Gleich: In the short-term T cell lines resulting from stimulation with Trichophylon antigen, you said it was a Th2 response, but your slide showed almost no IL-4 and predominant IL-5.
Platts-Mills: I don’t know what we are supposed to call a T helper cell that produces predominantly IL-5, perhaps Th-IL-5. The paper actually gives the real numbers for all the T cell lines and it’s quite clear that some of them are producing IL-4 but very little, and I think we are not out of line with many other groups who find it very difficult to get high levels of IL-4 production in these short-term T cell lines.
Gleich: That observation would fit very nicely with some observations we made in chronic eosinophilic pneumonia where we saw no IL-4 at all, but high levels of IL-5. Another quick question: the rationale for allergen avoidance not being efficacious in a given patient was not clear to me.
Platts-Mills: The question is: how much of the lung hyper-reactivity is due to current exposure to allergen in the patient’s house? There are lots of problems. One is that they may be getting exposure somewhere else, in which case their house won’t give the answer. The other is that they may have bronchial hyper-reactivity that has built up over many years and has become effectively irreversible, which we think happens in some children. Another thing is that there may be enormous differences between different patients. There may be patients who are so sensitive to allergen that, even if you achieve a 90% reduction, you still won’t make a big difference. If the epidemic was really due simply to increases in current exposure, allergen avoidance should be much easier than it is.
Gleich: May I take your argument one step further? As a clinician, you are treating a hypothetical patient who lives in a house with many cats; the patient has a strongly positive skin test to cat; and the patient shows a positive inhalation and challenge to cat dander. In this instance, do you not recommend the cats being removed?
Platts-Mills: Cat avoidance can be achieved. Of course you advise people to get rid of the cats, but they won’t get rid of them. You can advise them to do the whole procedure: washing cats, removing bedding, removing carpets, air filtration and the net result of that is they will get rid of the cat.
Creticos: I’m just wondering about the fascinating issues to what’s evolving here. You didn’t mention aromatic hydrocarbons and I’m just wondering about that process, because that’s certainly critically different between Western society and rural or, indeed, pastoral societies.
Platts-Mills: There are many arguments against the aromatic hydrocarbons. New Zealand is the most impressive. New Zealanders really have asthma in coastal towns like Christchurch where the wind blows in off the Pacific. They have good papers about air pollution of all kinds showing no correlation with asthma at all. David Lang’s study on asthma mortality in Philadelphia showed no correlation with changes in air pollution or distribution of air pollution. For traditional air pollution, that is particulates and SO2, the English data show an absolute inverse correlation. That is, as these particulates fell, asthma rose. So you can think about the car, but you can’t think about any other form of outdoor air pollution.
Lichtenstein: The message I got from you Tom is house-dust mite are not important and passive smoke doesn’t cause asthma any more.
Platts-Mills: The whole point is that there is an epidemic occurring in mite-allergic children and you can say either there’s been a massive increase in the number of children who are becoming allergic to mites because their immune system has changed, or the inflammatory system has changed and they’re making a much bigger inflammatory response for the same number of IgE antibodies, or something completely different has changed. But it’s clearly occurring in children who have become allergic to their indoor environment and they all spend most of their time indoors.
Togias: Could you elaborate a little bit on your ‘obsession’ with exercise and how do you see that being a factor. In other words, pathophysiologically, how do you envision this being a factor?
Platts-Mills: You are personally responsible for part of this obsession since it was your paper in the Journal of Clinical Investigation (96, 1995) that showed very dramatic effects if normal people do prolonged shallow breathing and then inhale methacholine, that they wheeze, and as soon as they take a deep breath that effect is broken; obviously the full argument would be that prolonged exercise with deep breathing has a protective effect on the lungs, and I think that’s the best hypothesis at the moment. Certainly I don’t think we are talking about intensive training, because we know there are side-effects of that; we are talking much more about the prolonged exercise that children normally do when they’re playing.
Raz: I wanted to consider another bullet in your last slide: this is conventional therapy which I think may contribute to the chronicity and maybe even to the frequency of the disease. I’d like to mention two points. For instance, all the ft agonists are increasing cyclic AMP. Cyclic AMP is known to bind as a non-system to Th2 so whenever you give this type of medication you reach the short-term goal, but you commit these patients to be more atopic in the long run. Very similar phenomena happen in rheumatology: all these non-steroidal anti-inflammatory drugs downregulate prostaglandin E2, which in a way biases the system to Thl, and if you believe that rheumatoid arthritis and its relatives are Thl-mediated diseases, so actually this intervention interferes with the natural healing process of counterbalancing Thl, Th2.
Platts-Mills: I’m not going to address the rheumatology, but the β2 issue. All previous copies of my model actually have β2 agonists as an enhancer, but several people have argued that there are equal numbers of studies showing no effect of β2– I think you can make a case about β2 and I think it should be one of the possibilities. I don’t think it’s convincing as a cause of the linear increase of a phenomenon (i.e. asthma) on the scale that we have seen.
Busse: To return to your Trichophyton model: you indicated that you think this is a causative factor with intrinsic asthma. Do you think it’s the cause of their disease or do you think it’s simply acting as a trigger antigen in susceptible individuals? And I think that it becomes a critical point in your argument.
Platts-Mills: Absolutely. Some of the patients are highly allergic to many allergens and also allergic to Trichophyton, but some of them are only allergic to Trichophyton. So you can do an intradermal skin test at the whole arm and there’s a big 3 + intradermal to Trichophyton and all the other allergens are negative. They have fungal infection on their toes and you give them fluconazole and it behaves as if the fluconazole was an anti-asthma medicine. In those patients it appears convincing to us that this is a primary cause of the disease; however, they have bad sinusitis as well, their sinus symptoms improve, their sinus CTs do not change. You can actually take it either way.
Busse: Why does the lung become the target?
Platts-Mills: I think that’s exactly the same as the old arguments about why one mite-allergic patient has rhinitis, one mite-allergic patient has asthma and another has atopic dermatitis with no lung disease, or the issues about why one food-allergic patient gets asthma while other food-allergic people get skin disease. That’s the whole issue of target specificity in allergy, which we clearly don’t understand very well.
Metzger: The New Guinea children don’t have any asthma. Do they have viral infections?
Platts-Mills: I don’t know that, and I don’t know that anyone has looked carefully enough at whether they have viral infections. I can take that one step further; there are very striking studies in old people: if they do 40 minutes of exercise a day they report a decrease to one-third of the number acute upper respiratory infections and no-one has documented what the cause of that damage is.
Metzger: I’m fascinated by this exercise business, because I’m involved with the fibromyalgia group, most of whom have rhinitis and sinusitis—the ones I see have a lot of allergies. Their biggest problem is they don’t exercise and of course they have many other disorders. Could there be a hormonal involvement in this?
Platts-Mills: I think there are far more questions than answers.
Proud: To return to the children in New Guinea and Africa and to your original thought that we treat inflammation and don’t even know if it’s there. In those children for whom you believe that exercise has a protective role and who have positive skin test reactivity, does anyone know whether they actually have lower airway inflammation but do not present with symptoms of asthma?
Platts-Mills: We know that people have done studies on exercise-induced asthma. Lucy Naganga did methacoline challenges on children in rural Africa and they have a very low prevalence of methacoline sensitivity. But that’s not quite the answer to your question. It doesn’t answer whether they actually have eosinophils in their lungs and I don’t think we know that. In most of those areas there are a lot of parasites.
Gelfand: In an immunological sense, to take a lot of these observations and instead of making random associations, the question is: have you looked at the children who are not asthmatic and who have the same house-dust mite asthmatic exposure and different genetic backgrounds, and looked at the protective responses? Namely, are they sensitized to house-dust mite and not making IgE, but making IgG or switching their T cells and so on? I believe that unless you’re able to show some of that sensitization with a skewing of the response in a different way than those that have a genetic predisposition, these tend to be somewhat spurious associations.
Platts-Mills: You said many different things. There are several phenomena; the first is that in any of these studies there are twice as many allergic children as there are asthmatic children. So simply becoming allergic doesn’t make you become asthmatic; it is a risk factor for becoming asthmatic. So we can ignore the allergic children, those who have clearly defined IgE antibody. Now let’s look at the others: in the Poole (UK) study, where we followed the children for 10 years, we measured IgE, IgG and IgG4 and we didn’t see anything. Other people have said they can see some evidence of an immune response and Jane Warner says she can see evidence of T cell responses in very early childhood. We think those T cell responses are spurious; we don’t think they represent proliferative immune sensitization at all. But you are implying that it is a simple matter to measure protective responses in the human, and I don’t think that’s true.
Gelfand: What do you think distinguishes those with an IgE response who develop asthma and those who don’t?
Platts-Mills: I don’t know that any more than I understand why one patient develops atopic dermatitis and one develops asthma. That’s a very big issue.
MacDonald: I know you don’t study this, but in the population of children that do not have asthma, does that continue into adult life in the New Guinea population?
Platts-Mills: Most of the villages in New Guinea didn’t have any asthma at all until the Australians introduced blankets and then there were a few highland villages where the adults developed asthma, but they actually wrapped mite-infested blankets around their heads and slept with the mite-infested blankets around their heads, when they had never had high levels of mite in the houses before. So, there are two different answers to your question.
MacDonald: If you’re right about indoor sensitization and decreased exercise, how do you propose to bring your own children into the millennium on the World Wide Web?
Platts-Mills: I think a modern digital computer with high-quality visual display and full television access is the most scary thing for parents that the world has ever invented.
He knows everything about medications – to which pharmacological group the drug belongs, what components are included in its composition, how it differs from its analogs, what indications, contraindications, and side effects remedy has. John is a real pro in his field, so he knows all these subtleties and wants to tell you about them.