IgE-mediated hypersensitivity reactions.

The immunologic mechanisms responsible for allergic reactions are well studied and are among the best defined of any immunopathologic disorder. New knowledge is expanding rapidly, and the type I Gell and Coombs immediate hypersensitivity reaction, which is the basis of the IgE-mediated allergic disease, is more accessible to accurate diagnosis and specific therapy than ever before. The mechanisms of the immediate, late-phase, and dual reactions are discussed. The role of the cyclic nucleotide system, nonimmune mast cell degranulation, and participation of cytokines in atopic allergy are investigated. The principles and pitfalls of specific immunotherapy are reviewed briefly.

A comparative study of the diagnostic characteristics of the modified RAST and Pharmacia CAP System.

New in vitro technology for the detection of allergen-specific IgE antibody continues to be developed. The manufacturer of one such system, the Pharmacia CAP System, claims that it has test qualities similar to those of the modified RAST. To evaluate this assertion we compared the results obtained with 12 allergens by both procedures on six negative control sera and four sera obtained from atopic patients; a total of 120 tests were performed. The data suggest that attempts to match the sensitivity of the modified RAST are accompanied by a significant loss in test specificity in the Pharmacia CAP System.

Chronic sinusitis, steroid-dependent asthma, and IgG subclass and selective antibody deficiencies.

In the past 20 years considerable progress has been made in understanding the ways in which subtle immunologic defects can adversely affect health. Immunoglobulin G subclass deficiencies have been identified and are related to an increased susceptibility to respiratory tract infections in certain patients. To assess the immunocompetence of such patients, the quantity and quality of their antibody response must be evaluated. Immunologic evaluation is best performed by measuring selective antibodies before and after a specific challenge. Patients with mild immunodeficiency may benefit from prophylactic antibiotic therapy; those with profound immunodeficiency require antibody replacement therapy.

Experience with RAST-based immunotherapy.

During its 80 year history, allergen immunotherapy has been used essentially as Noon and other early investigators described it. Immunotherapy is practiced mainly as an art based on uncontrolled clinical observations of individual patients treated in private practice. Dosing schedules and skin test interpretations are based primarily on the biases of the treating physicians. In an effort to improve the results obtained from immunotherapy, different approaches have evolved. Serial dilution skin endpoint titration (SET), practiced mostly by otolaryngologists, became popularized in the 1960s out of the need to optimize immunotherapy dosing regimens. SET can be viewed as a forward step in the direction of more aggressive yet safe initial immunotherapy doses. With the discovery of IgE in 1966 as the prime carrier of reaginic hypersensitivity in humans came the availability of a remarkable set of in vitro assays for the measurement of total and allergen-specific IgE reactivity. The radioallergosorbent test (RAST), which has been shown to correlate reliably with the major variants of the atopic state, was modified in 1977 in such a way as to enhance the sensitivity of the assay with minimal alteration of specificity. The modified RAST (MRT) has been carefully investigated and has shown reliable concordance with the major parameters of clinical allergy. Since its development only 14 years ago, the MRT has become a dependable adjunct for the determination of initial and in many cases final immunotherapy doses. An important contribution of RAST-based immunotherapy is that only patients with quantifiable serum titers of allergen-specific IgE qualify as candidates for immunotherapy. The fact that fewer allergens are used for treatment at higher initial doses and that potential reactors are identified before starting therapy are yet other advantages of RAST-based immunotherapy. The use of RAST as a method of allergen standardization only reinforces its value in patient management.

Efficacy of alternative tests for delayed-cyclic food hypersensitivity.

With the oral challenge food test (OCFT) used as the standard for delayed-cyclic food hypersensitivity diagnosis, blinded comparison studies were accomplished with 175 in vitro food specific IgE and 180 IgG radioallergosorbent tests, 180 food enzyme-linked immune complex assays, and 155 in vivo Multi-Test prick tests. The study was multi-centered, eight physicians and 37 patients participating. All of the compared tests were shown to be approximately 50% efficient when compared with the OCFT results, and, thus, nonefficacious.

Provocation-neutralization: a two-part study. Part I. The intracutaneous provocative food test: a multi-center comparison study.

This study investigated the clinical usefulness of the intracutaneous provocative-neutralization food test (IPFT). Thirty-seven patients were tested for five identical food allergies by eight physicians in different geographical locations. Throughout the study, comparison was made between the IPFT when interpreted by skin response (IPFT SK) and when interpreted by symptom provocation (IPFT PR). Double-blind IPFT results were compared with those of previously accomplished oral challenge food tests (OCFT). IPFT reliability was determined by a double-blind comparison of the initial IPFT, with two subsequent IPFTs performed 7 days apart. Correlation of the IPFT SK and IPFT PR with the OCFT provided validity coefficients of 0.78 and 0.61 respectively, both significant beyond the 0.01 level of confidence. Reliability of the IPFT SK and IPFT PR was shown to be 0.68 and 0.40, respectively. The IPFT SK was significant beyond the 0.01 level of confidence and the IPFT PR was significant beyond the 0.05 level of confidence.

Provocation-neutralization: a two-part study. Part II. Subcutaneous neutralization therapy: a multi-center study.

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.

The immunobiology and immunopharmacology of the allergic response.

Classic allergic reactions of the immediate type are IgE dependent. These reactions are associated with a complex orchestration of genetic predisposition, allergen exposure patterns, allergen processing by mononuclear macrophages, helper and suppressor immunocytes, pharmacologically active inflammatory mediators, early and late-phase reactions, neurotransmitters, autonomic nervous system participation, intracellular cyclic nucleotide equilibrium, cellular and molecular activity, and a genetically predetermined end-organ hypersensitivity to a variety of specific and nonspecific excitants.

Immunotherapy failure.

A great deal of the immunotherapy failures are preventable if certain criteria are met and guidelines followed. It is mandatory that immunotherapy only be used for those conditions known to be atopic IgE-mediated diseases. With an IgE mechanism established as a foundation for immunotherapy, adherence to certain guidelines (Table 9) will ensure an optimal response to specific therapy. Experience in recent years with in vitro allergy (Table 10) testing in conjunction with or as a replacement for skin testing has resulted in greater efforts as discontinuing immunotherapy previously placed on this treatment, for whom the original diagnosis of allergy cannot be confirmed based on stringent criteria for identifying an IgE-dependent genesis. Too many patients are treated by immunotherapy on the basis of minimal reactions to skin testing or of coincidentally positive skin tests unrelated to the etiology of the patient's complaints.

Serum concentrations of allergen-specific IgG antibodies in inhalant allergy: effect of specific immunotherapy.

The occurrence of antibodies belonging to IgG class of immunoglobulins with specificity for short ragweed and Bermuda grass in the sera of nonatopic subjects and patients with inhalant allergy (at the time of initial diagnosis, following specific immunotherapy was investigated with an enzyme immunoassay. The intra-assay and inter-assay coefficients of variation for this assay ranged from 1.74%-4.62% and 3.18%-9.12%, respectively. IgG antibodies were found in the sera of the majority of nonatopic and all of atopic subjects. The differences in the concentration of these antibodies between these three groups were statistically significant (P less than 0.001). Specific immunotherapy resulted in a rise in the serum levels of allergen-specific IgG antibodies and, following an initial period of modest increase, a decrease in the level of allergen-specific IgE antibodies. Specific IgG response correlated with both the cumulative antigen dose and the clinical benefit that accrued from specific immunotherapy (P less than 0.001). The increase in the serum concentration of specific IgG was most pronounced in patients with high RAST scores at the time of initial diagnosis (P less than 0.001). The concentrations of short-ragweed specific IgG antibodies assayed with multiple samples in three patients with ragweed hay fever appeared not to be affected by the short-ragweed season to any significant degree. We conclude that direct enzyme immunoassay for allergen-specific IgE and IgG antibodies are useful in vitro monitors of immunologic responses to specific immunotherapy for inhalant allergy.

A study of optimum dose immunotherapy in pharmacological treatment failures.

Forty-six patients with allergic rhinitis who were refractory to antihistamine/decongestant drugs were entered into a study to evaluate the effectiveness of optimal dose immunotherapy. Of the patients described, 91% reported symptomatic improvement within 24 weeks. Total IgE was seen to decrease in 76% of the patients in the same time frame. Nasal eosinophilia and specific IgE antibodies also were seen to decrease substantially. The results of this study indicate that immunotherapy, based on the patient's sensitivity as measured by specific serum antibody titers and titrated skin end points, is effective in alleviating symptoms and altering abnormal immunological factors.

The study of IgE in the diagnosis of allergic disorders in an otolaryngology practice.

Within months after the identification of IgE as the reaginic antibody and principal trigger of immediate hypersensitivity reactions, several radiomunnoassays were developed for its detection in serum. Observations and results obtained with the use of two commercially available in vitro assays in the screening diagnosis of inhalant allergic disease are reported. Over 80% of suspected atopic patients tested had detectable specific IgE to at least two allergens. Both total and specific IgE determinations served useful roles in the recognition of clinically significant allergic disease. Results obtained with these procedures correlate well with information previously obtained only by skin test endpoint titration.

An immunoperoxidase method for the demonstration of allergen-specific IgE in serum.

A solid-phase immunoenzymatic technique for the detection of allergen-specific IgE antibodies in serum is described. The binding of such antibodies to allergen insolubilized on cyanogen bromide-activated paper discs was detected by a subsequent two-step procedure involving the use of rabbit antihuman IgE and goat antirabbit IgG coupled with peroxidase. A solution of 3-3' diaminobenzidine and hydrogen peroxide, employed as the color indicator system, turned the discs dark brown in positive cases. Discs carrying 11 different inhalant allergens were tested with sera containing allergen-specific IgE antibodies. Agreement between the results of this technique and the RAST was seen in 85% of 310 tests performed. In the clinical practice of otorhinolaryngologic allergy, this test may prove to be an important laboratory adjunct ot clinical history and diagnostic skin test in the identification of the incriminated inhalant allergens.