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Current Standards of Care & Advances in Immunotherapy

A Roundtable Discussion:  

Subcutaneous Immunotherapy (SCIT) 

Listen to the podcast

Panelists

Indications

Dr. Cox:  For years, the specific indications for allergen immunotherapy have been allergic asthma, allergic rhinitis and stinging insect anaphylaxis.  In the third update of the Practice Parameters, atopic dermatitis with aeroallergen sensitivity and bothersome and frequent large local reactions to stinging insects were added as potential indications. 

Dr. Nelson:  The one common allergy that is not an indication is food allergy.

Dr. Cox:  And we might also mention that chronic urticaria does not have an indication for immunotherapy.

Prevention of asthma

Dr. Cox:  Up to 40 percent of people with allergic rhinitis are at risk of developing asthma.  A potential significant benefit of immunotherapy is that you may prevent that.

Dr. Finegold: If you have somebody who has moderately severe allergic rhinitis, and his or her parents have gone the route from allergic rhinitis to developing asthma, that’s the patient who would be a very good choice for immunotherapy used in a preventative manner.

Dr. Wallace:  On the other hand, if a patient has a strong family history of allergy or asthma and has, say, a mild case of atopic dermatitis or food allergies, one would not proactively do allergy skin testing and place that patient on immunotherapy to prevent the development of asthma.  So there needs to be a strong indication for immunotherapy with the potential for an add-on benefit.

Dr. Bernstein: There are currently and will be studies planned to answer if, for instance, sublingual immunotherapy is an effective modality for prevention of asthma in children.

Special patient populations

Children

Dr. Finegold:  The updated Practice Parameters state there is no upper or lower age limit for initiating immunotherapy.  That should be successful in changing the minds of some who adhered to a rigid 5-year lower age limit.  There are some long-term studies on children less than 5 years of age who have done well.  It’s up to the physician to determine the starting age and when it’s appropriate.  For example, we’ve not had any arguments about venom immunotherapy in very small youngsters because of the life-threatening nature of the reaction. So I think clearly we’ve moved away from that artificial 5-year marker.

Dr. Lanier:  The 5-year marker was not necessarily set just for the development of the immune system.  There also were socioeconomic factors, such as could the child tell you if they had a reaction? 

Dr. Finegold:  Well, first I want to get my chance to remind everybody that this is the 100th year of immunotherapy as an active treatment.  For a number of years, we gave allergy injections to small little kids and I reviewed one study3 of anaphylaxis from Australia talking about children less than age 5.  And it was clear that you didn’t need a child to tell you they were having anaphylaxis.  It’s quite evident from the examination and the behavior of the child.  So this whole idea that a person had to be able to voice something is sort of a specious argument, even though it crept into the Parameters for a number of years.

Dr. Wallace:  If we are using immunotherapy to prevent asthma and we know that asthma usually develops before age 5, wouldn’t it behoove us, given there’s an indication, to start immunotherapy as early as possible?  How does everyone feel about that?

Dr. Blaiss:  I think that’s fine.  The problem is that we still don’t have definitive data to show that there is prevention.

Dr. Nelson:  What is better established4,5, however, is that in children who are sensitive to only one aeroallergen, immunotherapy reduces the likelihood of additional sensitizations from about 65 percent to about 25 percent over the course of six years of follow up.  That prevention is very definite and to get that benefit it’s likely to be necessary to start before age 5 in monosensitized children.

Pregnant women

Dr. Blaiss:  The data state that it is safe to use immunotherapy during pregnancy.  If someone is on buildup, one holds at the dose the individual is on at the time she becomes pregnant.  In my practice, I leave it up to the mom and the OB.  I give them the safety information and let them go from there.

Dr. Finegold:  Has anybody had a patient who’s pregnant and has a lot of symptoms so you actually want to continue immunotherapy and slowly increase?  Are there any situations where we wouldn’t follow the rule of just maintaining the dose in pregnancy?

Dr. Cox:  In the updated Practice Parameter, we stayed with the previous recommendation not to dose increase, but we added the recommendation that if somebody begins immunotherapy and gets pregnant while at a dose not likely to be effective, you consider discontinuing and resuming treatment after the pregnancy. 

Dr. Wallace:  I think if there were an adverse event we would have a problem citing good established studies to indicate why we chose to increase.

Dr. Cox:  I do think the one exception for continuing a buildup would be venom stinging insect hypersensitivity.  Would you agree?

Dr. Blaiss:  Yes.

The elderly

Dr. Nelson:  Immunotherapy is a treatment for IgE-mediated disease and IgE levels peak in the early teenage years.  They decline somewhat through the fourth decade and then in the fifth decade start declining and go down quite precipitously into the 60s and 70s.  So we should consider very carefully whether we’re still dealing with an IgE-mediated disease in the elderly. It’s not that they should not be treated with immunotherapy but you should be very careful to be sure that this is IgE-mediated disease. 

Dr. Wallace:  On the other hand, I think all of us have patients in their 70s and 80s with significant allergic disease who do not have co-morbidities that would be contraindications to immunotherapy, and certainly those patients can be started and treated effectively.

Premedication

Dr. Lanier:  Premedication may be more a treatment for the physician than it is for the patient. It’s pretty commonly done across the country, but I’m not so sure whether we have sufficient data for it yet.

Dr. Bernstein:  It’s in the Parameters that premedication, particularly with antihistamines, seems to be most effective in reducing rates of systemic reactions for schedules that administer immunotherapy faster, like rush or ultra-rush or cluster therapy.

Dr. Finegold:  A paper a number of years ago by Muller6 looked at the effects of insect sting allergy and fexofenadine and found that patients getting the antihistamine actually had a somewhat enhanced result.  On the other hand, there’s a very recent study7 using montelukast that says the opposite, that montelukast may have interfered with an immune response.  So I suppose the answer is: it all depends.

Dr. Nelson:  There used to be a concern that antihistamine premedication would disguise mild local reactions, which at that time were thought to predict the occurrence of a systemic reaction.  There now are two papers – one from Denmark by Nielsen8 with cluster immunotherapy and the other from Japan9 that used antihistamine premedication with conventional weekly immunotherapy – and both showed reduction not only in local but also in the severity of systemic reactions. So I think there’s a good basis for using antihistamines and there’s no basis for being concerned about disguising or masking warning signs of systemic reactions.

Dr. Finegold:  In practice, because there’s a lag with standard immunotherapy to the time that patients get clinical benefit, we should caution them to continue their medications.  Some patients think they’re going to get better after the first shot.  They stop their medication and actually get worse.  So we generally continue medicines for the first few months of immunotherapy and evaluate the patient to determine when to stop or to continue the antihistamines and other symptomatic medications.

Adverse events and risk factors

Dr. Bernstein:  I’m currently conducting a surveillance study10 of systemic reactions to subcutaneous immunotherapy.  We are monitoring systemic reactions in the patients of all the members of the College and the Academy.  In the first year of our study we found that about 0.1 percent of all injections are associated with systemic reactions; and only 3 percent of these are of the severe nature that we consider anaphylactic reactions.

Dr. Blaiss:  When you look at the studies of subcutaneous immunotherapy, the group we have to be most concerned about are the unstable asthmatics.

Dr. Bernstein:  Additional risk factors for the most serious, near-fatal reactions appear to be administering injections during the peak of the pollen season and treating individuals with a past history of systemic reactions.  Another consideration is dosing errors, which often seem to be associated with more severe anaphylactic reactions.

Dr. Finegold:  I want to add that in the past two years there have been about 16 million immunotherapy injections and there have been no fatalities. Perhaps we’ve just been very fortunate but I believe that physicians and their staffs have become better at both recognizing and treating early signs and symptoms of anaphylaxis.

Dr. Cox:  Fatalities have never been very high – about 1 in 2.5 million injections was the historical number after a long period of tracking; those surveys go back to 1945.  Now it’s even lower.  I would like to bring up another potential risk factor and see what the group thinks.  There was one study11 that looked at systemic reactors versus patients who did not have systemic reactions and they found that the group that had systemic reactions had a higher frequency of large local reactions, about 35 percent of injection visits versus 9 percent in the non-systemic reactors.  So repeated large local reactions – defined in this study as 25mm or greater – may be a risk factor.

Dr. Nelson:  I think you have to consider how to take that study.  The two big studies12,13 that showed that a large local was not predictive of a systemic reaction the next time allowed people to continue the progression of the buildup of immunotherapy.  Now, if you’re defining a population that’s different because they have frequent locals, that still doesn’t mean that every time they have a large local you should cut back on the dose because the result is that people go for years on immunotherapy and never reach the maintenance dose.

Dr. Cox:  So what’s the take home message?

Dr. Nelson:  The take home message is for any individual injection, a large local the previous time should not modify your injection that time.  But if you observe patients having many large local reactions, then maybe you want to keep them in the clinic a little bit longer, maybe those are the patients you want for sure to give an EpiPen because they’re at increased risk for systemic reaction.

Dr. Bernstein:  Another concern in this area is the occurrence of late reactions beginning 30 minutes after injections.  In our survey10, we recently found that this represents about 13 percent of all systemic reactions. The vast majority of these are mild, although we did note a few anaphylactic reactions – all of which were treated appropriately.

Dr. Finegold:  Patients don’t enjoy large local reactions and it frightens them.  Even though we may know that we can proceed, what I do in actual practice is if somebody has a large local, I repeat the dose the next time or go down a dose and then come back up to see if I can proceed.  And so we do this back and forth a bit.  I think patients feel a lot better when doctors acknowledge their concern and seem to do something about it.

Dr. Blaiss:  Another thing we need to mention as far as risk factors is we need to know the medications patients are on, especially the problem associated with beta blockers.

Dr. Cox:  In the most recent update of the Parameters we looked at ACE inhibitors and patients on venom immunotherapy.  It’s been thought for some time that patients on venom immunotherapy who also are on ACE inhibitors may have more severe reactions. So the group basically placed ACE inhibitors in the same category as beta blockers in immunotherapy based on a few case reports of patients having severe reactions from venom immunotherapy while on ACE inhibitor and one large multi-center study that identified ACE inhibitor use with risk of more severe anaphylaxis from a field sting.  If you can find an alternative, equally effective medication for patients on venom immunotherapy, that is preferred.

Dr. Wallace: But does this hold true for patients who are taking ACE inhibitors and receiving aeroallergen immunotherapy?

Dr. Cox:  No, not aeroallergen, just venom immunotherapy. 

Dr. Wallace:  What about switching the patient to ACE receptor blockers; does that solve the problem?

Dr. Cox:  There does not appear to be an increased risk with patients who are on angiotension receptor blockers.

Rush and cluster immunotherapy

Dr. Nelson:  I don’t think rush and cluster should be considered co-equals.  Rush immunotherapy has been used for a long time and is associated with a greatly increased incidence of systemic reaction.  Even with fairly intensive premedication, systemic reactions affect up to one-third of the patients.  On the other hand, cluster has not been shown to be associated with an increased occurrence of systemic reactions – at least when it’s administered, say, twice a week over a period of four weeks.  The advantage of course is that with cluster you can easily reach maintenance in four weeks as opposed to six or eight months with conventional therapy.

Dr. Bernstein:  I agree.  Cluster is a very attractive new modality that we should all be thinking about because many of our patients don’t have the time to come in for frequent injections required in more conventional buildup regimens.  This affords them the opportunity to get to efficacious doses much more quickly.

Dr. Cox:  In many third-party payer plans there is a large co-pay associated with each treatment, which is defined as each day of therapy.  So cluster may be very cost-effective for the patient as well.

Dr. Wallace:  I do a fair amount of cluster and I’m running into a problem with large local reactions as I get close to target dose.  Are any of you seeing that?

Dr. Nelson: In rush I always had the impression that it was in the 1:10 dilutions of maintenance (1:10 vol/vol) that we got into the large locals.  If we just ignored them as we got into the final concentration they would subside.   You needed to push through it.

Needed research/unanswered questions

Dr. Finegold:  Let me throw out something that has always been a question in my mind.  If you go back to Cook and the way he originally treated allergy, he graded patients by sensitivity:  A, B, C, D, with A being the most allergic and D being the least allergic.  He did his immunotherapy schedules and dosing based on the grade.  We seem to have gotten away from that except when somebody is very sensitive, and then the allergist may alter the course. But so many times the course just proceeds at one set dose, bottle after bottle, regardless of how sensitive the patient is.  The second part of the question is, should we be dosing people by weight?  After all, now we’ve had seven or eight years of experience with Xolair therapy where weight is a definite factor in how you dose the patient.  Why don’t we do that with immunotherapy?

Dr. Nelson:  Why do we give the same dose to kids as we do to adults?

Dr. Bernstein:  We don’t really have the data and we don’t have the dose response studies with subcutaneous therapy that we may have with some of the sublingual formulations, so those studies really would need to be done.

Dr. Wallace:  And should maintenance level be different with those that are more sensitive?

Dr. Finegold:  Smaller people, more sensitive people?

Dr. Nelson:  Of course, another question that people bring up is the person who can’t tolerate getting above a dose of, say, 1/100th of the maintenance.  Do they benefit?

Dr. Bernstein:  Clinically, we see that some do.

Dr. Finegold:  If they come back we presume they’re getting some benefit.  But that’s not a great way of doing research.

Dr. Bernstein:  We need more data.


References

Other topics:

• Sublingual immunotherapy (SLIT)
• Other immunotherapy delivery methods (intranasal, epicutaneous and intralymphatic)
• The current and future role of the allergist in immunotherapy

Perspectives Article published in the November 2011 issue of Annals of Allergy, Asthma and Immunology.

 
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