Con: Immunotherapy Is Not Clinically Indicated in the Management of Allergic Asthma

N. Franklin Adkinson Jr., M.D.

Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland

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When immunotherapy was introduced by Noon in 1911 and for most of the 50 years that followed, it was about the only game in town. Not so in the new millennium. To be clinically indicated today, immunotherapy for asthma must be more effective or less toxic, or both, than alternative therapies. Or it must possess some unique advantages that can't be found elsewhere. This is the burden of proof to which I hold my worthy opponent.

So, how effective is immunotherapy, and compared with what? If you look at modern clinical trials of immunotherapy, where symptom indices, pulmonary function, and medication requirements were carefully monitored, the size of the therapeutic effect, if observed at all, is invariably modest (1, 2) and quantitatively comparable to effects observed with any of a number of bronchodilators (3) and cromolyn-like drugs (4).

One illustrative example of this is the collaborative study of immunotherapy for ragweed asthma (5). This careful study observed patients for asthma flares during one ragweed season followed by randomization to high-dose ragweed injections or placebo for the next two years. Morning peak flow measurements during the ragweed season after one year of treatment improved 5.1% (p = 0.06); symptom scores did not change, although medication use declined significantly (p = 0.01). After two years of treatment the results were even more modest. Numerous clinical studies have documented comparable degrees of effectiveness for drugs such as anti-leukotrienes, salmeterol, and nedocromil.

No published studies have demonstrated a steroid-sparing effect for allergen immunotherapy. A randomized study of perennial allergic asthma in children done at Johns Hopkins showed no difference in the requirement for either inhaled or oral steroids between immunotherapy and placebo groups (6). A direct comparison of inhaled steroids and immunotherapy has not been done, and is not likely to be done because of ethical and logistic constraints. So my first conclusion is that immunotherapy, although effective in model systems, produces modest clinical benefits comparable to what is readily achieved with bronchodilators and nonsteroidal antiallergy drugs.

The next issue is safety. Review of available data through 1992 has indicated that at least three to five individuals die as a result of immunotherapy mishaps each year in the United States (7). The British experience suggests that about 75% of immunotherapy deaths occur in patients with asthma (8), indicating that asthma is a strong risk factor for a fatal outcome from systemic reactions. This observation has led to guidelines that mandate prescreening subjects with asthma before immunotherapy injections.

I am sure that almost all qualified allergy specialists adhere to these guidelines, but the real world is a bit different. Injections are not always under the direct supervision of a qualified specialist, and dosing errors, which are responsible for as many as half of systemic reactions to immunotherapy, can be minimized but probably not eliminated. On the other hand, alternative pharmacotherapies, including inhaled steroids, have remarkably little acute toxicity, and no directly attributable mortality.

Immunotherapy could be clinically indicated in allergic asthma if it possessed advantages or benefits not obtainable with alternative treatments. Immunologic specificity is a distinctive feature of immunotherapy but such specificity is a double-edged sword. If important treatment allergens are omitted the clinical result will be suboptimal. And unlike pharmacotherapy, immunotherapy provides no protection against nonallergic asthma triggers such as viral infections, irritants, and exercise.

Some have suggested that compliance with immunotherapy injections every two to four weeks may be easier to achieve than daily compliance with medication. But in practice, for perennial asthma, it is rarely if ever an either-or proposition. Most perennial asthmatics are asked to do both (9). Some have calculated the cost of supervised immunotherapy to be approximately equal to the cost of daily inhaled steroids (5). Thus, there is no special advantage here.

We all know that moderate doses of inhaled steroids predictably dampen nonspecific bronchical hyperreactivity to a modest degree. With one or two exceptions, studies of immunotherapy, including our own (6), showed no effect on bronchial sensitivity to methacholine or histamine (1, 2). Similarly, we had postulated that broad-spectrum immunotherapy in growing children might induce remission of asthma earlier or more frequently than would otherwise occur. However, our own study showed no effect on partial or complete remission rates (6). Thus far, therefore, we have been unable to identify unique benefits of immunotherapy that could justify the use of this treatment if it is otherwise not more effective or less toxic than alternatives.

What about patients with moderate to severe persistent asthma who may have uncontrolled symptoms and exacerbations despite multidimensional pharmacotherapy including inhaled steroids? I personally believe that immunotherapy for asthma in the United States is most commonly employed for allergic asthmatic patients with intractable perennial asthma (9, 10). For this reason we targeted perennially allergic children with moderate to severe asthma when we undertook a randomized trial of broad-spectrum injection therapy of 121 children with allergic asthma. About one-half were taking inhaled steroids. Every two weeks medications were adjusted downward by masked physicians using an algorithm. To the surprise of some of us, the results were crisply negative. Immunotherapy had no discernible effect on the requirement for medications, days on oral or inhaled steroids, medical care utilization including urgent care needs, or asthmatic symptoms. Methacholine sensitivity decreased significantly but equally in both groups. Likewise, partial or complete remission from asthma occurred in 31% of the immunotherapy group, but in 28% of the control group. Peak flow rates did improve minimally (mean, 3.8%) in the immunotherapy group. We found trends toward effectiveness for immunotherapy for subsets who were younger at the start of therapy, and those who had milder disease as judged by medication requirements.

My conclusions from these considerations are as follows. I hope they will be your conclusions as well.

1. Immunotherapy may be modestly effective in symptom relief and protection against allergen challenge, but as an adjunct therapy it is not clinically indicated for allergic asthmatic patients with moderate to severe persistent asthma.

2. Immunotherapy for asthma has not been shown to possess unique benefits that are not achievable with alternative remedies.

3. The best clinical results from asthma immunotherapy are seen in younger patients with less established and/or severe disease, but the hypothesis that this targeted population benefits uniquely from immunotherapy has yet to be evaluated.

	References

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1. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials. Am J Respir Crit Care Med 1995; 151: 969-974 [Abstract].

2. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma (Cochrane review). In: The Cochrane library. Issue 3. Oxford: Update Software; 2001.

3. Kemp JP, Cook DA, Incaudo GA, Corren J, Kalberg C, Emmett A, Cox FM, Rickard K. Salmeterol improves quality of life in patients with asthma requiring inhaled corticosteroids. J Allergy Clin Immunol 1998; 101: 188-195 [Medline].

4. Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000:343:1054-1063.

5. Creticos PS, Reed CE, Norman PS, Khoury J, Adkinson NF Jr,, Buncher CR, Busse WW, Bush RK, Gadde J, Li JT, et al . . Ragweed immunotherapy in adult asthma. N Engl J Med 1996; 334: 501-506 [Abstract/Free Full Text].

6. Adkinson NF Jr, Eggleston PA, Eney D, Goldstein EO, Schuberth KC, Bacon JR, Hamilton RG, Weiss ME, Arshad H, Meinert C, Tonascia, Wheeler B. Perennial asthma in allergic children: a controlled trial of aeroallergen immunotherapy. N Engl J Med 1997;336:324-331.

7. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TAE. Survey of fatalities from skin testing and immunotherapy. J Allergy Clin Immunol 1993; 92: 6-15 [Medline].

8. Committee on Safety of Medicines. Desensitising vaccines. Br Med J 1986;293:948.

9. Donahue JG, Greineder DK, Connor-Lacke L, Canning CF, Platt R. Utilization and cost of immunotherapy for allergic asthma and rhinitis. Ann Allergy Asthma Immunol 1999; 82: 339-347 [Medline].

10. Expert Panel Report 2. Guidelines for the diagnosis and management of asthma. National Institutes of Health Publication number 97-4051. Bethesda, MD: National Institutes of Health; 1997, p 23.