6UM, EM, IM, PMUM =decreased concentrations, PM = increased concentrationsPM= Mostly caucasiun UM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity scorewatch for 2d6 inhibitors, also applies to imipramine and desipramine too
paroxetineCYP2D6UM, EM, IM, PMUM =decreased concentrations, PM = increased concentrationsPM= Mostly caucasiun UM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity scorewatch for 2d6 inhibitors
fluvoxamineCYP2D6UM, EM, IM, PMUM =decreased concentrations, PM = increased concentrationsPM= Mostly caucasiun UM – Avoid or lower dose, IM/EM same, PM avoid or start at 50% dose.  Must calculate activity scorewatch for 2d6 inhibitors
CodeineCYP2D6UM, EM, IM, PMProdrug, PM – lower concentration, UM = higherPM= Mostly caucasiun Beware of adding 2D6 inhibitors.Must calculate activity scoreDo not use in breastfeeding moms with known CYP2D6 UM.  Can harm baby.  Alternatives: morphine, non-opiod
tramadolCYP2D6UM, EM, IM, PMProdrug, PM = decresed response, UM = increased response and adverse effects.PM= Mostly caucasiun UM – Avoid, EM – As usual, IM – Consider alternative if it doesn’t work, PM avoid. Not as much evidenceDo not use in breastfeeding moms with known CYP2D6 UM.  Can harm baby.  Alternatives: morphine, non-opiod
hydrocodoneCYP2D6UM, EM, IM, PMProdrug, PM – lower concentration, UM = higherPM= Mostly caucasiun UM – Avoid, EM – As usual, IM – Consider alternative if it doesn’t work, PM avoidDo not use in breastfeeding moms with known CYP2D6 UM.  Can harm baby.  Alternatives: morphine, non-opiod
oxycodoneCYP2D6UM, EM, IM, PMProdrug, PM – lower concentration, UM = higherPM= Mostly caucasiun UM – Avoid, EM – As usual, IM – Consider alternative if it doesn’t work, PM avoidDo not use in breastfeeding moms with known CYP2D6 UM.  Can harm baby.  Alternatives: morphine, non-opiod
CodeineCYP3a4   not as much evidencealternatives: morphine, non-opiod
tegafurDPYDNormal, intermediate or low functionIM – increased conc, Low – much increased concen Normal – label recs, IM – decrase dose by 50%, titrate based on toxicity, low – DO NOT USEDPYD metabolizes to inactive form
5-FUDPYDNormal, intermediate or low functionIM – increased conc, Low – much increased concen Normal – label recs, IM – decrase dose by 50%, titrate based on toxicity, low – DO NOT USEDPYD metabolizes to inactive form
capecitabineDPYDNormal, intermediate or low functionIM – increased conc, Low – much increased concen Normal – label recs, IM – decrase dose by 50%, titrate based on toxicity, low – DO NOT USEDPYD metabolizes to inactive form
RasburicaseG6PD     
CarbamazepineHLA-B 15:02Not metabolism relatedPresence of 15:02=increased risk for TENS/SJS. Primarly in Asian or HAN Chinese, Vietnam, Cambodia, Runion Island, India, Hong KongDo not rechallenge. Do not initiate.  Should be pre-screened.  Also avoid phenytoin, fosphenytoin, oxcarbazepine, eslicarbazepine, lamotrigine 
PhenytoinHLA-B 15:02Not metabolism relatedPresence of 15:02=increased risk for TENS/SJS. Primarly in Asian or HAN Chinese, Vietnam, Cambodia, Runion Island, India, Hong KongDo not rechallenge. Do not initiate.  Should be pre-screened.  Also avoid phenytoin, fosphenytoin, oxcarbazepine, eslicarbazepine, lamotrigineAlso avoid phenytoin, fosphenytoin, oxcarbazepine, eslicarbazepine, lamotrigine
AbacavirHLA-B 57:01Not metabolism relatedPresence of 57:01=increased risk for TENS/SJS. Mostly in Southwest AsiansDo not rechallenge. Do not initiate.  Should be pre-screened.   
AllopurinolHLA-B 58:01Not metabolism relatedPresence of 58:01=increased risk for TENS/SJS.    
SimvastatinSLOCO1B1Normal, intermediate or low functionLF = decreased effect, increase side effects Not all statins are equally affected. OATP1b1 is affected. 
repaglinideSLOCO1B1Normal, intermediate or low functionLF = decreased effect, increase side effects Not all statins are equally affected. OATP1b1 is affected. 
ThiopurinesTPMTNormal, intermediate or low functionTPMT inactives drug Nm = normal dose, 2 week steady state, intermediate = 30-70% of dose, 2-4 weeks for SS, Low = 90% of dose, only three times a week, 4-6 weeks for steady state. Only use for low if malignency.inherited
AtazanavirUGT1A1     
WarfarinVKORC1decreaseddecreased mean less warfarin needed Vitamin K epoxide reductase 
       
Ondansetron CYP2D6UM, EM, IM, PMUM  decreased concentration UM should consider another choicegranisetron not metabolized by 2D6. Tripisetron is
TamoxifenCYP2D6UM, EM, IM, PMActive metabolite. PM have poorer drug response, less active metabolite.  Not as straight forward. No CPIC guideline. Don’t recommend testing as a tool.Dutch Working Group recomends in relapse. Level A on CPIC.  Most likely relevalent only postmenopausal women with ER-positive breast cancer deciding between aromatse inhib and tamoxifen.
ThiopurinesNUDT15Normal, intermediate or low function Asians and hispanics Low = 90% of dose 
IrinotecanUGT1A1UGT1AT*28decresed metabolism, increased accumulation and toxicity

Pro-drug, SN38 active metbolite inactivated and detoxified by a UDP-glucuronosyltransferase 		 No recs from CPIC.  May be pertinent to genotype in high dose (>240 mg/m2) situations. Watch neutrophil count7 TA repeats instead of 6 TA repeats. Homozygotes – Joubert’s syndrome

This chart was designed by Amanda Galiano, PharmD.
Sources: https://cpicpgx.org/ (CPIC Gudelines), https://www.pharmgkb.org/ (PharmGKB)