No Cure in Sight

— Few San Diegans know as much about allergies as Dr. Diane Marquardt. An associate professor of medicine at medical school, Marquardt lectures medical students, assists resident physicians, maintains a practice as an allergist, and spends much of her day at her fifth-floor lab on campus, researching allergies.

"I've been here for 22 years. The focus of my research is on the mast cell. It's one of the key cells that releases a lot of mediators -- histamines, leukotrienes -- things that are important in allergic inflammation." The "mediators" Marquardt describes are chemicals that cause inflammation in allergic reactions. She hopes that her research will one day help in understanding (and treating) the symptoms that make allergy patients miserable. "I'm also working on asthma, agents that provoke asthma, and their basic mechanisms. We use lab mice, try to make them allergic to things, then see if they'll wheeze or not. We're learning about mechanisms, causes, and interventions."

Besides looking at mouse models of asthma, much of Marquardt's research has focused on the relationship of adenosine to asthma. Adenosine is defined as a nucleotide (a structural unit of nucleic acid -- one of the components of DNA). "We've looked at it as a bronchospastic agent. Adenosine is released by your lungs when they don't have enough oxygen, and it is also released by mast cells, which are important during an allergic response. We've been making mice that are genetically deficient in one type of adenosine receptor [for testing and observation]. I'd like to think that something exciting will come of it. It's very slow, but eventually something exciting happens." The long-term results that Marquardt hopes for would ideally entail "some sort of pharmacological genetic therapy that works for asthma."

Like other allergists, Marquardt is skeptical about the notion that allergies are on the rise. "I think from a public-health standpoint, asthma is getting worse and much of asthma is allergic. There seems to be a much greater recognition of allergic phenomena. Whether it's worse is hard to say, but it seems like everyone has some sort of allergic problem in their life."

Marquardt has no explanation for the rise in asthma, but she does offer some theories that may explain the upswing. "I don't know how meaningful this is, but there's this thing called the 'hygiene hypothesis.' The nuts and bolts is that we have become too clean, and people aren't exposed enough to the earth, mud pies, or whatever! No one gets as much natural immunity anymore, and everybody's washing their hands too often. Maybe we've skewed ourselves to this allergic subtype as opposed to the bacterial subtype. For people who don't like to clean their houses or wash their clothes, it's great! I tend to lean toward the...if you drop the food on the floor and it's been less than ten seconds and the dog hasn't got it first, you can pick it up and eat it," she laughs. "Other people say that perhaps everybody's houses are so well insulated that we're not getting enough air turnover, so we have all these dust mites, cat hair, cockroaches, stuff floating in the air that really doesn't have much chance to get out because newer houses are so well made. That could be part of it. It's a lot of factors. With pollution, we have more fumes, more smoke, more irritants, and those things aren't good for asthma."

One new treatment Marquardt sees potential in is anti-IGE, a drug that will soon be gaining FDA approval for treating allergies. "IGE is the immunoglobulin [a protein that acts as an antibody] that people make a lot of when they are allergic, and they make it directly against certain things. So if you're allergic to peanuts, and your body makes IGE antibodies against peanuts, then you'll get an allergic reaction when you eat a peanut. The same holds true for dust, cat hair, mold, grass, pollen, or whatever. So to decrease the allergic antibody in your system has the potential to decrease general allergic responses, be they hay fever, asthma anaphylaxis, whatever. It's not likely to be a cure. You're probably going to have to keep getting treated, but that's how we treat most illnesses and disorders. We don't really cure that many."

Dr. Milan Brandon, another San Diego allergist, suggested in an earlier story that anti-IGE could cause some family-practice doctors to take allergy problems into their own hands, bypassing allergists and looking for a quick fix as opposed to developing immunities to allergens. Marquardt doesn't think that will happen. "It's not going to be that simple. You're going to have to get IGE levels, get approval...it's going to be very expensive. I don't think that will be a problem. Personally, I don't think most general-practice people will bother. I think it will be more of a specialty-prescribed drug because of the intricacies of getting someone to pay for it and having to give the shots regularly and all that."

Like Brandon, Marquardt finds allergies are "poorly understood by most physicians as well as the public." Especially drug allergies. "The penicillin allergy can develop at any time, but it also can fade. There's some data that suggests that 90 percent of people who have had more than ten years since their reaction will no longer be allergic. The problem is, you can become resensitized and become allergic again. So you could see someone today who ten years ago had a penicillin reaction, skin-test them, and they're negative. Then you'll give them penicillin. But if you give them penicillin again in three months, you would have to re-skin-test them because it's possible that the course of penicillin resensitized them and caused them to redevelop the allergy antibodies, the IGE to penicillin, and cause them to be allergic next time. If someone comes to my office and says, 'I want to know if I'm allergic to penicillin,' all I can really tell you is if you're allergic today. That's not very helpful, because if it's negative, it gives them a false sense of security the next time. And if it's positive, then yeah, you are allergic, but it still may fade away. It's not a 'yes' or 'no' question. It's really very dynamic. It's a 'today' question.

"Part of the problem with drug allergies is how people define them. A lot of people define drug allergies as anything bad that happens from a drug, so when codeine makes them nauseated, they'll say they're allergic to it, when it's just an expected side effect. When it comes to true allergies, it's defined more narrowly. It's making IGE antibodies to that drug. There are not many that we really understand well or that have been identified that you make IGE antibodies to. Most drug reactions are not true allergies, and we don't really know what causes most of them. It's a very confusing area."

In her own practice, Marquardt treats all types of allergies; like other allergists, the spectrum of severity can be extreme. "I had a patient who had a horrible allergy to bee stings. Bee-sting allergies are tough anyway, because to desensitize people to them, you basically give them shots of bee venom. That's very potent stuff. Even though the desensitization protocol is pretty straightforward, you're basically stinging them with a bee every time you see them! Ultimately, you'll give them a shot with two stings' worth. Well, I saw this woman back in the '80s, and she had tried three times before to be desensitized, and as she would move on, she would have horrible reactions. I had a lot of trepidation about seeing her anyway, but she was sure that if she ever got stung she would die. It wasn't clear to me if I would kill her first or if she would go out and take her chances in the world. I was very, very gingerly moving up on the protocol [increasing the dosage of venom], and she would have reactions, but they weren't that bad. But one time I gave her a shot and within just a minute, she slumped against the wall and said, 'My head is going to explode.' She was very red. She was having anaphylactic shock, and it was very scary. So we gave her some epinephrine, and she got better pretty fast. Then I gave her some antihistamines. I was kind of scared to see her, and I decided that it would be better to give her her own adrenaline, or we might kill her before the bees would!"

Carrying one's own adrenaline to shoot in the case of a reaction -- the "Epi-pen Kit" -- is a common necessity for people with severe allergies. "Pretty much everyone who's had what sounds like anaphylaxis gets an Epi-pen. If you know you're allergic to shrimp or a food or bee stings -- any people with the potential to have anaphylactic shock will get one. There's also exercise-induced anaphylaxis and drug-induced. Mostly things you think you could avoid. It can't hurt to have one. I keep one in my backpack -- not for myself, but for whoever may need it."

Although the progress in new allergy treatments has been slow, Marquardt is confident that there are innovations and breakthroughs yet to come. "We'll have to see. They will come up with a better drug after this one [anti-IGE] comes out. The concept of DNA vaccines is exciting too. They're actually working on that here at UCSD. This involves trying to alter your immune response and skew immune responses away from allergies by vaccinating people with certain types of DNA. It's a new concept being used in a lot of different diseases, but allergy is one that seems to be amenable to it."

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