Now I'm going to introduce Dr. Tom Platts-Mills who'll give us an overview for the Allergy Division. Tom, I'm sure you have a lot to tell us. You've actually asked for five minutes more. 

What have you done here? 

This advances, and then-- 

That's good. That's good. Thank you. No, no, that's good. Good morning. It's a pleasure to be here. 

I want to introduce the Division of Allergy, and the thing to understand is the Division of Allergy was the first subspecialty division in the department. It was established in 1935 with the recruitment of Oscar Swineford who was doing research in Vienna. I don't think he was doing research with Karl Landsteiner, but he might have been, because Karl Landsteiner was there and actually defined the ABO system. 

Oscar was recruited back to deal with the allergy epidemic. He was actually the professor of allergy and rheumatology, and he established the first subspecialty clinic on Wednesday afternoon, because he asked the chairman could he have a subspecialty clinic. And the chairman said, no, we are all real doctors. We don't subspecialize. 

He ran it on Wednesday afternoon, because the chairman played golf on Wednesday afternoon, so he never knew. And that established the mood of the relationship between our division and the chairman ever since. 

The first Oscar Swineford Professor was appointed in 1982, and he is still in position. I don't have to tell you who he is. But the current faculty, we have four professors-- myself, Larry Borish, Judith Woodfolk who does research in the lab, has been very successful, and Peter Heymann who is pediatric-- remember that this is a joint adult pediatric subspecialty. 

Peter and I have actually been running it for 30 years. The training program-- and Monica has only just recently taken over. But Peter, I think he's the only person I've ever worked for for any length of time with never having an argument. Peter and I have never disagreed about anything. It's a bit suspicious. 

Monica Lawrence runs the training program now. John Steinke does research with Barry Borish. Tim Kyin is going to talk to us later about penicillin. Emily McGowan is doing research on eosinophilic esophagitis, which I'll talk about a little bit. And Anna Smith has several clinics she deals with. 

We have adult clinics in Northridge and Culpeper, and we have pediatric clinics in Battle Building and Lynchburg. The special clinics, there are several. There's the Drug Allergy Clinic, which Tim will talk about, the Eosinophilic Esophagitis Clinics, and the thing I want to point out is we have a lot of collaboration with other divisions. 

Eosinophilic Esophagitis with adult with Bryan Sauer, pediatric with Barrett Barnes. Larry has a severe asthma clinic, which has just recently been started with Drew Harris in pulmonary. This is the [INAUDIBLE] Clinic, but I can't change this, because someone made this into a picture, and you can't touch it. It's very annoying. 

But we have two otolaryngology sinusitis clinics-- Larry Borish with Spencer Payne and Anna Smith with Jose Mattos. There's a special dermatology clinic, again, with Monica Lawrence and Barrett Zlotoff. The immune deficiency clinics, which have been a great success and are expanding rapidly, both adult and pediatric. 

Monica runs the pediatrics and partial adults, and they've expanded enormously, because of genomics. That is, you can get gene studies cheap, and I think you should all hear Monica talk more about it. Maybe you'd come and talk now. She's rather chicken. 

I want to talk about three research areas, which are funded, but in each case, because they have major collaboration with other groups. Peter Heymann has been doing rhinovirus challenges for a long time and has actually got much of the best evidence in the United States for the relationship between rhinovirus and acute episodes of asthma in children, both from here and from Costa Rica, both in the emergency department and in the hospital. 

And he works with Ron Turner who is in pediatric ID who has the two rhinovirus specimens that are fully FDA approved for challenge, and we have approval to challenge asthmatics with two different strands of rhinovirus. We might collaborate with adult ID, but adult ID is contaminated. 

Sorry. He's not listening, so-- 

[LAUGHTER] 

He genuinely wasn't listening. That's good. 

There are actually three [INAUDIBLE] involved in that parent, which Peter and I had, which really developed the model. Judith has a study looking at repeat rhinovirus challenges and looking at T cells to talk about. Larry Borish has a study to look at the events that occur in the epithelium immediately after the arrival of rhinovirus. 

Eosinophilic esophagitis is Emily McGowan, as I've said, and we have funded in that, but not yet fully, which we intend to become. Emily-- you there? I like the idea of ordering people to get funding. Only when you really know how hard it is can you enjoy that so much. 

And finally, delayed anaphylaxis to red meat, which has been my work for the last 10 years with an issue with Scott Commins now with Jeff Wilson, but also more recently, with Colleen McNamara and Angela Taylor in Cardiology. 

The rhinovirus challenge model, you look at controls in asthmatics. You challenge them. You take blood draws. You can really follow everything that happens from the moment you get the virus, and you see that you can actually-- 

Wow. That's weird, isn't it? Yes. Do you see this 21-day peak in symptoms? This is extraordinary, and no one else has really noticed that. But it's really, there is an increase in symptoms, and there are changes in cells that boost that late, and it really, in some cases, when children get a rhinovirus, and they get a cold, and they get an asthma attack, you treat them with steroids, but way after the course, you have to give them a second course. And we think that this may well be that event. 

Though, Lindsey Muehling, working with Judith Woodfolk-- Lindsey is a PhD from micro who actually was transiently a faculty member, but then she got some grant, which made her into a-- what are you? Doesn't matter. 

But it's very elegant data using tetramers to identify cells, and that you can actually show that here there are rhinovirus-specific T cells activate, and they are definitely different from the allergen-specific T cells, which are primarily related to dust mite. And these are Th1 cells, and these are Th2 cells. You can actually see that clearly in the rhinovirus model, which you could never do with a situation where you pick up patients in the emergency room and follow them, because you don't know when they got the virus. 

Eosinophilic esophagitis-- I hope you all know what it is. It's one of the leading causes of oesophageal obstruction today in young adults. It's a major cause of disease in children. 

This is an appearance of the esophagus in a young man who presented for esophagogastroduodenoscopy after an episode of obstruction while taking Flovent to treat his thing, and he was still eosinophilic. After three months of cow's milk avoidance, the situation is dramatically improved. 

I want to emphasize that for the first 30 years of being a doctor, I don't think I really understood about an inflammatory model of the esophagus. And I was taught at St. Thomas's by some surgeon called Barrett who had something to do with the esophagus. And we didn't hear about inflammation of the esophagus, and I don't think he was aware of it. 

Is this really a new disease? And I think most of us who have been around for a few weeks realize that it is a new disease, and we really need to understand what we've done wrong to make it happen. What we know about is IgG4 antibodies. 

I wanted to look at those. These are three components of cow's milk-- alpha-lactalbumin, beta-lactoglobulin, and caseins-- that's the caseins-- and they have very high titer IgG4 antibodies. I want to make sure everybody understands this. This may well be the highest titer IgG4 antibodies ever published. 

And it really strongly suggests that this disease could be an IgG4-related disease and a model for an IgG4-related disease where we know the specificity. That's cow's milk. We know that a lot of these patients get better with cow's milk avoidance, or it is an essential part of getting better. 

And the other one is wheat. This is the glutens. And the glutens are high too. The person who invented this assay and developed it, when we first showed this at our annual meeting, he said, wait a minute. How did you get titers this high? 

We said, we diluted the serum. It's perfectly normal. He said, I don't think anyone has ever diluted serum on this assay ever before. That is, these are really high tighter, so why do we have such high titer? 

We published this last year, and all I want you to look at here is this. That is, in teenage boys if you have greater than 10 micrograms of IgG4 specific for cow's milk, the odds ratio for EoE in comparison with a true birth cohort, random birth cohort, is 22. It's an odds ratio that most of us would be happy with. 

Why could you get a disease like this? Do any of you know what milk you're drinking? Do you know? What kind of milk do you drink? 

[INAUDIBLE] 

What? 

Costco's brand. 

Costco's brand, great. What temperature's it heated to? Is it pasteurized? 

[INAUDIBLE] 

No? Pasteur recommended 84 degrees centigrade. Your milk is heated to 135 centigrade. Yes? You're happy about that? It's dead. 

This is a Rube Goldberg machine. No, that's what happens to all your milk. You're happy with that? You don't believe it, do you? 

What you really have to understand is homogenization. If you heat milk to 135, it's dead, and in the industry they call it dead milk. And you can put it on the shelf, but you don't buy it off the shelf, do you? You buy it from a fridge. 

Everywhere else in the world it's on the shelf, but in America, because American housewives don't like the idea of getting milk off the shelf, it had to go back in the fridge. It's dead. It's not going to do anything. 

If you have dead milk, and you put it on the shelf for six weeks, the cream on the top goes to rubbery, so you think you can't do that. You must homogenize it. But when you homogenize it, here, this process takes the fat particles from four microns in diameter to 400 nanometers. 

400 nanometers-- four microns to 400 nanometers-- James, what's the number of particles? It's 1,000. It's 1,000 or more. I've tried to teach James for the last-- how many years is it? 30 years? More than that. 

But these particles get coated with casein, so this turns out to be the ideal method to immunize-- if you want to immunize a rat to casein, you would make 400 nanometer particles, coat them with casein, and make them swallow it. We are doing to our children exactly what you would do if you wanted to immunize children to casein, and casein is the IgG4 antibody that's the biggest. That's enough of this. 

We need to have a patient-- oh, I didn't tell you that we got a patient. He's just coming. He might be late, so we'll talk about him anyway. Now, actually, he's not coming. He lives in Shipman, and I did a house visit there last week. It's normal in the Allergy Division to do house visits. 

This is his house. I thought you'd appreciate the delightful nature of this. You buy a shed for a tractor. It's a wooden shed. It costs about $4,000. 

You call that your house, and then you put a front on it. You put a wood stove in it. Then you put another one on the side, and you make it into a real house. And then you put a bit on the back and a bit on the front. That's what he lives in. 

That's where he was when he anaphylaxed. It needn't be four hours earlier, he started to itch, and he felt bad. He sat down. He didn't feel good. He thought, maybe I'm sick, and he rang 911. And the ambulance arrived, and they came up this road. 

That's not my car. That's his car, because he came down to fetch me, because he didn't think my car would get up the road. So he's the normal redneck living in the woods. And in his house, he's got a whole line of guns in there. Very nice. 

Oh, and actually a picture that his great grandfather brought back from the war of the generals he'd fought with, which we needn't work out, who went and volunteered. And he says marched with a black guy down to volunteer for the Confederate Army. 

Matt Stressor described his great grandfather volunteering for the war, and the tone with which they described their volunteering was exactly the same. That is, Matt's as respectful of his great grandfather as he is of his great grandfather, but they actually fought on opposite sides in the war. 

The episode of anaphylaxis was severe by the time the ambulance got there, and the two people who'd come could not pick him up, and they had to make him walk. And as he walked out to the ambulance, he said, I'm blind. He had gone blind. 

In clinic, he said it was black. When I got there, he said it was brown, but he couldn't see for the next two hours. He got into the emergency room. He couldn't see. 

I think he'd gone blind because of cortical blood loss. I don't think it's retinal blood loss. I think it's cortical blood loss, and 99.9% of cases would lose consciousness before they go blind. It was a beautiful description, but he was certainly sick. 

He went into MICU overnight. I can't work out who looked after him, but McCall Walker-- is that a name? 

[INAUDIBLE] 

Is he a real person? I tried to contact him. Is he here? 

Yes. 

Stand up. You saved his life. No. No, the ambulance people probably saved his life. It's that first shot of adrenaline. 

James has an older brother called Tim who is an emergency room doctor. He says that about 99% of anaphylaxis cases are getting better before they get to the emergency department, and they don't use adrenaline very much. And he hadn't really used very. And it is very unusual for people to spend a night in the MICU. That's bad. 

His serum IgA to alpha-gal is 23. His total IgA is 150. His tryptase is 95.5. That is very high. I can assure you that the normal range, upper range, is 12. And I beg you, when you see anaphylaxis in any shape or form, or you think of it, get a tryptase. It changes the whole game. 

When you present this, and you say the tryptase was 96, there is absolutely zero doubt, but what he did was to release a lot of mediator for mast cells, because that enzyme comes out of mast cells and not significantly from anywhere else. 

Delayed anaphylaxis to red meat-- I hope you all know about it by now. I've been preaching about it for 10 years. Radiolab, NPR, the newspapers, all sorts of things-- it's been such fun. Most subjects report delays of three to six hours, and one of the critical questions is what that delay is about. 

The data here is a paper from which Jeff Wilson is writing, and it's currently under revision. When you get tick bites-- this is all related to tick bites. There is no question about that. 

There's questions about which ticks and the different ticks in different parts of the world, and in this part of the world, it's lone star ticks, and they're there on your lawns, because we don't have dogs. For the first time in 10,000 years, we have villages in the United States without a pack of dogs. 

For 10,000 years, the definition of a village is when you have a pack of dogs to tell you if a stray animal or a stray person comes into the village. We now have leash laws, so that the deer are on your lawn, and they are covered with these ticks. And that's why this disease has become so common. 

I want to talk about the delay, and the only realistic hypothesis is that alpha-gal enters the circulation via the thoracic duct as a glycolipid, and the form it'll be in initially is chylomicrons, which are 400 nanometers in diameter. They progressively over the next few hours change to LDL, and the number has gone up higher again, James, by a factor of 1,000. 

[INAUDIBLE] 

[LAUGHTER] 

Never trust your father. LDL at 20 nanometers, small enough to pass straight through endothelium, so that when I, as a case of alpha-gal, and get hives on my skin, which I can do, about six hours after eating lamb and three glasses of wine, I will get hives. 

These particles are small enough here to go straight through the endothelium. When they're getting into my skin, it means they're getting out of blood vessels, and they can do that equally in coronary arteries. 

Why do I say coronary arteries? Because this is a standard model of coronary artery disease today. I want to focus on that spot. That is in this article, which is one of the major articles about the coronary artery disease by Hansson and Hermansson in Nature Immunology. 

It shows LDL coming through the wall with oxidized LDL or other antigens. We are putting alpha-gal in there, so if LDL comes through with alpha-gal in an alpha-gal allergic patient, you will get mast cells. There are mast cells in the coronary arteries. You can get mast cells activating. 

Though, finally, last year we published together with Angela Taylor and Coleen McNamara-- a paper-- Jeff Wilson-- published paper-- this is [INAUDIBLE] picture of the left coronary artery with fibrotic arteriosclerotic plaque. Those are relatively stable. These ones are not stable, and we showed that there is a significant correlation between atheroma burden and the necrotic state of these lesions and having IgE to alpha-gal. 

What is scary about it is it looks very much from the data as if IgE to alpha-gal does not have to be associated with hives. The implication is there must be people in the community who don't know they've got IgE to alpha-gal, and have never had an allergic reaction, but nonetheless, get this inflammation in their coronary arteries. 

In conclusion, traditionally, A/I has had multiple areas of practice research that overlap with other specialties. Indeed, there have been times when we felt that there was no disease that we're really entitled to, that there were pulmonary guys wanting the asthma, there were ENT guys wanted the sinusitis, the dermatologists wanted atopic dermatitis, and periodically, you can actually find dermatologists who like urticaria. They're very rare. 

But the development of food allergy and anaphylaxis is ours. No one wants anaphylaxis. None of you who are not allergists like anaphylaxis. 

Dr. Lobo, how nice to see you. I hadn't noticed you there. So in addition, the practice of immune deficiency has expanded dramatically. How many genes can you get for $130? 207 genes for $250. It was $1,000 a gene only a few minutes ago. It is becoming cheap and easy and it really has made the whole science of immunodeficiency much, much better. 

But finally, taken together the developments have made a major impact on our curriculum and a real challenge to the current two year training program. But since the payment of fellows is obscenely low and is an absolute scam organized by the hospital, the match was introduced purely to keep fellows' salaries down, less you should doubt that. Do I have to ask you that question, too? Or do I have to warn you about that one? You don't know the answer? You'd know the answer [INAUDIBLE]. Thank you. Thank you. Tim? I'm very sorry. 

All right. That'll be a tough act to follow. I'll happily pass it on to Dr. Kyin as quickly as possible. So just to be brief and some remarks. We're very excited to have Dr. Kyin here today, again, also from the division of Allergy and Immunology. Just in the way of some background, Dr. Kyin earned his medical degree from the New Jersey Medical School, he went on to residency at Tufts University, and then fellowship at Brigham and Women's. He stayed on there as an instructor in medicine at the Harvard Medical School and practiced clinically at the Brigham. We were fortunate to recruit him down here in 2014 and since then he served as the Director of Ambulatory and Outreach for the division. 

Through his early career he's become an extremely effective teacher both for residents and fellows and has developed an expertise in a number of areas in particular for drug allergy, drug desensitization, and management of anaphylaxis. So we're lucky today to have him give us some insight in the area of drug allergy, in particular penicillin allergy. I think something that we've all run across a number of times. Without further ado, please join me in welcoming Dr. Kyin. 

Right. Thank you very much. Is this good? Can you guys hear me? No? Is that better? We're good? All right. Yeah. Thanks for having me here today. It's definitely a hard act to follow, there's no doubt about that. So my talk might be little dry compared to what you guys just heard. [INAUDIBLE] got nothing to report. So hopefully by the end of this talk you'll have better understanding of the health care burden associated with penicillin allergy. And also hopefully, just hopefully, you'll have a better appreciation and understanding of how to navigate this penicillin allergy. 

Why don't we start with some basic terminology. Now average drug reactions are defined by the WHO as just unintended or noxious effects of medications. And that can be further categorized into a couple different groups, type A and type B, which are predictable and unpredictable reactions. Type A counts for the majority of adverse drug reactions. These are typically dose dependent, somehow related to the pharmacology of the drug, and can happen to just about anybody. And that can be further categorized to include overdoses, for example, liver toxicity from acetaminophen. It can be considered side effects of the shakes from broncodilators, secondary effects like pseudomembranous colitis from clinda, or it can be results of drug-drug interactions like beta blockers versus beta agonist. 

Now type Bs are the unpredictable ones. These are usually dose independent. They're not related to the pharmacologics of the drug and are more likely in certain people. Again, these can be further categorized. Examples include intolerance, just like tinnitus from Aspirin. It could be idiosyncratic reactions such as dapsone to a G6PD-deficient patient. Then there are reactions that look like true allergic reactions but are not. For example, the standard contrast reactions. And all the way at the bottom are quote unquote "allergic reactions," and these are the ones for which we have an underlying new mechanism that can be used to explain the reaction. As you can see, this is the minority of adverse drug reactions. 

And step one board review for you guys. The average reaction you might remember from the boards is categorized here. Type I are the IgE-mediated reactions. These are what allergists typically deal with. And this is what we worry about because these reactions are the ones that could snowball and move to anaphylaxis. Type II reactions are IgGG or IgM-mediated and they attach to the cell surface and cause things like hemolytica anemia. Type III are immune complex [INAUDIBLE] form and end up giving you things like serum sickness. And there's type IV, which is your T cell-mediated delayed reaction. Examples include delayed drug eruptions and contact dermatitis. 

So now as anything else here, nothing always fits into a nice little neat box. So there are certainly reactions that we can't explain. Things include SJS, TEN, DRESS. All those things that you've been warned about in medical school to avoid. And certainly from allergy world we also try to avoid that as well. So in those cases, we shy away from drug challenges and desense. Right, so going forward with the dual overview of penicillin allergy followed by some basics and cross reactivity with cephalosporins. And we'll delve into the burden associated with carrying a penicillin allergy and possible interventions that we can do. 

In case you missed it, this topic made the popular press last month. This was following a JAMA article that was published highlighting penicillin allergy and [INAUDIBLE] review of that. This is me trying to do a Tom impression. It's a little bit of history. In case you forgot, penicillin was accidentally discovered by Alexander Fleming in 1928 when some penicillin in mold accidentally landed in his Petri dish and prevented his bacteria from growing. This is an allergy which 10% of the population believes that they have. And this is an allergy that could wane over time. So after about five years, 50% of people have lost this allergy. And after 10 years it's about 80%. And after a formal evaluation, the majority of these patients can have their penicillin allergy disproven. So that makes you wonder what those 10% of people who thought they were allergic were actually reported. 

And this is what this next slide gets at. So this was a study by Blumenthal out of Mass General Hospital. It was a retrospective study of surgical patients and it found that having a penicillin allergy label resulted in a 50% increase odds of a surgical site infection when they elected to use other things besides cefazolin, which is the preferred surgical prophylaxis agent. And what was more interesting to me was what the patients had listed on their EMR as a reaction to penicillin. Though 38% of the patients required a not [INAUDIBLE] rash, those could be a lot of things. to mean a delayed rash from amoxicillin. This could be that I inadvertently treated EBB with amoxicillin. That kind of rash. 

Interestingly enough, a quarter of the patients did not know what their reaction was so presumably this is the, my parents always told me to avoid penicillin. I don't know why but they said stay away. Or the patients who imperically avoid it because they have a strong family history of penicillin allergy. And further down the list is a GI upset. That to me is intolerant and non-allergy. And 5% for anaphylaxis. I highlight this because we know that the risk of anaphylaxis from penicillin is one of the realm of 1% or less. 

So where exactly do people mean when they say anaphylaxis? This is something that I harp on to our fellows. If our patient throws up medical jargon at you, instinctively you should be asking, what do you mean? Our fellows have really fished out subjective symptoms rather than [INAUDIBLE] the patients' self-made diagnosis. And for anaphylaxis it's rather hard because there's really no universal agreed upon definition of anaphylaxis. Different societies have their own criterias for it. 

Now because penicillin's been around for a long time, we do have some good data on it. We like to utilize skin testing and that's got great predictive value and specificity. The positive predictive value and sensitivity is not too shabby either. Of note, there is a serum testing available but that's not something we utilize just because it's not been great. And so we've got skin testing, which looks very good. Better predictive values. 

Then when we say we're testing for penicillin allergy we're actually testing for the breakdown products of penicillin. Those include the major determinant and minor determinants. And what you see here in asterisks are Pre-Pen and Pen G. Those are the only commercially available agents in the US. That's different from Europe where they've got all of them available. And so that leads to an area of possible debate. There's some allergists who believe that you can miss up to 10% of patients by not being able to test all of the minor determinants. That being said, there are several studies showing that the use of just Pen G and Pre-Pen followed by an oral challenge to amoxicillin is pretty accurate. And so that's what most of us do in clinic and that's also what's recommended on the CDC website. 

Before we get too far along I just want to go over some basic definitions because this usually throws people off. So when we say graded challenge or test dose we're really saying I've got pretty low suspicion for an actual allergic reaction and I'm really trying to disprove an allergy. And so we typically do that by giving split doses and there's really no consensus for this but this is what I use. 

For oral agents, I prefer to start with that 25% dose, followed by an observation period anywhere from 30 to 90 minutes depending on the drug, and then the remainder of the dose. For IV agents, I just split it up to 10% and 90%. Like I said, the goal is really to disprove this allergy. I'm not trying to have a reaction on the floor. 

Now this is different from drug desensitization, or drug desense. When we're saying desense, we've committed to one of two things. We're saying, OK, we knew the person's allergic. Let's just get them on this drug. Or, the person is unstable, and we don't want to muck around. We want to risk allergic reactions. So let's just briefly do a drug desense. And drug desense is a way of providing temporary tolerance. It allows us to manipulate the way we introduce the drug to get this temporary tolerance, and this should circumvent any major reactions. 

And one thing that always freaks out the nurses on the floors. We always order PRN Benadryl, steroids, epinephrine, even before the drug challenges. That's really out of an abundance of caution. Whether the drug desense actually needs to be [INAUDIBLE], that's another area of debate. 

Just the basics. These are the structures of penicillins and cephalosporins. Highlighted in blue is the beta-lactam backbone that we once heard about, and up to the top left is the R group [INAUDIBLE] side chain, and that's the R groups that we worry about when we talk about cross reactivity. The rate of cephalosporin allergy is not that bad. It's actually about 10 times less than that of penicillin. As I mentioned, the reaction is usually to the side chain, and not beta-lactam backbone. The teaching is really just to avoid agents which share the same side chain as the initial allergy. 

Cross reactivity between penicillins and cephalosporin is not as high as we used to think. Recent studies suggest that it's more in the realm of 2% to 5%. Typically, it's to the first or second generation cephalosporins. And the reaction is more likely if your history of allergy to penicillin was anaphylaxis. Now carbapenems. Cross reactivity between penicillin and carbapenems is really not there, and so that's something to think about. And there is no cross reactivity between beta-lactams and monobactams, with one exception. Azteonam does cross react with ceftaz. That's a classic word question for our fellows. 

So this is a general graphical representation of the shared side chains. It's nothing that you need to memorize. It's readily available on the internet. It's examples of a grouping of cephalosporins based on the side chains that they share. Now we'll talk about a few different scenarios that usually come up for our fellows when it comes to drug allergies. In this first case, you have a patient who reports a penicillin allergy, and you want to administer a cephalosporin. What do you do? 

You've got a few options. It really depends on the circumstances. You really need them to be on cephalosporin. The recommendation is, go ahead, just give it to them. Just do it with a graded challenge. That's one option, just give it to them. Second option is, OK, you've got the means to do skin testing, so let's test to the cephalosporin of your choice. If the test is negative, then go ahead, give them that cephalosporin. That'd be a graded challenge. And if the testing is positive, then fine. Either pick something else or do a drug desense. 

The third option is, really, let's just tackle the hard problem. The hard problem is that the patient reports a penicillin allergy, so in which case, you turn around and do testing for a penicillin allergy, and if negative, great. You're free. Just give the cephalosporin. If the penicillin testing confirms the patient's reported allergy, then you either pick a different drug or do a drug desense. 

In this scenario, you've got a patient who says they have a cephalosporin allergy, and you want to administer a cephalosporin. So in this case, you're worried that could be either beta-lactam allergy or allergy to the side chains. You're not sure. The one option includes skin testing to penicillin, and if negative, you're home free. If it's positive, then you either pick a different drug or desense to penicillin. And again, because the cross reactivity between penicillins and cephalosporin is so low, the other option is, OK, just go ahead and give it. 

And so in these cases where you don't have the means to skin test, IE. you integrate in a hospital, and not a treasury academic center. Most cases, there would be challenges. The third scenario is, of course, I've got a history of a cephalosporin allergy, and I need a different cephalosporin. Again, two options. Skin test to the cephalosporin of your choice. If negative, go ahead and administer it. If skin testing is positive, then you either pick something else or desense to that cephalosporin. And if you don't have skin test available, go ahead and challenge them with the caveat that these cephalosporins don't share the same side chain that the patient reacted to. 

So now I'm going to switch gears and talk about the complications of carrying a penicillin allergy. As you can imagine, my patients get admitted to the hospital. It's possible that they get anti-microbial coverage, and if they carry a penicillin allergy, there's a good chance that there are broad spectrum agents used, and that could probably lead to hospital acquired infections, and of course, increased cost of care. In the next few slides, hopefully, I can highlight that for you. 

This is a study by Macy and Contreras. They did a retrospective, matched cohort study looking at Kaiser patients in Southern California. They found that 11% of their patients carried a penicillin allergy label, which would be consistent with what I said before about 10% of patients learned to have this allergy. And they show that the penicillin allergy resulted in increased broad spectrum antibiotic use, as well as increased associated healthcare infections. They found 23% increase in Cdiff, 30% increase in VRE, and 14% increase in MRSA. 

In that same study, they went a step further with their cost analysis. So in their three year study, they had over 50,000 patients that came through with a penicillin allergy. And they found that there was almost a full extra day length of stay, and that equated to about 30,000 extra days in the hospital, which they calculated to be about $65 million. I don't know how they calculated this, but they predicted that they could test all these patients for only $6.8 million. So a fraction of the cost of the actual hospital stay. Again arguing that proactive [INAUDIBLE] evaluation is worthwhile. 

In this study out of Europe, this is a prospective matched cohort study. They found that penicillin allergic patients tended to receive, quote unquote, "reserved" antibiotics, which would be like our broad spectrum agents. They're also more likely to get more antibiotics at once because of inadequate coverage. The interesting piece about the study is that they found an increased risk of readmission at 12 weeks post discharge. 

This study by Sade looked at patients in the outpatient setting we have. A chart review of patients who carry the penicillin allergy compared to non penicillin allergic patients. And they show that the mean antibiotic costs of patients with a penicllin allergy were 63% higher, which is not surprising. But the interesting piece is that, upon discharge, the patients with the penicillin allergy were prescribed things that were 38% higher in cost to the patient. So not only does this allergy have an inpatient burden, but also an outpatient burden on patients. 

And this just food for thought This is UVA's wholesale acquisition costs for various antibiotics. So it costs UVA $0.63 to buy a dose of penicillin, which is if you're meropenam, it's five-fold higher. If you're moxi, it's 50-fold higher. So there is definitely cost saving measures that would apply if we can purge this penicillin allergy. Hopefully, in the last few slides, you've realized that having a penicillin allergy results in increased hospital acquired infections, increased length of stay, increased risk of readmission, and increased cost. And so, as you imagine, antimicrobial stewardship programs put this on their radar. 

I want to highlight a couple of different programs because they are unique. This is out of UT Southwestern, and instead of having the physician be the primary driver, the primary driver here is the clinical pharmacist. And the reason they picked pharmacists was because they felt the pharmacists were better at understanding drug-drug interactions and also would be better at educating patients. And so they screened their EMR, picked out patients who were prospective patients or high risk patients, and tackled the penicillin allergy. 

They were able to disprove 90% of the penicillin allergy labels that they encountered. But what was interesting is that 7% of patients who had their allergy cleared had it relisted upon subsequent admission, suggesting that there is an educational piece that really needs to be imparted on the patient about what had just transpired. And this is a flow diagram of the workflow. Screen patients, left out patients that were on [INAUDIBLE] to not be tested, make sure they were not about to get discharged, and then picked up patients on broad spectrum agents and were at high risk. 

This is something out of the Partners system in Boston. This is a decision making algorithm as a way to find safe, alternate beta-lactams. This was an online software that you could access through your desktop or your smartphone, if you have one, and it helps the provider navigate the penicillin allergy. They also had the same pathway for cephalosporin allergy. And this is what it looks like on paper. The top half- The reactions in the bottom half are the decision tree. 

The far left column is the bad stuff, the things you're always told to avoid. The dress, the TEN, and the recommendation is of course to avoid beta-lactams, call allergy if you're desperate. In the middle are your plastic allergy symptoms: wheezing, angioedema, hypertension. Even in that case, they said, no sweat. If you use a third, fourth, or fifth generation cephalosporin, just make sure you do a graded challenge, or if you need aztreonam, go for it. Because remember, aztreonam does not cross react with penicillin, only that one beta-lactam. And if you needed a penicillin or first or second generation cephalosporin, then fine. Call allergy, and we'll sort it out. 

On the far right column are the mild reactions, or the distant ones. They say, game on. Meaning third, fourth, fifth generation, they'll think about it, give it. If you need a penicillin or first or second generation of cephalosporin, fine. Do a test dose, and [INAUDIBLE] are fair game. So as you can see, this gives the provider ample room to work with as far as finding an appropriate agent. One thing that I want to point out is, that nowhere on this chart does it say, please remove penicillin allergy. That's something that they need to do a better job of. We're trying to purge that allergy from the system. 

So is this something feasible? I mean, how much does it cost to actually evaluate patients for penicillin? Again this is Blumenthal out of Mass General. They did a time driven activity based costing analysis where they not only factored in tangible resources but personnel and their times. And they followed 30 patients through the drug allergy clinic to get some data, and they ran several permutations of possible outcomes. 

This is their workflow. From check in through contact with the provider, through the nurses, through testing, and then the wrap up. Highlighted in grey is the amount of time spent at each station. And in US dollars, they found that the average case costed of $220 with skin testing and $84 with no skin testing, and the range of cost was $40 all the way up to $500. The $40 was contact with a mid-level, no testing straight challenge, and the $500 involves bad outcomes of anaphylaxis, needing epinephrine, and all of this is for care. And the one thing they highlighted is that they do not account for facility fees, since, even though they were at Mass General, most of their readers were not at academic centers. 

And I put this slide up more as food for thought. So one of our Fellows pulled up these numbers for me. Dr. [INAUDIBLE], thank you. In the year 2018, there were over 2,000 patients admitted with a penicillin allergy. More than half got antibiotics. The allergy was called 26 times. In this week in mid-January, 600 admissions. 10% reported a penicillin allergy. About half of those got antibiotics and three allergy consults. 

So there are one of two scenarios here. One is you guys already know all this information and are doing a great job, great [INAUDIBLE] alternatives [INAUDIBLE]. The other alternative is maybe there's something we're missing here. Granted, I'm not asking for consults. Our consult [INAUDIBLE] has grown steadily since I've been here, more like a three-fold increase in the past few years. So I'm not asking for immediate consult. 

But I think there may be something here that we can do better, as far as tackling from an institutional standpoint. Now, let's be realistic. There are 32 million people who report a penicillin allergy. Only 5,000 of us allergists, and so that's a lot of work. I'm pretty sure [INAUDIBLE] about the lab, so [INAUDIBLE] allergy patients. 

And that gets at the JAMA study. So this was a study written by an infectious disease doctor who's the primary author, an internist, and two allergists. And they did a good job of reviewing the penicillin allergy, but they went one step further, which I think was important. 

They actually put on the onus to-- they actually pushed the primary care provider to be more active in tackling this penicillin allergy. So this is a risk stratification chart. And what I really want you to focus on is the left-hand column. So they're saying that in low-risk patients who've got a distant history, or a vague history that sounds more like intolerance, or a family history, you know what? Go ahead. Just give them that amoxicillin in clinic. 

Try to purge that allergy [INAUDIBLE], and it's only when there are more serious concerns that you refer to allergies. So that's one key piece from this article that I like that really tries to push the primary provider to play a more active role. And they also provided a toolbox of resources available to help them make that happen. 

So not to worry. Oral challenges are safe. There are several studies showing that you can do oral challenges in the right setting without prior skin testing. There are reactions, but only a few percentage points, and none of them were life-threatening. There were mainly cutaneous and responded well to antihistamines. 

And doing that oral challenge in clinic will not resensitize the patient. They may see review 500 penicillin allergy patients follow them for five years. There's only about a 3% rate of resensitization. So that one dose of amoxicillin your client will not resensitize [INAUDIBLE]. 

So I'm sure there's some fidgeting in your chairs, because after I spoke to my wife about this article, she had a similar reaction. My clinic is busy enough as it is. I don't have the time. I don't have the resources. And maybe I just don't want to deal with potential risk of a reaction in my clinic. But not to worry. We've got a drug allergy clinic that we've established. 

This was started about a year ago in conjunction with ID as a conduit to get your high-risk patients to us, to preemptively screen for penicillin allergy. And over time, we've slowly tried to expand our clinic to specific clinics, and now to a general crowd. So we've started working with cardiology in the pacemaker clinic to get patients in if they need device changes. 

And then anesthesia is also [INAUDIBLE] anesthesia is interested in having us on board with their pre-op clinic. So the predominant focus is really just beta lactams, but we also evaluate for other allergies. This clinic is at both Northridge and Culpeper. And Northridge is twice a month. They're [INAUDIBLE] the whole gamut. And Culpeper is really just restricted to beta lactams. 

And we'll test and challenge if appropriate. Like I said, the goal for me is really to disprove the drug allergy. So what can we do differently? I think there are things that we can certainly improve upon. On intake side, I think we could do a better job of documenting the allergy, really pushing the patients to really tell us what happened, and also maybe, maybe willing to take that allergy off the label if we feel like it's really not there. 

I think there is definite an inpatient aspect that we need to tackle. And this is something that our buddy allergist in [INAUDIBLE] are working on as part of their medicine QI project. I think we also need to standardize workflow and educate staff better. One of the things that I've noticed since I've got here is that there is an inherent angst here about what the allergist does on the floor. 

I mean, there's conceptual hesitancy with challenges in a drug use sense. I also think that we need to document a little better, especially in the allergy tab. So I asked my Fellows to write more in an allergy tab and hit Save. So for me, the patient comes on this date. It's been tested, got challenged, passed, Save. Then I hit Delete. That way, when the patient tries to reenter that allergy at the subsequent visit, we've got a track right here of what we've done before. 

And that ties into the last piece, where there needs to be a better education of the patient as well. Granted, it's not used in outpatient setting, when the patient comes in just for drug allergy testing, as opposed to the inpatient setting, where they're there for three or four other reasons. And oh yeah, the allergist stopped by as well. 

And don't forget, September 28 is National Penicillin Day. It was this state in 1928 that Dr. Fleming discovered penicillin. And I want to thank all these people. I want to thank my beautiful wife, Kim. She's been the biggest supporter throughout the years. And then I want to thank the division. 

They took a chance on me five years ago, as the spouse hire when the-- 

[LAUGHTER] 

--Department of Medicine was recruiting my wife. Larry reminds me of this routinely. And then I want to acknowledge the Brigham for shaping into the physician I am today. Thank you. 

[APPLAUSE] 

Questions? 

[INAUDIBLE] general medicine [AUDIO OUT] remote [INAUDIBLE]. We ordered an amoxicillin drug challenge, and at both from pharmacy and [INAUDIBLE] on the floors. [INAUDIBLE] allergy [INAUDIBLE]. Progress on the inpatient side in terms of [INAUDIBLE] drug challenges in the absence of-- 

So we'll have a meeting with them next Tues-- yeah, next Tuesday. So that's something that we'll address, as far as-- and also standardize the workflow. 

I will say that [INAUDIBLE] like [AUDIO OUT] drug challenges and why you're ordering epinephrine [AUDIO OUT]. 

Yeah. 

It's just what you mentioned. 

Great. Yes. 

[INAUDIBLE] [AUDIO OUT] when we have an emergency [AUDIO OUT] start showing up [AUDIO OUT] somebody else [AUDIO OUT]. 

That's a great question, and I'm not sure I know the answer to that. 

[INAUDIBLE] 

Well, the question was, why is it that allergic reactions predominately manifest themselves as cutaneous reactions followed by pulmonary reactions? And the concern is whether there's some other in organ damage that we just cannot visualize. And so that's a great question. I'm not sure. Larry, you have any idea? Yeah. 

[AUDIO OUT] Drives me crazy. [INAUDIBLE] imagining that we can [AUDIO OUT] question [AUDIO OUT] when we were talking about the cardiac connection, [INAUDIBLE] and I just said, you thought about [AUDIO OUT] end up doing [AUDIO OUT] focusing on the heart or the lungs [AUDIO OUT]. 

It seems like an obvious at-risk population are those [AUDIO OUT] for those who [AUDIO OUT]. 

That is the goal. So one thing is we've been working with ideas to see beyond that little checklist of things to do for pre-transplant patients. And so that's certainly something that we would welcome. And I think if you're not eager to do the challenge in your office, then we'd be certainly happy to see them if you wanted to put us on your workflow. 

[INAUDIBLE] [AUDIO OUT] 

Yeah, no-- 

[INAUDIBLE] [AUDIO OUT] 

Yeah, no, [INAUDIBLE] like I said, we've been trying to target specific clinics, to really get at the problem. And pre-transplant evaluation is certainly one of those clinics that would benefit from this. So we'll talk further about how to make that work. 

What's emphasizing is that [AUDIO OUT] care about penicillin [AUDIO OUT] real effects from penicillin [AUDIO OUT] penicillin [INAUDIBLE] [AUDIO OUT] in this hospital [AUDIO OUT]. 

Yep, less than 1%. 

Thank you so much. [INAUDIBLE] 

[APPLAUSE]