Elizabeth Phillips, MD, FIDSA, FAAAAI, a Professor of Medicine and Pharmacology, John A. Oates Chair in Clinical Research, and Director of Personalized Immunology at Vanderbilt University, explains a rare but severe allergic reaction to common drugs.
Interview conducted by Ivanhoe Broadcast News in May 2017.
How many people are affected by an allergic reaction to a drug in general? Would you say more severe or less severe?
Dr. Phillips: Many people might think they’re affected by an allergic reaction, they might have mild symptoms like hives or just a mild skin rash and this is very common with antibiotics. For instance, this can occur in about five percent of courses of antibiotics but they’re mild and there are no consequences of them. People feel generally unwell with this mild rashes that occur near the end of the usual 1 week course of antibiotics. In addition many of these “rashes” may be the effect of a virus or an interaction between the drug and an infection and they cannot be reproduced even if the patient is exposed to the drug in the future. These mild non-specific skin rashes are often what both physicians and patients think of with respect to allergy – they don’t think of taking a drug and it being a life threatening event.
How then exactly is that as far as a severe allergic reaction to a drug? Is it called drug toxicity?
Dr. Phillips: Any reaction regardless of the severity if it is mediated by the patient’s immune system is under the broad category of drug allergy. But fortunately the severest of these are relatively uncommon reactions. When I say uncommon it’s somewhat dependent on the population and the drug. It can be anywhere from say one in a hundred to one in ten thousand per course of medication that a person becomes affected by this. The more common reactions tend to be the ones that physicians will recognize that they’re well equipped with how to deal with them. The ones that happen every now and again but are really quite infrequent or that may send patients straight to hospital may totally be out of reach to the physician treating patients in the community.
Give us kind of an idea of the symptoms that you may see, perhaps in your child or in a family member, if they are starting to have some type of reaction to a drug?
Dr. Phillips: The most worrisome symptoms are not just a rash itself or like a measles type rash or even hives; which you can get due to environmental allergy to foods or a number of other products. The most significant reactions are those where patients actually start to feel unwell. They have fever, may lose their appetite, they just may feel flu-like, and really unwell. An important clue is that if this persists even after a few days and worsens if the drug is continued. A normal viral infection will be self-limited, it will go away after two, three, four days the patient will be feeling well again. The problem with these types of drug reactions is they mimic so many other things. If a patient presents you with a fever and some swollen lymph glands, feeling a little bit unwell and feeling flu like, they may very well be told that they just have the flu or they may be put on another medication to control their symptoms. Sometimes even more than that, they may be put on a drug like an antibiotic in addition to what they’re already taking thinking that they have an infection. This just confuses the picture because it’s adding drug to drug. At the end of this you can imagine that you could be left with patients that are sometimes on many drugs and it’s not clear which one has caused the reaction. This is the common trajectory, for patients to initially be seen and the drug reaction related to a drug a patient may have started > 2 weeks ago is not the first thing on the physician’s differential diagnosis.
So often times it’s misdiagnosed or the physician just doesn’t know at that point that it could be something very dangerous?
Dr. Phillips: I mean with common things being common and especially depending on what time of year it is a physician in a busy practice would be seeing hundreds of viral infections. When these come out of the blue like this a major clue could be the presence of a drug that has been started in the last 2 months. They can present a viral infection for example, and commonly this is why younger people and teenagers in particular may get diagnosed with something else, a drug reaction won’t be at the top of the list because they’ve been so healthy otherwise. It’s a time of their life when they do get these types of infections like mono that present with swelling lymph glands, fever, feeling unwell and tired. It’s just assumed that they have something like that and the drug gets overlooked.
Tell us what happened in Izzy’s case and how common is this?
Dr. Phillips: Well this is fortunately an uncommon reaction but Bactrim, an antibiotic, is one of several drugs that can cause severe skin rashes, and it can the full range of drug allergic symptoms from a very mild rash to life threatening disease. The severe form occurs in <1/1000 in the population. A message that needs to be reinforced is that when a drug gets started in the picture then it has to be high up on the list if an otherwise healthy individual suddenly presents a fever and a skin rash, this is going to be something that has to be put to the top of the list rather than something that is like rare very down at the bottom.
In her case and in many of these cases, when the doctor says they’re having some kind of a reaction and to stop taking the drug, that’s not always going to solve the problem?
Dr. Phillips: Yeah, certainly the most important thing is to stop taking the drug. It’s important to see the patient, examine the patient, and find out what’s going on with them at the time. Stopping the drug immediately is crucial. If a fever and feeling unwell has occurred then that also indicates there’s going to have to be some more detailed management there. You may have to measure the function of other organ systems like the liver and the kidney. The patient will need to be monitored over several days, if there is any evidence of anything happening in any organ systems then hospitalization may be indicated. Observation and other treatments may need to be put in place like steroids.
Tell us a little bit about these syndromes and why is it so difficult to diagnose this?
Dr. Phillips: So DRESS is a really specific type of drug allergy. It used to be called drug rash with eosinophilla and systemic symptoms, but this was later renamed to drug reaction with eosinophilla systemic symptoms since a very small number of patients do not have a rash. If you break that whole acronym down into individual terms, although they often have the full spectrum, they don’t always and any one of those can be missing, it’s confusing to physicians because it’s not a common disease. There are so many different flavors of drug reactions that happen in clinical practice that are not DRESS like just a rash, a mild fever, self-limited symptoms. DRESS however is a syndrome to be taken seriously. It has a low mortality, however it’s sneaky so it presents itself after a patient has been on a drug for some time, usually at least a couple of weeks and it starts with fever. It can start with a lower fever and then it escalates to a high fever. There may be some swollen lymph glands. A normal individual may think, oh I’m just coming down with the flu. Then the rash comes and then that’s often a common point that physician care will be sought. The rash is usually the trigger point that the drug has to be stopped and further investigations need to be done. In a normal individual that just has a fever, rash, facial edema, swollen lymph glands and mild liver involvement, even with no treatment whatsoever just stopping the drug and watching, the symptoms will go away. DRESS is a major assault on the immune system and causes the immune system to be totally out of whack. The immune system compensates to try suppress the response to that drug, and this could be two or three weeks after the drug has been stopped the patient appears to be getting better. Then out of the blue they can have an apparent recurrence of symptoms in the absence of the drug and after the initial improvement This commonly happens when patients have been on a steroid and they’re being brought off the steroid. Sometimes even in the absence of that this strange turnover of the immune system, that’s really being knocked about seems to come in to play and there seem to be things happening like reactivation of latent viruses that live within us sometimes recurrence or new organ dysfunction. It’s a time that requires close monitoring. All of this is usually happening within the first twelve weeks of DRESS, manifesting as a syndrome but there can be even longer term effects on organ systems. Even some diseases like autoimmune diseases most commonly thyroid disease but also diabetes, and lupus have been described following DRESS. The three month period following the disease is the most critical, but patients really need to be followed for four years or so after their diagnosis to make sure there’s nothing else that the immune system has recovered.
So what you’re saying is doctors need to be made aware that DRESS or one of these severe reactions is a possibility, and these patients need to be monitored for a very long period of time essentially?
Dr. Phillips: Right. It’s important to know that really any drug or any pharmaceutical product could in theory cause DRESS or another severe immunologically mediated drug reaction but there are a few common ones that are at the top of the list. This varies a little bit according to geography, according to regions but within regions we know for instance in the United States antibiotics would be at the top of the list of drugs that would be causing these problems. Drugs used for seizures, mood disorders and gout are also in that category. There’s a limited armamentarium, if you will, of drugs with the highest. We think this varies according to genetic factors that are dependent on ancestry and geography. Apart from the science part of the management is education, actual recognition that physicians are aware of these and that they can actually not only stop the drug, but get the patient to the right care early in the disease, and its key. Appropriate medical management is critical to saving lives because as I mentioned with DRESS the mortality is still in the less than 10% but failure to diagnose involvement of organs such as the liver and the heart can be actually driving bad outcomes in patients. It really needs to be a disease that is monitored carefully.
Tell us a little bit about why is Izzy’s mom here today.
Dr. Phillips: An exciting research breakthrough not only for DRESS but other drugs, has been sciences driven discovery of specific genes that have been defined to be associated with them. This of course opens it up to a whole new world where for some drugs we can actually now test patients to see if they carry a risk gene to develop one of these terrible toxicities. Patients who are in that category can simply avoid the drug. However, the science is still evolving and we don’t have these types of tests available for all drugs in all populations. The dream would be that in the future on a single visit to their primary care provider and based on a panel of genetic tests a patient could have a fairly comprehensive idea of the drugs that will be both safe and effective for them in the future. We know that very soon after these genetic discoveries have been made really globally it’s very clear that the genetics sets the boundaries for the disease. In other words, in the case of severe drug allergy like many other genes for cancer and autoimmune diseases there are already genes that tell us who could get the disease however we still do not know of those who carry a genetic risk factor who will get the disease. We know within the ecology of a patient’s life for instance, there are several factors that happen from birth through adulthood. Continuing research will be instrumental in understanding the mechanisms of these drugs reactions to understand why some but not other individuals of a certain genetic makeup, will be affected. It’s when we’re talking about drug induced diseases, of course this is very challenging because it’s not like cancer where we can go back and say, okay your mother, your grandmother, your aunt, you’ve got this strong family history. Most people that actually have a family member that has actually been tragically affected by one of these terrible drug reactions would never have another member in the family that’s ever been exposed or developed a similar disease.
The best advice that you can give right now to people out there is to be aware of this and to be aware of possible reactions?
Dr. Phillips: The genetic research is really exciting. We’re at the point now where we can define a spectrum of genes that are likely to be risk genes and I think this is a breakthrough that we and others have brought; you have defined genes that seem to be coming up again and again. These are important clues as to the immune responses the patients are making that could be driving these reactions. We think that maybe not today, maybe not tomorrow but maybe in the next five to ten years we will have a greater understanding of the mechanisms behind these drug reactions and also ways to prevent them. This is the mission of personalized medicine research into serious adverse drug reactions – to be take the threat out of taking drugs – to get the safest drug to the right person at the right time.
And if people wanted to learn more about the research they can go on the website for Vanderbilt, right?
Dr. Phillips: Yes.
Like you said before if you get a rash from a drug that you’re taking don’t panic, probably you’re not going to have a fatal severe reaction but you need to get checked out?
Dr. Phillips: That’s right. It’s just as important for patients that have mild rashes to drugs like amoxicillin that may not be drug related or may not be permanent, that they don’t get labeled with something unnecessarily for the rest of their life. It’s very important for anyone that’s having a severe reaction where the risk is genetically mediated and will persist over the course of their lifetime that they get immediate and appropriate medical care and that they get appropriately labeled not just regarding the drug that they could be having a reaction to, but other chemically similar drugs that they could be at risk to have a reaction to in the future.
END OF INTERVIEW
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