Are You Really Allergic to Penicillin?

They say that the new year is a good time to express gratitude. So here’s what I’m most grateful for right now: my health. For much of last year, I was sick. It started in the spring with a cough that turned into a respiratory infection that turned into a whole other thing, and for a few months, I was miserable. It hurt to talk or swallow; every time I laughed, it would trigger a coughing fit, which is a problem because I like to laugh. Thanks to the cough, I couldn’t sleep through the night; I also had some ferocious night sweats and crazy dreams. During the day, my entire body ached, like I’d been hit by a car. Also, no appetite and no energy. Physically, it was the worst few months of my life. But at least I got a story out of it — this one. Today’s episode is about penicillin. You may remember the famous story of how penicillin was discovered, accidentally, nearly 100 years ago by Alexander Fleming. This was at St. Mary’s Hospital in London. Fleming was just returning from holiday; in his lab, he had left behind a petri dish where he had been culturing bacteria, and he found some mold growing in the dish. Interestingly, where the mold grew, the bacteria did not. It turned out that this “mold juice,” as Fleming called it, could kill many of types of bacteria, not just the one growing in that petri dish.

Penicillin was eventually used to treat strep throat, meningitis, dental infections, gonorrhea, and much more; it came to be thought of as something like a miracle drug. The penicillins are in fact a family of antibiotics, including amoxicillin, ampicillin, methicillin, and several others. All these years later, they are still among the safest, cheapest, and most reliable drugs around; they have saved hundreds of millions of lives. Even with all the new antibiotics since then, penicillin is still prescribed at the highest rate of any antibiotic. But there is one big problem: 10 percent of Americans, more than 30 million people, are allergic to it. At least that’s what the conventional wisdom says. But the new year is also a good time to tear down conventional wisdoms, especially if they are disastrously wrong. And this one is. So, today on Freakonomics Radio, why do so many of us think we have this allergy?

Elena RESNICK: Huh, this patient told me they were allergic to penicillin. “Oh, it’s that your mom told you when you were a kid. Well, what happened? Oh, you don’t even know what happened?”

What should be done about all these false positives?

Kimberly BLUMENTHAL: We should be screaming from the rooftops. This is a misdiagnosis. 

And what about all the other allergy controversy we hear about, like food and environmental allergies? How bad is the confusion there?

Theresa MACPHAIL: It’s bad. It’s one of the reasons I can’t tell you how many people actually have an allergy.

What can we tell you? A lot. Starting now.

*      *      *

Okay, here is the startling fact that I recently learned. While it is true that around 10 percent of Americans believe they are allergic to penicillin, fewer than 1 percent actually are. How can there be such a huge gap? And what are the costs of that gap — the medical and economic and social costs? Those are some of the questions we’ll try to answer today, starting with this new friend of mine.

RESNICK: Elena Resnick. I’m an allergist and immunologist.  

DUBNER: And how does one get interested in allergy and immunology?

RESNICK: I always knew I wanted to be a doctor. My dad’s a doctor, and there was never any doubt about that. I was lucky to have a lot of great mentors along the way. My mentor in college, Jerry Groopman, who’s up at Harvard, was very instrumental in my choices. I worked in his lab for four years, applied to medical school, thought I wanted to be a hematologist-oncologist like him, explored that field. And later into my residency, I explored allergy immunology, which has fascinating medicine and amazing potential to make people feel better. 

DUBNER: Give me a little bit of fascinating medicine. I find almost every branch of medicine pretty fascinating, in part because there is so much mystery still. I mean, as much as we’ve learned, there’s still so much that we don’t know. So what was it that really got you hooked there? 

RESNICK: The immune system in particular is fascinating, because we know so little about it. It’s so important, right? We need our immune system to protect us from disease and to fight things off. When it goes haywire, we can end up with autoimmune disease, which is where our own antibodies attack us, or we can end up with allergic disease, which is when different types of antibodies, IgE antibodies, react against substances that are harmless but if we make antibodies against them, we can run into big trouble. 

DUBNER: Define IgE for me.

RESNICK: IgE is immunoglobulin E. It’s an immunoglobulin that’s made by B cells. It probably had more of a function evolutionarily in terms of fighting off parasitic disease, etc. It certainly was not evolutionarily made to react to peanuts and pollens. But we don’t know why in some people those types of antibodies are made that are specific against harmless substances.  

Peanuts and pollens, milk and eggs, soybeans and shellfish — these are just a few of the most prominent allergies that tens of millions of people report today. Like Resnick says: “harmless substances” — for most people — that cause allergic reactions in some. Given the magnitude of allergies, especially in the U.S. you might think that there are a million Elena Resnicks out there. But she is one of just 5,000 allergists in the U.S. If you need an anesthesiologist, there are more than 40,000. If you need a pediatrician, there are 60,000. But I needed an allergist, and Elena Resnick was the one that my primary doctor sent me to. Here’s what happened. Like I said earlier, I got sick last year. It started with a dry cough that wouldn’t go away. So I went to my primary doctor, who I’ve been seeing for years. Her name is Rebecca Kurth. I love Dr. Kurth: she is very smart, a true scientist. She’s determined and methodical, but also a friend and an ally. She has taught me to be vigilant about my health without being paranoid, which I think is a good middle ground.

There was one thing she’d been wanting me to take care of for a while, but I never did. My medical history says that I am allergic to penicillin. The first time I saw her, she asked, “How do you know?” And I told her the story that lives in my memory — that I’ve been allergic since I was a little kid, based on what my mother told me, which was based on what our family doctor told her. And that’s when Kurth told me that this kind of story is very common, but that the vast majority of people who think they’re allergic to penicillin are in fact not. So at some point — this was still years ago — Dr. Kurth told me I should try to get my penicillin allergy “cleared.” This was the first I’d ever heard of being “cleared” of an allergy; it’s also called being “delabeled.” Way back then, she gave me Elena Resnick’s phone number. But I never called. It just seemed like a hassle — time-consuming and expensive. And I didn’t see why getting cleared for penicillin was a big deal, since there are so many modern antibiotics. So I did not go see the allergist back then. Fast forward to 2024, and here I was, sick with a cough that wouldn’t go away. Dr. Kurth gave me what’s called a Z-Pak, or azithromycin; that’s a short course of antibiotic that’s used in a variety of cases, especially for patients allergic to penicillin. The Z-Pak didn’t help. I got sicker, the cough got worse. I went to a radiologist and had a lung scan to look for cancer. No cancer. I began to wonder what would happen if I could take penicillin. Would it fix me? Or would it maybe kill me? There is a scary-sounding word we all think of when we think about allergies: anaphylaxis. Here’s Elena Resnick again:

RESNICK: It’s the most serious type of IgE-mediated allergic reaction, where the allergy cells explode, they release all sorts of mediators, histamine, tryptase, etc., and that causes your vessels to vasodilate. Fluid runs in, people get hives, people get swelling, people’s throat closes up, or you have difficulty breathing.   

DUBNER: So what’s happening when you die from anaphylaxis? Your airway is basically constricted?

RESNICK: Exactly. Your airways constrict, and because the vessels all over the body are dilating, your blood pressure drops. You can’t get blood back up to your heart, and you have a cardiac arrest.

DUBNER: So, what share of people in the U.S., let’s say, who believe that they are allergic to penicillin are, in fact, allergic to penicillin? 

RESNICK: The studies show that 90 percent of people who believe that they are allergic to penicillin actually can tolerate it. 

DUBNER: So that sounds absurd, obviously, that so many people are walking around with this false belief about themselves. Are there any similar wrongly-held beliefs in medicine that you can think of? 

RESNICK: Oh my gosh, I don’t know that I can think of any. I think that the vast majority of people either have or were told that they had some sort of reaction in childhood, so that is the most common history.

DUBNER: The story that I told myself my whole life when I was thought to be allergic to penicillin was, well, you know, medical research has been so amazing that there are all these other drugs, and penicillin, or the class of drugs called penicillin, it doesn’t really matter if I can’t have access to them. How wrong was I in that assessment? 

RESNICK: I think you are 100 percent wrong, I’m sorry to say. The other drugs, we’re so lucky to have them, but many of them have much more severe side-effect profiles than penicillin does. They can have more serious complications. They’re much more expensive. And in certain cases — for example, vancomycin — they can actually increase the risk of drug-resistant bacteria. 

So you can see the problem here. A lot of people who could benefit from penicillin think they’re allergic to it, and that they might die if they take it. The vast majority of them are not allergic, but many of them don’t even think to get cleared, and doing so takes some effort. It starts with what’s called a prick test. Elena Resnick again:

RESNICK: How do we do that? So, every good experiment has a control, and the controls that we use are saline, which is salt water — nobody’s allergic to that — and histamine, which is the body’s allergic chemical. So we prick you, and when I say prick, I mean we clean off the forearm, and then we use tiny needles to introduce just under the surface of the skin saline, histamine, and our penicillin reagents. So it’s four small pricks under the surface of the skin. 

DUBNER: So you’re not giving me enough to hurt me if I am allergic. 

RESNICK: Exactly. 

DUBNER: But if I am allergic, then what happens? 

RESNICK: If you are allergic, we would expect that where we pricked you with the saline, nothing would happen. Where we pricked you with the histamine, you’ll get a red itchy bump. And where we prick you with the penicillin, you will also get a red itchy bump. That’s considered a positive test. We say you’ve tested positive for penicillin allergy — that’s it, go home, continue to avoid penicillins. If it’s negative, we go on and do the intradermal test, which hurts a little bit more. We’re using the same reagents and we’re putting them just under the surface of the skin. And again, we look to see, do those bumps get any bigger during the waiting period? And we’re comparing them again against saline. If that test is positive — again, you go home, that’s it, you’re allergic. But if that test is negative, we now have a skin prick and intradermal tests that are both negative. And the studies show that in those cases — it’s 95 percent likely that you’ll then pass a penicillin challenge. I think in real life, it’s probably much, much higher than that. But we go ahead, and we do an oral challenge, which is just what it sounds, we give you a dose of a penicillin. We use amoxicillin, which is a common oral penicillin. We give you that dose, we have you wait in the office for about two hours just to make sure that you’re fine, and that’s the gold standard, right? Tests are tests. But if you take the medication and you’re fine, then we know you’re not allergic. 

This clearing process that Dr. Resnick just described — that’s what I did, in her office, a few months ago. I did the skin-prick test, I did the intradermal test — both negative — and then, at a later visit, I took a dose of penicillin, and I waited in her office for a couple hours to see if I had an allergic response. I did not. I could now definitively say that I am not allergic to penicillin, and probably never was — although it is true that some people grow out of allergies over time, just as some people grow into them. But whatever childhood rash or temperature spike had led our family doctor to declare me allergic to the penicillin he gave me was likely due to something else — perhaps a viral infection rather than a bacterial one. So now I could take penicillin if I needed it — and it appeared I might. Because my illness had deepened. I went back to Dr. Kurth’s office for another round of tests — and we turned up some interesting evidence this time. By now I had something called non-Group A strep throat, which seemed to be responsible for some of my symptoms. But I also had thyroiditis — an inflamed thyroid gland. This was the first time in my life I’d ever thought about my thyroid gland; I didn’t even know where it is. It turns out it’s in the front of the neck, and it’s shaped like a butterfly. It is also a quiet superstar of the immune system; the thyroid produces hormones that help regulate everything from brain and muscle function to body temperature and heart rate. It can also pitch in when your immune system is already under attack — and that’s probably what happened to me: the strep got so bad that the thyroid marched in, like some auxiliary army. But without any specific orders, it just started shooting out hormones. So I was a mess. But: I was no longer allergic to penicillin. So: I swallowed as much amoxicillin as Dr. Kurth would allow, and even though it took a while, the healing began. My cough gradually died down, my voice started to come back, and then my energy too. I started sleeping through the night; that was probably the biggest thing. For the first time in months, I felt human. Could all that suffering have been prevented if I’d taken penicillin back when the trouble started? It’s hard to say for sure, but it’s quite possible. Here is another physician who specializes in allergy:

BLUMENTHAL: Nothing kills bacteria better than these drugs. 

This is Kimberly Blumenthal.

BLUMENTHAL: I’m an allergist-immunologist and clinical-population-level researcher at Mass General Hospital and Harvard Medical School.

Blumenthal has written dozens of papers about penicillins — not just about the allergy confusion, but about their effectiveness.

BLUMENTHAL: If your infection is sensitive to these drugs, they are the best drugs out there. From an adverse-effect profile, they are also much more benign than other antibiotics. 

DUBNER: Unless you happen to be allergic. 

BLUMENTHAL: Unless you happen to be allergic. Penicillin allergy was described immediately after penicillin was releasedand it’s the same with all drugs — you release new drugs, and we find patients that are allergic. But antibiotic allergy is misdiagnosed most of the time. 

DUBNER: Why is that? 

BLUMENTHAL: When we have infections, we get rashes. 

DUBNER: It’s really as simple as that?

BLUMENTHAL: Yeah, especially in children. Children get rashes when they have infections. Those infections are treated with antibiotics. There’s misattribution of allergy. 

DUBNER: So often it might even not have been a bacterial infection, might have been a viral infection?

BLUMENTHAL: Absolutely. For years and years, we have had this idea that an infection requires antibiotics. And only like the past five, ten years, we’ve tried to pull back on that because of antibiotic resistance. 

DUBNER: So the moral of this story is, if your kid is really sick, just let him stew. Is that the moral of the story, or not quite?

BLUMENTHAL: Don’t act too fast, right? I think it’s good to be a really busy parent and not be on top of it and rushing them in right away. 

DUBNER: But to be fair, when the parent rushes them in, then it’s the physician’s opportunity to slow things down.

BLUMENTHAL: Yeah, and some people do it better than others. There are these fantastic discharge prescriptions that aren’t actual prescriptions, things like, “Rest, and drink plenty of water, and Nana’s chicken soup, take Tylenol or Motrin for fever, and then if things, a week later, are still in the same place, or things worsen, then call me back and then we treat it with antibiotics.”  

When Blumenthal was in medical school, she became fascinated by the idea that two patients with the same infection could have entirely different outcomes, depending on how they were treated.

BLUMENTHAL: I really was drawn to the idea of how important the choice of what drug was the key decision. What drug is right for this patient? I pretty immediately realized that regardless of what nonspecific garbage was listed on the allergy list, it really changed care. And I just got totally distracted as to like, Does it need to change care? Why is there a two-tier system? If you have an allergy, you treat with this, but everyone else who doesn’t have an allergy gets this. I realized that what we were calling allergy was mostly side effects.

DUBNER: So if we’re drawing a kind of SAT-style analogy and, “Penicillin is to these bacterial infections as a hammer is to a nail,” let’s say. It’s the right tool for the right moment. What would the typical non-penicillin antibiotic, what would that be, if one suspects that a patient is allergic to penicillin? 

BLUMENTHAL: Something way too big to hammer in the nail. Some sort of mallet — you know, I don’t do tools and hardware.

DUBNER: Would it be like a leg of lamb perhaps? 

BLUMENTHAL: Sure. Maybe could get the job done, but by kind of making a mess. 

DUBNER: So, talk about your own practice as a clinician. And tell me roughly if you can, how many people have you tested over your career who thought they were allergic to penicillin, and what share of them actually were? 

BLUMENTHAL: If I were to see something like five patients for this a week, myself, and I’ve been doing it for over a decade, we’re near 3,000 patients. I’ve seen probably 20 allergic.

DUBNER: And when you say you’ve seen 3,000, those are 3,000 who are suspected of being penicillin-allergic? 

BLUMENTHAL: Yeah. They present to my clinic at the suggestion of their primary, or their surgeon, or themselves. Yeah, I would say it’s probably been 3,000 patients that I’ve seen myself. I know and remember two severe reactions. That’s it. The rest have been rashes. 

DUBNER: It’s even worse than most of the published numbers I’ve seen. Most of the published numbers say that roughly 10 percent of the U.S. population is thought to be penicillin-allergic but of that 10 percent, roughly 90 percent are not. According to you, it sounds like it’s more like 99 percent that are not. 

BLUMENTHAL: Ninety-nine in my practice. 

DUBNER: Can you think about another area of medicine where that rate of false positives exists? 

BLUMENTHAL: No. And this is why we should be screaming from the rooftops, is misdiagnosis. This is a missed diagnosis. Everyone has something on their chart that’s wrong. And nobody is screaming about taking it off. We reconcile medicines every visit — ”I’m taking this, I’m not taking this.” We try to take care to make sure what is in the chart is correct. This is something that is not ever addressed and is incorrect in the majority of people. 

Coming up: we take a look at misdiagnosis around food allergies:

MACPHAIL: He used to fight with people to get them to recognize that their issue was food allergy. And now he fights with people to get them to recognize that their issue is not food allergy.

*      *      *

You could imagine that artificial intelligence will soon be helpful in sorting out things like who’s allergic to what. But we’re not there yet. For now, allergy is often a guessing game, a bit of grasping in the dark. It’s estimated that roughly 40 percent of humans have some kind of allergy; that’s expected to rise to 50 percent by the next decade. Why? We’ve already heard from a couple of allergists. But to answer this question, we need someone with a broader view. We need a medical anthropologist.

MACPHAIL: Medical anthropology is looking at all the social and cultural factors involved in healthcare systems. We think about how all those beliefs, and politics, and economics — how all of that factors into the choices people make about their health, and how they view their health. 

This is Theresa MacPhail.

MACPHAIL: I’m associate professor of science and technology studies at Stevens Institute of Technology.  

MacPhail recently published a book called Allergic: Our Irritated Bodies in a Changing World. She writes that roughly half a billion people suffer from food allergies alone.

MACPHAIL: That’s been a puzzle, as to why an immune cell will take a look at something that is otherwise harmless and decide that it’s not, and do it after sometimes years of tolerating it just fine, and suddenly now it’s a problem.  

DUBNER: Just tell me why and how you became interested in the notion, the big notion of allergy. 

MACPHAIL: My father died of a bee sting. He died from an anaphylactic reaction to bee venom. He had had a reaction in the past, but it was fairly mild, just swelling at the site. That’s mostly what happens to anyone who gets stung by a venomous insect. And he died on the second sting. We really don’t know how many times he was stung because he was a Vietnam vet, so there’s a chance that he was stung prior to that. And I got curious about my own susceptibility to such things. Years later, I was diagnosed with allergies, but I am one of the rare people that do not react to skin or blood tests. I have low levels of IgE, the antibody that is driving the allergic response. So, there’s no way to tell what I’m allergic to except that clinically you can see the signs and symptoms that I am allergic to something. 

DUBNER: So, what are you allergic to? 

MACPHAIL: I think, based on my years of detective work, that I am allergic to grass and probably ragweed, and maybe dust mites.  

DUBNER: Can you just say what an allergy is, and what an allergy is not? 

MACPHAIL: Oh, boy. How much time do we have? This is part of the problem. There’s a lot of confusion about what an allergy is and isn’t. The easiest answer I can give you is that an allergy is when your body responds to something that is otherwise harmless and triggers an immune response. If your immune cells are not involved in the response, then it is not an allergy. The classic example is milk allergy versus milk intolerance. On the surface, if you have a mild milk allergy, it’s going to look the same, perhaps an upset stomach, feeling kind of gross, some gassiness. But the difference is, with the intolerance, there’s something else going on. In this case, you’re not able to digest lactose because you lack an enzyme. But it’s producing symptoms that would seem familiar to someone whose immune cells — whose T cells and B cells — are producing antibodies and attacking that milk protein. Except that the allergy can escalate. You can get a skin rash, you can get wheezing, and you can end up in the E.R. with a full-on anaphylactic event. That’s not going to happen with intolerance. But if you have mild forms of this, you’re going to be confused, and you might just assume that you have an allergy. And the only way to know for certain is to see an allergist. The problem there is we don’t really have enough of them. They’re specialists, and you need a referral to see one. And so a lot of people are out there self-diagnosing. 

DUBNER: Are allergic rates rising? Or is there just more awareness and/or diagnosis and/or treatment? 

MACPHAIL: We think, as far as we can tell, that they are rising. But it’s complicated. We know that rates of asthma and hay fever started to rise post-World War II — late 1950s, 1960s — and continued right up until the 1990s, and now they seem to have been flattened. But what has been rising in the wake of that are rates of food allergies. We know this because of several reasons. One is, you can look at E.R. visits. You can see when someone is showing up with asthma or with a rash, like a very bad eczema eruption, or they are having anaphylaxis. The other thing that we can track is EpiPen, or adrenaline, prescriptions. Those raised three to four times from the 1990s to around 2018, 2019. 

As with penicillin, the discovery and isolation of adrenaline is another great story from medical history. I won’t go into the details here, but it’s worth reading about if you’re so inclined. A dose of adrenaline, or epinephrine — administered in an EpiPen, for instance — is the first-line treatment for anaphylaxis. When Theresa MacPhail cites the huge spike in EpiPen prescriptions as evidence of a huge spike in allergies — well, she also points out that much of the demand was driven by the supplier. Mylan Pharmaceuticals marketed the EpiPen aggressively, across many channels. Over one 10-year period, MacPhail writes, “They hired more lobbyists than any other U.S. company.” This led to a relabeling of the drug by the FDA, which made more people eligible to take it. Mylan also lobbied state legislators, as a means to get more EpiPens into schools. They also partnered with Disney to produce children’s books about allergy sufferers. So how big is the allergy market? The global market for epinephrine is about $2 billion a year, with 60 percent of that sold in the U.S. If you look at hay fever, one recent study put the cost of treating Americans at over $4 billion a year, more than a billion of which goes to medication. If you look at the entire category of allergy remediation, the global sales of tests and treatments is around $40 billion a year. So how much of the allergy boom has been driven by more allergies, versus well-run pharmaceutical campaigns? It’s hard to say. There are a variety of factors that may be driving allergy increase: some research shows that environmental and chemical disruption may play a big role. I asked Theresa MacPhail about some other potential drivers:

DUBNER: Many, many, many people have by now heard or read about the notion of allergy rising because we — especially we of the children variety — are not exposed to enough things, pathogens or allergens or whatnot, that we don’t roll around in the dirt and so on.  

MACPHAIL: Right. So, in the 1980s — this is after the massive rise of asthma — we’re starting to see food allergies. An epidemiologist was curious about this, and started collecting data on families, and realized that older siblings seem to have more allergic disease than younger siblings. The theory was that older siblings bring home colds and track in bugs to expose their younger siblings, and there was something about that earlier exposure that had somehow protected these younger siblings. It was called the hygiene hypothesis. That has morphed over the years to what is now called the old-friends hypothesis, which is nice, isn’t it? That’s a nicer way to put it — that there’s something about getting the right exposures to the right bacteria or the right viruses and fungi that will help train our immune system. You’re born with a novice and naive immune system that hasn’t seen anything, and you’re born with an innate immune system, which means there are things online from the very beginning that just act as a brute force response to anything that threatens the individual. And then you have an adaptive immune system, which involve your T cells, and your B cells, and your antibodies that remember the things that you’ve been exposed to. And so the theory is those have to be trained, and they have to be trained in the right order, and they have to be exposed to the same types of bugs, microbes that they would have been evolving with for millennia. The theory is that we’ve changed so much that some of those are missing. It has confused our immune system to the extent that you’re seeing more allergic disease because you’re not getting the training. 

DUBNER: It feels as though every time I go to a restaurant these days, the server will ask, “Is anyone allergic to anything?” Do you know anything about that? 

MACPHAIL: It’s basically advocacy. And at the forefront of that is a group called FARE, which is Food Allergy Research and Education. They are privately funded and run by a group of parents. When I started researching the book, one of the first people I sat down with was Helen Jaffe. Her and her husband, David, are some of the founding members of FARE, and they also have helped to fund the Jaffe Center at Mount Sinai for food allergy research. When they started the foundation, it was because two of their children had quite severe food allergies, but it was at a time where no one was doing this. They live here in New York City, and they had to take the train down to Johns Hopkins to see Dr. Hugh Sampson — he’s a renowned food allergist and researcher, and he has been doing this for over 40 years. But at the time, there were maybe half a dozen people focused on food allergy. And so, initially, Helen told me that their focus was really on education and research funding to try to figure out what was going on, why the rates seemed to be rising, figure out more about the biological mechanisms that drove this response. I spoke with Dr. Hugh Sampson, now, we’re talking about years later, and he said he used to fight with people to get them to recognize that their issue was food allergy. And now he fights with people to get them to recognize that their issue is not food allergy.  

DUBNER: Can you explain? I do see on the FARE website that 50 to 60 percent of all blood tests and skin prick tests for food allergy testing will yield a false positive result.

MACPHAIL: Correct. 

DUBNER: So, that sounds absurdly bad. Is it not as bad as it sounds or is it that bad? 

MACPHAIL: No, it’s bad. It’s bad. I mean, diagnostics are one of the sticking points. It’s one of the reasons I can’t tell you how many people actually have an allergy, because we’re stuck with primarily the skin tests — which, were invented in the late 1800s by a U.K. physician, Dr. Charles Blackley. 

DUBNER: Wait — the late 1800s? 

MACPHAIL: Yes, and if I exhumed him and revived him, he would have no problem giving a skin test today. 

DUBNER: What about false negative? That’s what we should be really concerned about. 

MACPHAIL: That is the better situation. It’s around 95 percent certain if you do not respond, that you are not going to respond in real life. 

DUBNER: So that’s good news at least. 

MACPHAIL: Yes, that’s good news. That’s why we still use them, because it’s almost like a differential diagnosis. We can rule some things out. 

DUBNER: So, you mention in the book that your aunt and your grandmother were allergic to penicillin. Given everything we’ve discussed about testing, or the lack of great testing, and the murkiness surrounding this area, do you think that they actually were allergic to penicillin, or maybe?

MACPHAIL: In my grandmother’s case, we know because she was in the hospital and had an actual skin eruption and reaction to penicillin. I honestly don’t know about my aunt. Sorry, if she’s listening to this. Because to my knowledge, she’s never been tested. So, I don’t know. She does avoid them, though. At the end of the day, I suppose it doesn’t matter. 

“I suppose it doesn’t matter,” MacPhail says. That’s what I used to think — that a penicillin allergy is no big deal since there are other, newer antibiotics that do the same thing. But the allergists we heard from earlier — Elena Resnick and Kimberly Blumenthal — they told me that is simply not accurate. Resnick told me about a pregnant patient of hers who showed up with a penicillin allergy on her chart.

RESNICK: Penicillins are an amazing drug also because we know them to be safe and effective in pregnancy. When a pregnant woman goes in to deliver, if she is colonized with Group B strep, which is a very common vaginal infection, she must be given antibiotics before delivery to ensure that the baby is not exposed to the Group B strep. So the antibiotic of choice for Group B strep is in the penicillin family. Mom comes in, she’s ready to deliver, she gets a dose of penicillin, she gets her second dose four hours later, she delivers the baby, everything is fine. If she is thought to be penicillin-allergic, instead she’s given vancomycin. Vancomycin dosing interval is every 12 hours. So, if she’s not dosed appropriately, the baby can be considered inadequately treated, and that leads to all sorts of other potential decisions — maybe getting put on antibiotics, maybe going to the NICU — again, the complications just from this penicillin label are intense. So in this particular scenario, this mom went in to deliver, she was thought to be penicillin-allergic, they gave her vancomycin, she developed red-man syndrome from the vancomycin — which is just what it sounds like, where the body becomes completely red and flushed, and other medications have to be given. And then she had a wound infection from her C-section. Because she was still thought to be penicillin allergic, they gave her clindamycin to treat the wound infection. And she developed C. diff. from the clindamycin.

DUBNER: And how did that play out?

RESNICK: So when you develop C. diff., then you have to be put on oral vancomycin and then treated usually for two weeks. It’s just a nightmare. It’s one thing after another, and then she came to see me and we were able to clear her of that penicillin allergy.

DUBNER: Why did she come to you in the first place?

RESNICK: So, her OB-GYN — we also rely on the OB-GYNs to find people who in their charts have this penicillin allergy. The problem with that is we’re not going to test a pregnant woman just on the off chance that she does end up being one of these rare people who is truly allergic. Obviously, we don’t want to put a pregnant woman into anaphylaxis. So we’re sort of stuck with that label, which is hard for the O.B. because then their patient gets a simple infection, they can’t use a penicillin. So a lot of the O.B.s will say to their patients, “Before you get pregnant again, better go get cleared of your penicillin allergy.”

The fact is that a mislabeled penicillin allergy — and, as we’ve established, the vast majority of penicillin “allergies” are mislabeled — this is a serious thing. The risk of post-surgical infection is much higher. So are your chances of dying. Kimberly Blumenthal, from Mass General/Harvard, published a study comparing the long-term outcomes of 60,000 patients with a penicillin allergy in their medical record versus more than 200,000 patients without.

BLUMENTHAL: We did an all-cause mortality study, in a very nicely controlled observational study — 14 percent increased all-cause mortality if you have — 

DUBNER: Wait a minute. If being labeled penicillin-allergic is producing that many more deaths — what, exactly, are the adverse outcomes that you’re avoiding if you’re able to take penicillin?

BLUMENTHAL: There’s avoiding antibiotic resistance, c. diff. colitis, avoiding too long of hospital stays, avoiding surgical infections if you had needed an operation, and then there’s avoiding other adverse events that result from a choice of antibiotic that is just more toxic and by its nature caused more renal failure, or caused more diarrhea or whatnot.

DUBNER: This may be impossible to say, but let’s say there are two observationally equivalent patients, let’s say me and let’s say I have a twin, okay? And one of us has been labeled penicillin-allergic. The other hasn’t. We have the same medical problem come up. I’ll let you pick the problem. One of us receives a penicillin drug. The other is not eligible to do so. Even if his allergy isn’t real, we think it’s real. How would you think about comparing the medical and economic outcomes of person A and Person B?

BLUMENTHAL: It’s such a no-brainer. I mean, when you give me this description, what comes to mind is two people who have strep throat. Strep throat and a penicillin allergy label. One person gets penicillin, that’s indicated for penicillin. Strep throat goes away. No long term sequelae. They’re fine. It was cheap. And then the other person gets a Z-Pak, azithromycin. And it doesn’t fully go away. Then they call back and they get another antibiotic. Maybe this time they get a bigger antibiotic, and that causes some problem, they might get a tonsillar abscess. They’d get aquinolone, ciprofloxacin unnecessarily, or some other medication, and then.

DUBNER: I mean, I don’t know what any of those are, but all those syllables sound bad to me.

BLUMENTHAL: Yeah. There’s no rule, like the more syllables the antibiotic has it’s worse. I wish it were that simple.

Okay, that’s not simple. But this is: misdiagnosed penicillin allergies are costing all of us a lot of suffering and dollars. So why isn’t more being done to solve this problem?

Thomas PLATTS-MILLS: Because the public doesn’t decide which grants get funded.

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Once you know about the benefits of penicillin, and how millions of people wrongly believe they are allergic, you can’t help but think about the costs of this misdiagnosis. Not just the bad health outcomes and the complications, but the financial costs too. That’s why some specialists are pushing for more testing and delabeling of people who think they’re allergic. That might cost a lot upfront but: when 1 in 10 people think they have a medical handicap, and don’t — this actually presents an opportunity to save money. It might even be worth testing every single person whose medical history says they’re allergic. Here, again, is Kimberly Blumenthal from Mass General/Harvard.

BLUMENTHAL: We can evaluate for penicillin allergy with simple tests. And these simple tests need to be delivered to that 10 percent of America and reimbursed appropriately, and taught to a non-specialist workforce. Could be a welcome-to-college visit, a welcome-to-Medicare visit.

DUBNER: How much money could you save by doing this?

BLUMENTHAL: Just my healthcare system would be millions if we evaluated penicillin allergy, de-labeled the appropriate ones — we would save millions of dollars, just my healthcare system. So it must be in the billions.

DUBNER: You’d save it how?

BLUMENTHAL: You save on antibiotic expenditure.

DUBNER: Just because penicillins are cheaper than the other antibiotics?

BLUMENTHAL: Yes. You’d save on adverse-effect avoidance.

DUBNER: Meaning penicillins don’t cause as many adverse effects as other antibiotics?

BLUMENTHAL: Yes. And some of these adverse effects lead you to the emergency room and another hospitalization. You’d would save on surgical infections, a tremendously costly thing.

Blumenthal is trying to make these cost savings a reality in the Mass General Hospital system.

BLUMENTHAL: In our hospitals, without an allergist involved, there is sort of algorithmic care that can clear allergy in low-risk situations with just a protocol, just a little bit more observation. You’re already in the hospital, you’re being observed.

DUBNER: Your vital signs are already on record there. And is the idea as simple as you feed the key vital signs into the allergy algorithm and see if, indeed, there’s a likelihood that that person is not allergic, and then maybe do some challenge testing, is that the way it works?   

BLUMENTHAL: We do it when patients have infection. So, we don’t do it electively, like if you’re there for something not related. But if you have an infection that an allergy is getting in the way of best care, we have a two-step drug challenge process. And as long as the patient’s healthy enough to do that, we do it. So, we give a small amount, watch the patient, give a full amount, watch the patient, and then if that’s the drug that they need to be treated with, they just continue that drug right then and there.

DUBNER: Since there is a treatment for the allergic response, but the default is to not give penicillin if there’s a suspicion of allergy, what would happen if you just flipped the default and said, “No, no, no, we’re just going to give penicillin. And if they happen to be in the small group of people who are allergic, then we’ll watch and will treat it.” Is that such a terrible idea, or would you kill a bunch of people by accident that way?

BLUMENTHAL: You would kill some people by accident. And in America, it’s just a nonstarter.

DUBNER: Because we don’t want to kill anybody, you’re saying?

BLUMENTHAL: Well, there’s also this doctor first-do-no harm, like the oath we take. It just feels wrong to just disregard allergy labels entirely.

The hospitals where Blumenthal works have achieved a 9 percent delabeling rate over a decade; the national delabeling rate is less than one percent. There’s something interesting to notice about Blumenthal’s approach. Many specialists, in many industries, are always trying to grow their leverage, to become ever-more-powerful gatekeepers. Blumenthal is moving in the opposite direction; she wants to shift leverage away from the allergists in order to help more patients. This would happen through better technology, better training, and better regulation. In some states, pharmacists are now allowed to perform the skin tests for penicillin allergy. Last year, a Republican congressman, with Democratic support, introduced the PAVE Act — that stands for Penicillin Allergy Verification and Evaluation; it would fold allergy awareness into annual wellness visits and the preventive “Welcome to Medicare” visits that Blumenthal mentioned earlier. So, that all sounds good. But let’s not get too excited: overall, the false-positive problem in penicillin is underexamined and underfunded.

BLUMENTHAL: I can tell you with confidence that I was the first penicillin-allergy grant that the NIH funded in 30 years. Whose area is it? Is it infectious disease? Is it allergy? Is it multidisciplinary? Is it surgery? Is it obstetrics? Because penicillins are used by everybody — dentists. It was very hard to know who takes ownership of something that crosses every single discipline.

And when disciplines cross, disciplines compete. Given the cost of medical research, these can be multi-billion-dollar competitions.

PLATTS-MILLS: There’s a pecking order in medicine.

This is Thomas Platts-Mills.

PLATTS-MILLS: I’m a professor of medicine at the University of Virginia, and I’ve been studying allergic disease for a long time.

And where does allergic disease fall in the pecking order of medical research?

PLATTS-MILLS: It’s actually much worse than anything you imagine. Neurosurgeons are at the top, cardiac surgeons, and all these people fight with each other, but they know that at the bottom there are dermatologists and psychiatrists and allergists. I got very little from the university — a little bit in the first few years, but then basically in the last years, nothing. We’ve always had to get our own money and I was getting N.I.H. money, and the N.I.H. has been very generous. This last time I actually got a 1 on a grant. It’s actually means you’re in the top 1 percent. And then I got a merit award, and a merit award is absolutely wonderful because from ‘18 to ’28, I’m funded by the N.I.H. — 10 years instead of five. Tick bite research is hot.

Platts-Mills is a giant in the field of allergy research. Some of his early work was on the connection between asthma and dust mites. More recently, he and his team have found that getting bitten by the Lone Star Tick can trigger an allergy to a sugar molecule called alpha gal, which is found in the blood of mammals, which means the tick bite can therefore render a person allergic to red meat. As Platts-Mills said, tick bite research is hot.

PLATTS-MILLS: The Congress voted $100 million for it, so that we can get tick bite related grants for different aspects of our research. And that’s been tremendously helpful.

DUBNER: Why do you think ticks are such a good selling point for voters, Congress, etc.? Just because it’s relatable?

PLATTS-MILLS: Oh, come on. God had finished making the earth, and then the devil reached over and sprinkled ticks all over it. You know that. No, ticks are very interesting. The deer are absolutely infested with ticks. It is not unusual for hunters to shoot one of our deer and find the thing with so many ticks, they couldn’t possibly count them. 

DUBNER: When you were embarking on the research about the alpha-gal red meat allergy related to ticks, did your colleagues think or maybe even say that you were bonkers?

PLATTS-MILLS: They always say I’m bonkers. No, I’ve got away with murder several times. My father taught us that if we think A and the rest of the world thinks B, that is formal proof that A is correct. Being educated in an environment like that is really extraordinary.

DUBNER: It does strike me — and I’d love you to tell me if I’m wrong­ — but my sense is that when it comes to allergy, the pharmaceutical side of the equation is doing very well. There’s a lot of money being made selling treatments that may or may not work. But on the research and the public health side of the equation, plainly not nearly as robust. And I’m curious why it would be in a case where if you think of just supply and demand, there’s plainly a lot of demand for allergy remediation and so on, the public would like to know more, to suffer less and so on. If the split I’m describing is accurate, why do you think there is such a big split?

PLATTS-MILLS: Because the public doesn’t decide which grants get funded. The trouble is that the drug companies are so powerful, and they advertise so much that people just get the idea that that’s what it is. And actually, the guidelines are warped. I’ve been on a guideline panel for asthma where we were told that we should focus on large, controlled trials published in the last five years. Well, that basically means drug studies. The number of large controlled trials of tick avoidance that are being done is zero. No one could afford to do them. Companies have a lot of money, and they do big, well-controlled trials, some of which are really important, but many of which are me-too — or trying a new drug which is a very tiny variant of the previous. It’s much more important to try and understand what’s happened. I’ve written a history of food allergy, and there are three forms of food allergy which are peanut and the other allergens that cause immediate hypersensitivity, eosinophilic esophagitis, and the Alpha-gal syndrome. And why I’d pull those apart is because they’re mechanistically completely different, causally different, and the reasons why they’ve increased are different. Peanut is probably ridiculous washing of the skin with detergents. EoE, we’ve just published a hypothesis that the processing of milk is a major part of that. Instead of pasteurizing milk at 84°C, all the milk you drink is heated to 135°C. It’s dead and it’s homogenized, which means the particles are all changed. So they’re much smaller, and we say weaponized to immunize the esophagus. And the third one, the Alpha-gal syndrome, we believe is primarily due to the loss of dogs in the suburban areas. What happened in the early ‘80s is leash laws and now, the dogs can’t get together to drive the deer out. And so we all have a herd of deer on our lawn, and the deer are covered with ticks.

This connection that Platts-Mills has drawn, between leash laws and a boom in the tick population, is not his only unusual theory.

PLATTS-MILLS: I was very well known in the ’70s for saying that television had had a major effect on asthma. We published a paper in which we showed that if people watched a screen, they took less deep breaths. If they’re reading a book, they still breathe normally. If your child is watching television and you touch their shoulder, they actually jump slightly, because they’re in a trance. They’re not unconscious, they’re not asleep, but they’re in a trance. And during that time, the hypothesis was that that prevents their breathing. And the deep breaths are a better bronchodilator than albuterol. What’s happened since then, if you want something really silly, is that children are no longer watching television because they’ve got cell phones. And the cell phones don’t put them into a trance, and asthma has actually become less of a problem. The asthma doctors will be horrified if they hear anyone suggesting that asthma is anything but a total problem. But actually, peanut allergy has become more of a problem than asthma. 

DUBNER: But a totally different causal mechanism, yes?

PLATTS-MILLS: Totally different, yes.

DUBNER: What are your views on celiac disease and gluten allergy?

PLATTS-MILLS: Yeah. Gideon Lack, who did the LEAP study, has been looking at celiac and seeing whether natural exposure to wheat in early childhood would prevent celiac disease, and I think he’s got some evidence but it’s not of a level comparable to the LEAP study. The LEAP study was a tremendous breakthrough. 

This LEAP study — that stands for Learning Early About Peanut allergy — was published in 2015 by the pediatric allergist Gideon Lack. It argued that feeding peanuts to babies will actually reduce their risk of a peanut allergy. Much of the evidence came from Israel, where babies routinely eat Bamba, a puffy, peanut-butter-flavored snack. Full disclosure: some adults also love Bamba. Given what we’ve been hearing about allergies these past few decades, especially peanut allergies, you can imagine that many parents would be terrified to let their baby get anywhere near a peanut snack. Once a conventional wisdom is established, it can be hard to dislodge. Which gets us back to the allergy with which we began this episode.

PLATTS-MILLS: A whole generation of doctors were trained thinking that penicillin allergy was very dangerous.

DUBNER: And very common.

PLATTS-MILLS: And very common. And it isn’t. When I got here in ‘82, I already was saying things like, “No, you don’t need to worry about it as much as this. You need to ask the question, and take precautions and be sensible.” If someone had no history in 15 years, the chances that they’re penicillin-allergic are very small.

DUBNER: So what are some solutions? Can you talk about clearing people of penicillin allergy, for instance? By the way, this is the reason we’re doing this episode, is this is something that happened with me. I was told as a child I was allergic to penicillin, I avoided it for approximately 50 years, my current doctor, she said, “You know, we should test.” So I did. I was negative, but I had to go through this, you know, two-day — first the test and then the challenge test where you actually get a little bit of it. And it’s plainly something that’s not scalable right now, so I’m curious what you think are solutions.

PLATTS-MILLS: I’m breaking my head. People have been trying for a long time. I can’t tell you how many of the residents who apply for our fellowship have been doing a study on de-labeling penicillin. So this is not something that people are ignoring. 

DUBNER: Can you explain why it’s so difficult? Because as much as medical technology has changed — I mean, everything from time-release medicines to the mRNA vaccine, I mean, there’s so much technology that has accelerated discovery in medicine. Why is it so hard in this case to come up with a, let’s say, cheaper, faster, more scalable way to clear people?

PLATTS-MILLS: Well, there’s quite a lot of literature that says you can’t quite rely on a blood test. And that’s what we should have, is a simple blood test for IgE to penicillin that absolutely solves the problem. 

Kimberly Blumenthal is one of the people who has been working on a better blood test for penicillin allergy.

BLUMENTHAL: We were trying so hard. I was working with Thermo Fisher Scientific. They have developed a blood test panel, and they wanted to see if it worked in allergic individuals from America. We identified in the Boston area everyone that reacted to penicillin in front of our faces in the last few years. We sent them the blood of these individuals, and I think it picked up, like three. It was three of 20. It didn’t pick it up yet.

DUBNER: What makes it so hard?

BLUMENTHAL: The conclusion was — well, they were allergic in the last five, ten years, maybe they weren’t allergic now. So I have to bring them back, retest them. And then these patients, they’re like needles in haystacks, right? We combed the records of all Mass General Brigham to find these 22 penicillin allergics. We really need to say, “Okay, you reacted to penicillin in front of my face today, grab your blood,” and then send it to be able to know that they were true positives.

DUBNER: But you’re making progress, it sounds like.

BLUMENTHAL: Slowly.

DUBNER: I mean, by the time you’re 600 years old, this problem will be solved?

BLUMENTHAL: One of my mentors said to me, “If you do your job well, you have no job.” And I’m like, “I just don’t think that’s going to happen.” There’s always something else. We need better tests now, back to the basic science in the lab. And then on the population level, we’re thinking about implementing penicillin allergy evaluation in primary care. We just created a measure of delabeled patients in our healthcare system. And even just now that I can measure it — I can measure it in this clinic and that clinic — and I can see what types of interventions move the needle towards a higher percentage of delabeled patients.

DUBNER: So what would your message be to anyone who believes that they are allergic to penicillin now?

BLUMENTHAL: Get tested. Get tested.

DUBNER: If we were to jump ahead 20, 30, 50 years or something, I would imagine that, given the benefits of gene sequencing and machine learning and artificial intelligence, that it would be pretty simple at birth to either understand everything that a given person might be susceptible to allergy-wise, or just correct it.

BLUMENTHAL: I think it’s possible, and it’s also possible that we could alter our drugs to be less allergenic.

DUBNER: How would you do that?

BLUMENTHAL: Oh, goodness. We’d have to know what metabolite of the drug is forming bonds in our body to make the allergen. And so it requires a lot of combined intelligence from different people.

DUBNER: I realized, though, as I asked that question, that it’s a little touchy for you because I’d be putting you out of business. You okay with that?

BLUMENTHAL: Yeah, I would stop happy. If we have some sort of way that, like, everybody knows if they can or cannot have penicillin or any drug, or they’re going to be allergic or not, if we were able to correct the 30 million mislabels in just America, I’m happy, I’m retired.

DUBNER: And you’d just open a florist shop or something like that? You’d be okay?

BLUMENTHAL: I do like floral design.

DUBNER: Well, there you go. 

I’d like to thank Kimberly Blumenthal for the good conversation today, as well as Thomas Platts-Mills, Theresa MacPhail, and Elena Resnick. Thanks also to Dr. Resnick for clearing my stupid penicillin allergy label; and thanks to Becky Kurth, Dr. Deb Jones, Dr. Lainie Hurst, and all the other medical professionals who helped turn me from a bone-tired coughing machine into — well, back into me. I am grateful. Making this episode was a good reminder of how much I love physicians — their drive, their curiosity, their willingness to admit what they don’t know yet, and then to work ridiculously hard to find out more.

*      *      *

Freakonomics Radio is produced by Stitcher and Renbud Radio. This episode was produced by Dalvin Aboagye. The Freakonomics Radio Network staff also includes Alina Kulman, Augusta Chapman, Eleanor Osborne, Ellen Frankman, Elsa Hernandez, Gabriel Roth, Greg Rippin, Jasmin Klinger, Jason Gambrell, Jeremy Johnston, Jon Schnaars, Lyric Bowditch, Morgan Levey, Neal Carruth, Sarah Lilley, Theo Jacobs, and Zack Lapinski. Our theme song is “Mr. Fortune,” by the Hitchhikers; our composer is Luis Guerra.