A triple-blind crossover study that investigates the efficacy of subcutaneous neutralization food hypersensitivity therapy

William P. King, MD, Richard G Fadal, MD, Walter A Ward, MD, Richard J. Trevino, MD William B Pierce, MD, J Alan Stewart, MD, and John H. Boyles, Jr. MD, Corpus Christi, Texas, Teaneck, NewJersey, Winston-Salem, North Carolina, Oakland, California, Batavia, New York, and Dayton, Ohio.

Presented is a triple-blind crossover study that investigates the efficacy of subcutaneous neutralization food hypersensitivity therapy. Seven physicians and thirty-three patients from various parts of the country participated. Each patient underwent three 2-week treatment sessions, with 1 week off treatment between each session. During each treatment session, one injection a day was given. The injection consisted of a placebo for one 2-week session, and the active allergen during the other two sessions. The active dose was determined by earlier intracutaneous provocative food testing. The diet during the study period was not varied. Medication-symptom diaries were maintained and treatment result evaluations for both individual complaints and overall results were detailed on a standard form at the end of each treatment session. While the number of foods treated per patient varied from 1 to 13, the majority were treated with 3 to 5 foods. Treatment with the active medication was more efficacious than with placebo. A few patients’ symptoms were aggravated with the active medication. This indicates a correct diagnosis, but incorrect treatment dose. In the clinical setting such adverse response should be reversed. Overall, neutralization subcutaneous treatment should be beneficial approximately 75% of the time, and further enhanced by supplemental diet manipulation. (OTOLARYNGOL HEAD NECK SURG 1988:99:272.) From the Department of Otolaryngology and Communication Sciences, Baylor College of Medicine (Dr. King), the Department of Immunology, Holy Name Hospital (Dr. Fadal), Oak Knowl Naval Hospital (Dr. Trevino), Genesee Memorial Hospital (Dr. Pierce), and Children’s Medical Center and St. Elizabeth Medical Center and Wright State University (Dr. Boyles), Drs. King (Corpus Christi), Ward (Winston-Salem), Pierce (Batavia), and Stewart (Lake Jackson) are in private practice.

Sponsored by the American Academy of Otolaryngic Allergy.
Presented at the Annual Meeting of the American Academy of Otolaryngic Allergy, Chicago, Ill. Sept. 18 1987
Submitted for publication Jan. 26 1988: revision received April 18, 1988: accepted April 25, 1988
Reprint requests: William P. King MD, 1415 Third Street, Suite 507 Corpus Christi, TX 78410.

_____________________________________

The efficacy of using the neutralization or endpoint final dose, determined by the intracutaneous provocative food test (IPFT) for prevention of delayed food hypersensitivity symptomatology, remains a subject of some contention. The IPFT technique and neutralization treatment was first suggested by Lee in 1961, and since that time various refinements have been recommended. While there have been a number of individual studies that illustrate the effectiveness of this treatment technique there has not been a multi-center blinded study reported. This study on the efficacy of neutralization treatment is a continuation of the previously reported 37 patient multi-center double-blind comparison study of the IPFT (Part I.).

METHODS AND MATERIALS

Objective. This study was designed to investigate the efficacy of subcutaneous neutralization therapy. The study protocol was approved by the Research Committee of the American Academy of Otolaryngic Allergy.

Materials. This study used the same five food extracts and 50% glycerin placebo listed in Part I. The source and lots are the same.

Participants. Seven of the original eight physician-participants in the primary IPFT technique study participated in this neutralization treatment study. Two of the physicians provided data on four patients rather than five, therefore, only thirty-three patients participated in this study. All had participated in the primary IPFT study and had read and signed a standardized release form. None were on any other form of injection treatment, other than for inhalant allergy.

Study procedure. The study covered an 8-week period, subdivided into three 2-week treatment sessions, each divided by a 1 week off treatment period. An identical appearing placebo was used for treatment during one of the 2-week treatment sessions. The patient was aware only that a placebo might be substituted for one or more of the treatment sessions. The order of the treatment sessions was determined by lot by an out-of-office individual, to provide security for the testing conditions. At the beginning of each treatment session, this out-of-office individual was provided with both a vial of the active material and a vial of an identical appearing placebo for him to provide one of the two to the patient. The placebo was composed of the same dilution of the 50% glycerin control present in the active treatment material. Thus, if a neutralizing base was on a #3 dilution, the placebo for the patient was on a #3 dilution of 50% glycerin, and so on, for every active ingredient in the treatment set.

Before the study was begun, the placebo was verified to be identical to the patient by injection of both the active and placebo material simultaneously in different arms. The vials were appropriately coded by an individual other than the tester, and the coder alone knew of their contents. If the patients thought they could identify the active material by "feel," and their opinions were correct, the test was repeated, in no shorter than 1-day intervals, until they were either 50% wrong (that is, 1 out of 2, or 2 out of 4 trials) or were correct 75% of the time (that is, 3 out of 4 times). If the latter instance had taken place, the patients would not have been eligible for participation in the study. This did not occur.

In addition to those five foods to which the patient responded positively during the IPFT study, additional foods were tested at the discretion of the physician, based on the patient’s diet diary and allergic history. The total number of foods used for treatment varied from 1 to 13 per patient, but the majority of patients were treated with 3 to 5 foods.

Over the 8-week study period, the patient’s diet was not altered in any way. Subcutaneous injections were the only form of food hypersensitivity treatment administered, other than necessary symptom-relieving medications. Each injection of the active treatment material contained the exact amount of allergen present in the IPFT determined neutralizing dose or, when the skin response was positive without symptom provocation, the end point final dose. As in the 1977 double-blind neutralization study by Miller. Injections were administered once a day. Self-administration from the provided 20-dose multiple treatment vial was allowed after the first injection was given in the office under direct observation to assure compatibility between the vial and the patient. All treatment vials were kept refrigerated throughout the study.

Table 1. Example of patient score sheet used for treatment results

 
 
 
 
 

Symptoms

First 

2-wk Session

Second 2-week

Session

Third

2-week

Session

1 Much worse ______ ______ ______
2 Some worse ______ ______ ______
3 No relief ______ ______ ______
4 Some relief ______ ______ ______
5 Good relief ______ ______ ______
6 Excellent relief ______ ______ ______

Each patient’s individual symptom complaints were enumerated in his pre-study history and physical examination. They were provided symptom-medication diary sheets to record their day-to-day symptom fluctuations and need for symptom-relieving medications. At the end of each 2-week treatment period, they filled out a second sheet (Table 1) that enumerated each symptom’s response to treatment. In addition, each patient filled out a second score sheet that indicated the overall treatment results.

All recorded symptom-response diaries were forwarded to a central collector, and information regarding the data was not shared with any participant until completion of the study.

Response to treatment was scored numerically by comparing the reported results of the active treatment sessions with those of the placebo treatment session. Scores were calculated for both individual 2-week active treatment sessions and the combined sum of the two 2-week active treatment sessions. For example, if on a given score sheet the second 2-week session was the placebo session and this session was marked "no relief." (which is number 3 on the score sheet), and the first and third 2-week session – which were both active treatment periods – were marked respectively "some better" and "good relief" (that is, numbers 1 and 5), then the individual scores would be – 1 for the first 2-week session and – 2 for the third 2-week session. The combined score would be a combination of the two active treatment sessions, or – 3. If the placebo session was marked "some better," the number 1 active session would have to be marked "good relief" and the active third 2-week session would have to be marked "excellent relief" to total the same overall score of 3.

Results

Figure 1 presents a bar graph illustrating the responses of the 66 individual treatment periods. Sixty five percent reported symptom improvement. Twelve percent of the responses were no better than with the placebo. Twenty-three percent indicated symptom aggravation. When the individual scores are added, the aggregate unit total indicates overall degree of aggravation vs improvement. The aggravation total was 19 units, whereas the improved total was 4.6 time greater at 87 units. These data were analyzed for significance by means of the chi square fourfold contingency test, which showed they differed significantly, with significance beyond the 0.001 level of confidence.

Figure 2 illustrates each patient’s overall combined treatment results. The final score represents the total responses of both 2-week treatment sessions. Twenty-four percent reported aggravation. Sixty-four percent reported improvement. Twelve percent again reported that their response to treatment was no better than with the placebo. The aggregate aggravation totaled 18 units, whereas the improvement total was 4.2 time greater at 75 units. These results were also submitted to a chi square fourfold contingency test to determine significance, with results again revealing significance beyond the 0.001 level of confidence.

Figure 3 illustrates the combined treatment responses by individual symptom. The more frequent complaints of rhinitis and headache proved quite responsive to treatment, as did the less frequent broncho pulmonary and complaints of chronic fatigue. Gastro-intestinal complaints responded least of the common complaints.

Figure 4 illustrates that the combined response scores tended to parallel the number of positive responding foods treated. Of course, this parallel is only a trend with expected exceptions, and would be self-limited by the law of diminishing returns.

Discussions.

When results of treatment are reported to be no better than placebo, clinically this indicates one of three possibilities: the complained of symptoms were not caused by food allergy, the symptoms were caused by a food allergy for which the patient was not tested, or the symptoms were caused by a food allergy for which the patient was treated but attained no relief. Considering the relatively few foods tested on the average patient in this study and some of the symptoms under consideration, the likelihood of the third possibility might seem diminished.

Significant aggravation of symptoms by neutralization treatment indicates accurate diagnosis, but provision of the wrong treatment dose. In a clinical setting, those individuals should be recognized, retested for a shift in sensitivity or some technique inaccuracy, and their doses altered. Such action would probably reverse their negative treatment response. If those patients who scored – 2 or worse when converted to an improved status by this method, an ultimate improvement percentage of approximately 75% for this group of patients might be anticipated (Table2).

Table 2. Final clinical improvement.

Treatment Sessions Individual Combined
Patients improved 43 21
Aggravated but reversed 5 4
Clinically improved 48 25
Total Sessions 66 33
Clinical improvement 73% 76%

In addition to effectively treating delayed food hyper sensitivities that involve all four types of Gell and Coombs reactions. The studies of Scadding and Brostoff and Boris et al suggest that neutralization therapy is also effective for Type I inhalant allergy. Clearly, as reviewed in the Part I IPFT study, the mechanisms of neutralization therapy differ from those of traditional build-up immunotherapy. Build-up immunotherapy is currently used only for Type 1 inhalant allergy. Response to neutralization occurs within minutes, as opposed to the weeks or months required by the build-up technique. Successful build-up immunotherapy response appears to last longer once achieved.

Neutralization treatment in the clinical setting is typically combined with some sort of dietary manipulation. Commonly, a rotary diversified diet is used in combination with strict avoidance of severely offending foods. Such a combination of approaches appears not only to enhance treatment results, but also to allow control with less frequent injections. Under such circumstances, neutralization injections are usually provided initially every 2 to 4 days, and the interval is lengthened after symptom stabilization.

Considering that the most common food hyper sensitivities are to foods like wheat, corn, egg, milk and yeast – all hidden foods in most prepared American staples – successful neutralization treatment should allow the patient a much more practical way to manage the problem than does strict dietary avoidance. With neutralization treatment, nutrition is more easily maintained, quality of life is improved, and patient compliance is increased.

Conclusion

This study provides evidence that subcutaneous neutralization treatment is an effective form of food hyper sensitivity therapy and suggests that this form of treatment should prove beneficial in the clinical setting approximately 75% of the time, with further enhancement of results when supplemented by appropriate diet manipulation.

This study was sponsored by the American Academy of Otolaryngic Allergy.

The Research Committee of the AAOA wishes to thank statistical consultants John L. Fletcher. PhD (Physiological Psychology, University of Kentucky, 1955) and D. Theron Stimmel, PhD (Biostatistics. University of Michigan. 1963) for their review of the data. The Research Committee also wishes to thank Meridian Bio-Medical, Inc. for its cooperation.
 
 
 
 

Symptom

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Rhinitis

·  

·

···  

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Headache

· · · · · ·· · ·· ····· ··· ·  

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Br Pulm.

 

 

 

 

 

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· ··  

·

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Chr. Fatigue

 

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·

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G.I.

 

 

··

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Urticaria

 

 

 

 

 

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Throat  

 

 

 

 

 

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Arthralgia

 

 

 

 

 

 

 

 

 

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Mood

Change

 

 

 

 

 

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Palpitation

 

 

 

 

 

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Hot Flash

 

 

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Response

Score

-5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 +8 +9 +12

Fig. 3 Response of individual symptoms to treatment (33 combined 4-week treatment sessions). BR PULM = Broncho pulmonary: CHR = Chronic and GI = Gastronintestinal.


 
 

Number of Foods Treated
 
 

Response

Scores

13  

 

 

 

 

 

 

 

 

 

 

 

 

 

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12

 

 

 

 

 

 

 

 

 

 

 

 

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7

 

 

 

 

 

 

 

 

 

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3

 

 

 

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2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1

 

 

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-5

-4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 +8 +9  

 

Fig 4 Possible influence on treatment response by the number of foods treated (33 combined 4-week treatment sessions).

Figure 1. Response to treatment (66 individual 2-week treatment sessions)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Figure 2. Response to treatment (33 combined 4-week treatment sessions.)

 

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