Enzyme-potentiated desensitization in otolaryngic allergy.

Abstract

This is a preliminary report of a new method of treating otolaryngic allergy with enzyme-potentiated desensitization (EPD). The nature of EPD and its use in otolaryngology are described. Thirty-six patients have been treated and followed in a private medical practice since February 1997. This article reviews the clinical features of EPD and provides six cases as examples; the clinical features described include allergic rhinitis, serous otitis media, asthma, dermatitis, fixed food allergy, and Meniere's disease. EPD is an effective technique for the treatment of otolaryngic allergy and offers advantages over conventional techniques.

Introduction

Allergic conditions represent a significant part of otolaryngology. The work of Hansel and Rinkel has contributed to the generally successful methods of treatment employed for inhalants, molds, and many other allergens involved in diseases seen in our specialty. Despite the overall success of our treatment with desensitization, we are not always able to control symptoms caused by allergy.

This is a preliminary report on the use of a relatively new technique--enzyme-potentiated desensitization (EPD)--that utilizes a mixture of extremely dilute antigens mixed with the enzyme beta-glucuronidase. The method was developed and refined over the past 30 years by McEwen. (1-8) EPD can provide effective desensitization to agents that have been difficult or impossible to treat with conventional techniques. (9) It is not only useful for inhalants, but it is valuable in the treatment of allergic conditions caused by foods, (10-12) terpenes, formaldehyde, Proteus and Klebsiella spp., detergents, and a variety of dusts, spores, woods, and danders.

The frequency of injection is once every 2 months or less. The record of safety is extremely high. The method is currently available in the United States only under an investigational protocol approved by the federal Food and Drug Administration (FDA). This article describes the nature of EPD and provides examples of its use in otolaryngic allergy.

Methods

Before desensitization therapy is started, it is necessary to establish an accurate diagnosis. Neoplasms, specific infections, diseases, and conditions that are not allergic in nature must be identified. Only after a clear diagnosis of allergy has been established by a thorough history, physical examination, and allergic testing should immunotherapy be considered.

EPD involves the use of intradermal injection once every 2 months for 18 to 24 months. Afterward, injections are given as required, depending on treatment response. These subsequent injections can be administered as infrequently as once every year or even once every 5 years. Each injection involves the use of ultra-low-sized does (10-14) of 1, 3-diol activator mixed with low (6-10) or ultra-low (10-14) precise doses of specific antigen. The technique involves the use of a 0.3-ml insulin syringe with an integral needle. The syringe contains 0.01 ml of beta-glucuronidase and 0.04 ml of antigen mix for a total volume of intradermal injection of 0.05 ml. As many as three antigen mixes can usually be combined with a single dose of beta-glucuronidase per injection. This means that a very allergic person requiring multiantigen treatment might need up to three separate injections for each treatment. The injections are placed on the forearm 6 inches apart.

Vials containing beta-glucuronidase and antigen mixes are manufactured in England by McEwen Laboratories, Ltd. (*) The materials are temperature- and time-sensitive and are sent by Federal Express overnight service. They are packed in special Styrofoam containers designed to maintain temperature between 36[degrees] and 43[degrees] F. The reagents are kept at those temperatures in a refrigerator for up to 2 weeks while they are used. Because the antigen mixes contain extremely small amounts of antigen- often at levels similar to those found in the environment- best results are obtained when the patient avoids unnecessary exposure to environmental antigens for several days before and after an injection. Most medications should likewise be avoided around the time of injection.

The EPD antigen mixes that are available and commonly used include IC (high-dosed mixed inhalants), XE (high-dosed mixed allergens), XO (low-dosed mixed allergens [a dilution of XE]), terpenes, formaldehyde, P/K C (Proteus/Klebsiella), odds and ends, and detergents. Additional antigen mixes are available for special problems; they include woods (designed for woodworkers), experimental animals (useful for laboratory workers), and mosquito.

Use of EPD in otolaryngology

Since February 1997, 36 patients have been on treatment by the author with EPD on a regular basis. In addition, other physicians' patients on EPD have been sporadically treated as a convenience to them when they are in the Los Angeles area. The following brief case reports are used as examples:

Case 1: Allergic rhinitis. A 33-year-old man complained of nasal obstruction and watery rhinitis of 1 year's duration. Testing revealed extensive reactions to trees, grasses, molds, and many foods. Conventional immunotherapy was only partially effective. EPD treatment every 2 months, beginning March 19, 1997, has resulted in excellent relief of symptoms.

Case 2: Allergic rhinitis. A 59-year-old white minister had been transferred to California from the Midwest. He complained of cough, postnasal drip, and recurrent sinus infections. He had undergone endoscopic sinus surgery and immunotherapy, but he continued to experience recurrent symptoms and episodic sinusitis. EPD therapy was initiated on Feb. 11, 1997. After the second series of shots, symptoms improved, and the patient has been free of sinus disease and nasal symptoms.

Case 3: Serous otitis media and asthma. A 49-year-old white woman was referred because of recurrent left otalgia and intractable serous otitis media of 1 year's duration despite the repeated use of antibiotics, placement of ventilating tubes, and the use of oral steroids. She also complained of asthma, and she had had three sinus operations. She complained bitterly of ear pain with any manipulation of her ears, and she could not tolerate local injection for myringotomy. With ventilating tubes in place, there was a thick meat-like material within the middle ear. EPD therapy was initiated on Sept. 22, 1997. Continued treatment has led to significant improvement.

Case 4: Allergic rhinitis, dermatitis, and asthma. A 17-year-old girl had had a recurrent rash all over her body, allergic rhinitis, and asthma for most of her life. She had taken prednisone and antihistamines. She was known to be allergic to seafood. Allergy tests confirmed that she had major reactions to seafood, molds, and trees. EPD therapy was started on May 21, 1997, and had produced complete relief until she failed her fourth appointment. Treatment was reinstituted on a regular basis, and she has been free of symptoms.

Case 5: Fixed food allergy. A 64-year-old man had a life-long food allergy to both onion and garlic. Exposure to onion resulted in the prompt onset of severe drowsiness that lasted for 2 hours. Exposure to garlic produced severe memory problems and violent gastrointestinal discomfort for 36 hours. EPD treatment has been used regularly since March 1997, and it has eliminated these reactions, other than very mild gastrointestinal discomfort.

Case 6: Meniere's disease. A 43-year-old white woman whose mother and brother were known to be allergic was troubled with bilateral Meniere's disease, characteristic of bilateral allergic etiology.

Bilateral endolymphatic subarachnoid shunt operations and extensive allergic testing and immunotherapy in the past had provided only partial control of fluctuating symptoms. EPD therapy was initiated on Dec. 10, 1997, and discontinued by the patient in February 1998. Treatment has been regular since April 13, 1998. Control has still not been complete, but symptoms seem to be less troublesome.

Discussion

EPD seems to be a valuable addition to our ability to treat allergic conditions in otolaryngology. (13) Its primary advantage over conventional immunotherapy is its ability to treat antigens not previously treatable. In addition, it offers effective treatment for patients who are unable or unwilling to be compliant in avoiding known allergens.

The development of EPD stemmed from experience by Popper, a Czech otolaryngologist who in 1959 began an experiment to try to dissolve nasal polyps by injecting them with hyaluronidase. The treatment failed to dissolve the polyps, but it seemed to relieve the symptoms of sneezing in his allergic patients. By 1962, Popper discovered that only some batches of hyaluronidase were active and produced the desired results of desensitization. When he later undertook a pilot trial using a very pure form of hyaluronidase, his patients actually did worse.

McEwen in London heard of Popper's work and visited him to learn about it firsthand. McEwen proceeded to test six of the enzyme contaminants in commercially available hyaluronidase and discovered the active principle of beta-glucuronidase that is now used in EPD. McEwen has worked since that time to define the characteristics of this technique and to create extremely pure antigens that are used with the enzyme. In England, EPD is the major method used for immunotherapy, and the technique is available and used routinely throughout the world. In addition to treating rhinitis and hay fever, EPD has been used to treat asthma, eczema, urticaria, angioedema, migraine, bowel disease, arthritis, psychological irritable bowel migraine syndrome, attention deficit, autism, and chronic fatigue immunodeficiency syndrome.

In the United States, EPD is currently available to only a limited number of physicians who are participating in a carefully controlled study supervised by the FDA. EPD has not been approved by the FDA for general use.

It is not possible to provide a complete discussion of the diagnosis or treatment of allergic disease, nor of all the important aspects regarding EPD. But there are several unique aspects of EPD that are of special interest and warrant comment. For the average patient complaining of allergies, the initial treatment can include the stronger dilutions of antigen. However, patients who are known to have relatively severe allergic reactions or severe asthma should begin with the weaker antigens. It is best to add terpenes at the third treatment because they are more likely to cause a reaction than most of the other antigens. In that way, the cause of the reaction can be more easily determined.

Although no patient has died from EPD therapy, immunotherapy injections can cause a flare-up of symptoms. Should a patient develop uncomfortable symptoms after an injection, the treatment is administration of oral Tofranil (no generic form of imipramine is allowed) 25 mg every 4 hours. Some patients can only tolerate 20 mg/day. The dose must be drastically reduced if vertigo or atropine-like side effects occur. For more severe symptoms, the treatment is an oral or parenteral steroid. These are the only two agents that are known to not interfere with the desired immune reaction. Any reactions usually subside within 4 days. There are five different patterns of response to EPD, with early and late relapses and early and late responses to therapy. In the average patient, treatment provides relief within 2 years.

Because the enzyme enhances the reaction to extremely small amounts of antigen, attention must be given to the avoidance or elimination of potential antigens in the environment to which the patient is exposed a few days before and a few days after each injection. In some cases, Candida albicans requires preinjection treatment. Patients are urged to either fast or eat a special low-antigen diet consisting of foods that they normally would not eat or a diet restricted to boiled vegetables.

EPD therapy need not replace existing methods of immunotherapy that have been proven to be successful. It does, however, offer a new dimension and an opportunity to treat some patients effectively who have not been successfully treated with existing techniques. In addition, EPD allows for the treatment of problems previously untreatable, such as reactions to formaldehyde, detergents, and perfume (fumes). It has been shown to effectively treat fixed food allergies, and it offers great convenience for the patient with food allergy who does not wish to comply and desires to eat in a near-normal way.

In conclusion, EPD is a valuable addition to our armamentarium for the treatment of allergic conditions. It is exceptionally safe, offers convenience for the patient, and provides effective treatment for antigens previously not treatable, such as foods, terpenes, formaldehyde, Proteus and Klebsiella spp., detergents, and a variety of dusts, spores, woods, and danders.

(*) McEwen Laboratories, Ltd., 12 Horseshoe Park, Pangbourne, Berkshire RG8 7JW, U.K.

References

(1.) McEwen LM, Ganderton MA, wilson CMW, Black JH. Hyaluronidase in the treatment of allergy. BMJ 1967;2:507-8.

(2.) McEwen LM, Starr MS. Enzyme-potentiated hyposensitisation. I. The effect of pre-treatment with beta-glucuronidase, hyaluronidase, and antigen on anaphylactic sensitivity of guinea-pigs, rats and mice. Int Arch Allergy Appl Immunol 1972;42:152-8.

(3.) McEwen LM. Enzyme-potentiated hyposensitization: Effects of glucose, glucosamine, N-acetylamino-sugars and gelatin on the ability of B-glucuronidase to block the anamnestric response to antigen in mice. Ann Allergy 1973;31:79-83.

(4.) McEwen LM. Effects of sugars and diols on enzyme potentiated desensitization. J Physiol 1972;230:65-6.

(5.) McEwen LM, Nicholson M, Kitchen I, White S. Enzyme-potentiated hyposensitization. 3. Control by sugars and diols of the immunological effect of beta glucuronidase in mice and patients with hay fever. Ann Allergy 1973;31:543-50.

(6.) McEwen LM, Nicholson M, Kitchen I, et at. Enzyme potentiated hyposensitization: IV. Effect of protamine on the immunological behavior of beta glucuronidase in mice and patients with hay fever. Ann Allergy 1975;34:290-295.

(7.) McEwen LM. Enzyme potentiated hyposensitization: V. Five case reports of patients with acute food allergy. Ann Allergy 1975;35:98-103.

(8.) McEwen LM. A double-blind controlled trial of enzyme potentiated hyposensitization for the treatment of ulcerative colitis. Clinical Ecology 1987;5:47-51.

(9.) Shrader WA, Jr., McEwen LM. Enzyme potentiated desensitization: A sixteen month trial of therapy with 134 patients. Environmental Medicine 1993;9:128-38.

(10.) Egger J, Stolla A, McEwen LM. Controlled trial of hyposensitisation in children with food-induced hyperkinetic syndrome. Lancet 1992;339:1150-3.

(11.) Egger J, Stolla A, McEwen LM. Controlled trial of hyposensitization in children with food induced migraine. Cephalalgia 1993;216 (Suppl 13):216.

(12.) Galland L, McEwen LM. A role for food intolerance in childhood migraine. World Pediatric and Child Care 1996;6:2-8.

(13.) Pulec JL. Enzyme-potentiated desensitization: A major breakthrough [editorial]. Ear Nose Throat J 1996;75:640.

(14.) Di Stanislao C, Di Berardino L, Bianchi I, Bologna G. A double-blind, placebo-controlled study of preventive immunotherapy with E.P.D. in the treatment of seasonal allergic disease. Allerg Immunol (Paris) 1997;29:39-42.

From the Pulec Ear Clinic, Los Angeles.

Reprint requests: Jack L. Pulec, MD, Pulec Ear Clinic, 1245 Wilshire Blvd., Suite 503, Los Angeles, CA 90017. Phone: [phone]; tax: [phone]; e-mail: [e-mail]

Originally presented at the Eastern Section Meeting of the Triological Society; Providence, RI.; Jan. 29-31, 1999.

This work was supported by Ear International, Los Angeles.