Hypersensitivity studies in asthmatic patients with broncho-pulmonary aspergillosis

The serum IgE levels of four patients with allergic bronchopulmonary aspergillosis ranged from 201 to 16,800 I.U./ml. The corresponding mean level for control subjects was 205±68 I.U./ml. A considerable proportion of the patients' serum IgE was found to be specific reagin directed against extracts of Aspergillus fumigatus. Notwithstanding the high levels of reagin, the circulating basophils were relatively insensitive to histamine release with allergen or antiserum to I gE. The effects of steroid therapy may have contributed in part towards this lack of reactivity of the basophiis. Two of the patients showed in vitro evidence of Type IV in addition to in vitro Type I hypersensitivity but did not demonstrate the presence of precipitins to A. fumigatus in their serum, one of these previously having a positive precipitin test. Precipitins were present in the sera of the two other patients, both of whom demonstrated in vivo Type I hypersensitivity. One of these was tested in vitro for Type IV hypersensitivity but was adjudged negative. The sputum of one patient (L.P.) contained fungal mycelia which was conjugated with both IgA and IgE antibodies.     

IgE antibodies in sera of patients with allergic bronchopulmonary aspergillosis

(1) Elevated IgE antibody to A.fumigatus is present in most patients with allergic bronchopulmonary aspergillosis, but not in the sera of patients with a variety of pulmonary conditions that contain A. fumigatus precipitins. (2) The RAST assays for measuring IgE antibodies to this antigen are relatively simple to perform and have a practical clinical value. (3) The exact pathophysiologic role of these IgE antibodies is not yet denned, and several hypotheses are proposed.     

Use of a Synthetic Peptide Epitope of Asp f 1, a Major Allergen or Antigen of Aspergillus fumigatus, for Improved Immunodiagnosis of Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is an immunologically complex allergic disorder caused by the fungal pathogen Aspergillus fumigatus. Elevated levels of total immunoglobulin E (IgE), specific IgE, and IgG antibodies in sera are important immunodiagnostic criteria for ABPA. International reference standards or standardized immunodiagnostic assays are not available due to a lack of well-defined diagnostic antigens. The present study was carried out to identify and evaluate the immunodiagnostic relevance of synthetic epitopic peptides of Asp f 1, a major allergen, antigen, or cytotoxin of A. fumigatus. Five overlapping peptides were synthesized from the N terminus of Asp f 1, one of the potential immunodominant regions predicted by algorithmic programs. The 11-amino-acid synthetic peptide (P1) significantly inhibited both IgG binding (89.10% ± 4.45%) and IgE binding (77.32% ± 3.38%) of the standardized diagnostic antigen (SDA) (a well-defined pool of diagnostically relevant allergens and antigens of A. fumigatus). With a panel of sera of ABPA patients, allergic patients with skin test negativity to A. fumigatus, and healthy individuals, P1 showed a higher diagnostic efficiency than SDA (specific IgG, 100%; specific IgE, 98.3%). The diagnostic efficiency of P1 could be attributed to the presence of homologous epitopes in various immunodominant allergens or antigens of A. fumigatus. The ability of P1 to induce histamine release from sensitized mast cells and a Th2 type of cytokine profile in peripheral blood mononuclear cells of ABPA patients suggests its potential for use in intradermal testing. P1 could be further explored for development of a standardized, specific, and sensitive immunodiagnostic test for aspergillosis.     

Hyperreactivity of mediator-releasing cells from patients with allergic bronchopulmonary aspergillosis as evidenced by basophil histamine release

Histamine release was performed on 28 patients with allergic bronchopulmonary aspergillosis (ABPA) in various stages and on 14 patients with mold-sensitive asthma, by using Aspergillus antigens, other mold antigens, and anti-IgE. Total serum IgE, IgE and IgG antibodies to Aspergillus fumigatus (Af), and end point cutaneous titration for Af were determined for each patient. There was greater histamine release to Aspergillus mix (p = 0.0000) and anti-IgE (p = 0.047) in patients with ABPA than in patients with mold-sensitive asthma. Patients with stages IV and V ABPA had greater histamine release to Aspergillus mix than patients with stage I, II, or III ABPA (p = 0.0014). There was greater histamine release to other molds in ABPA patients than in mold-sensitive asthmatics. There was no correlation between histamine release to Aspergillus mix and total serum IgE, IgE or IgG antibodies to Af, ratio of IgE and IgG antibodies to Af to total IgE, or cutaneous end point titration for Af in ABPA patients or mold-sensitive asthmatics. Peripheral basophils from ABPA patients demonstrated marked hyperreactivity as evidenced by histamine release to Aspergillus antigens, other molds, and anti-IgE. This hyperreactivity is the first cellular difference recognized in ABPA patients when compared to mold-sensitive asthma patients. If this hyperreactivity is manifested by mediator release from other cells such as pulmonary mast cells, which would be in close contact with growing Af, a possible mechanism for pulmonary response in ABPA would be suggested.     

Allergic bronchopulmonary aspergillosis and sensitization to Aspergillus fumigatus in chronic bronchiectasis in adults

Fifty adult subjects for whom a diagnosis of idiopathic bronchiectasis (excluding those secondary to tuberculosis or hypogarnmaglobulinaemia) had been confirmed previously were investigated by: questionnaire; blood eosinophil count; sputum culture for Aspergillus fumigatus and eosinophil count; chest radiography; skin-prick tests with several aeroallergens and four preparations of A. fumigatus, including a reference extract; measurement of specific IgE antibodies; precipitin testing and self-crossed immunoelectrophoresis with A. fumigatus. Five subjects were possible cases of allergic bronchopulmonary aspergillosis in whom the condition had been previously misdiagnosed or in whom sensitization to A. fumigatus had occurred after the onset of bronchiectasis. These five subjects had positive immediate skin reactions to A. fumigatus and a history of recurrent pneumonias. Four had a previous history of asthma and the others showed increased bronchial responsiveness to inhaled methacholine. At the time of the survey, A. fumigatus grew in the sputum of one out of five subjects. These subjects had increased levels of specific IgE. Two had precipitins by double diffusion and three subjects were positive on self-crossed immunoelectrophoresis. It is concluded that allergic bronchopulmonary aspergillosis or evidence of sensitization to A. fumigatus can be identified in a significant proportion of adult subjects with so-called idiopathic bronchiectasis.     

Aspergillus fumigatus components distinguish IgE but not IgG4 profiles between fungal sensitization and allergic broncho‐pulmonary aspergillosis

Aspergillus fumigatus is the causative agent of allergic broncho‐pulmonary aspergillosis. Prompt and accurate diagnosis may be difficult to achieve with current clinical and laboratory scores, which do not include immune responses to recombinant A. fumigatus allergens. We measured specific immunoglobulin E and G4 directed to recombinant A. fumigatus allergens in 55 cystic fibrosis patients without allergic broncho‐pulmonary aspergillosis but sensitized to A. fumigatus and in nine patients with allergic broncho‐pulmonary aspergillosis (two with cystic fibrosis and seven with asthma). IgG4 responses to recombinant A. fumigatus allergens were detected in all patients, but neither prevalence nor levels were different between the two patient groups. On the other hand, both prevalence and levels of IgE responses to Asp f 3, Asp f 4, and Asp f 6 helped distinguish allergic broncho‐pulmonary aspergillosis from A. fumigatus sensitization with good negative and positive predictive values.     

Cytophilic antibodies in bronchopulmonary aspergilloma and cryptogenic pulmonary eosinophilia.

The immunoglobulin class and subclass of cytophilic antibodies have been studied using peripheral leucocytes from twenty-two patients with allergic bronchopulmonary aspergillosis, aspergilloma and cryptogenic pulmonary eosinophilia. In patients with allergic bronchopulmonary aspergillosis, significantly increased histamine liberation occurred following challenge of their leucocytes with antisera to IgE, IgG2, IgG3 and IgG4 as well as with Aspergillus fumigatus antigen. The results were considerably modified if the patient was receiving corticosteroids at the time of the test. The presence of IgG2-specific antibody to A. fumigatus in the serum of one patient, capable of sensitizing donor leucocytes, was demonstrated in passive sensitization experiments. In two patients with uncomplicated aspergillomas no evidence of cytophilic antibody to any class was found although large amounts of precipitating IgG antibody was present in the serum. Two patients with aspergilloma and systemic symptoms of weight loss and fatigue (which have been interpreted by others as 'hypersensitivity' responses) had increased amounts of cytophilic antibody similar to those with allergic bronchopulmonary aspergillosis. Six patients with cryptogenic pulmonary eosinophilia were also studied. No evidence of specific antibody to A. fumigatus was found but, as a group, significantly increased histamine liberation using antisera to IgG2 was demonstrated. Individual patients also showed evidence of other classes of cytophilic antibody, one having IgE, three IgG3 and two IgG4. The relationship between heat-stable short-term sensitizing antibody (IgG STS) inducing immediate skin responses and the pattern of cytophilic antibodies found in our patients with bronchopulmonary aspergillosis having dual (immediate and late reactions) is discussed. Clinically these tests are of diagnostic value and they may be helpful in assessing symptomatic patients with aspergillomas for corticosteroid treatment.     

Increased release of histamine by anti-IgE from leucocytes of asthmatic patients and possible heterogeneity of IgE

A study was made of the significantly increased amounts of histamine released by anti-IgE from the leucocytes of asthmatic and allergic patients, particularly in patients with a low level of serum IgE. By measuring cell-bound IgE and histamine release with anti-IgE, particularly after passive sensitization of human leucocytes, it was possible to show that serum IgE in some allergic patients differed from that in normal subjects in two respects. Firstly, it appeared to have a relatively high leucocyte binding affinity, though this could not be proved conclusively. Secondly, and more importantly, IgE of some patients could more readily mediate histamine release with anti-IgE, that is to say it had a greater efficacy. These properties should be differentiated from another feature of allergic individuals, that is the more ready releasability of histamine from the patients' own leucocytes.     

Sensitivity to two major allergens (Cry j I and Cry j II) in patients with Japanese cedar (Cryptomeria japonica) pollinosis

Background: Japanese cedar (Cryptmeria japonica: CJ) pollinosis is one of the most important allergic diseases in Japan. Recently, the second major allergen (Cry j II) was isolated from CJ pollen. There have been no prevalence studies of sensitivity to Cry j I and Cry j II among a large number of patients with pollinosis. Objective: This study was conducted to evaluate the prevalence of sensitivity to Cry j I and Cry j II. We measured specific IgE antibodies to these allergens in the sera of 145 patients. Furthermore, comparison of the sensitivity to Cry j I and Cry j II was examined by the hisiamine release assay. Methods: Specific IgE antibodies to Cry j I and Cry j II were assayed by a fluorometric ELISA. Allergen-specific histamine release was measured by a radioimmunoassay kit, Results: More than 90% of 145 patients had specific IgE antibodies to both allergens. the remainder had specific IgE to either one or the other. There were seasonal changes in the level of specific IgE. The changes in the levels of anti-Cry j II IgE antibodies were parallel to those of anti-Cry j I IgE. The histamine release assay with leucocytes from the patients demonstrated that the allergenic potency of the two allergens is almost the same. Conclusion: Cry j II is an as important a major allergen as Cry j I.     

The uptake of Aspergillus fumigatus protein by serum IgG antibody from patients with pulmonary aspergillosis

A method is presented for measuring the uptake of Aspergillus fumigatus protein by IgG antibodies from human serum. The human IgG is first isolated with an anti-IgG conjugated immunosorbent and then incubated with radio-iodinated A. fumigatus protein. A group of twenty-three control sera gave the same background levels as tests without sera. The highest uptake of A. fumigatus protein was given by the sera of patients with aspergilloma, and lower values were obtained with six out of thirteen sera from patients with asthma and twenty-five out of twenty-eight sera from patients with asthma and pulmonary eosinophilia, i.e. allergic bronchopulmonary aspergillosis. These results were in agreement with precipitin tests. Inhibition studies with unrelated antigens showed that the reactions were specific for the A. fumigatus protein, of which more was bound by test sera than with a crude extract.     

In vitro reversed anaphylaxis: characteristics of anti-IgE mediated histamine release

Leucocytes from allergic and most normal human donors release histamine when challenged with antibodies against human γ-globulin. This reaction (reversed in vitro anaphylaxis) is due primarily to anti-IgE antibodies although there is some response in most donors to antisera against IgG even after it has been absorbed with light and ε chains. The anti-IgE is, however, several 100-fold more potent than the anti-IgG. By passive sensitization of the leucocytes of a normal donor with serum from a ragweed-allergic patient it was shown that the normal cells became sensitive to anti-IgE and ragweed antigen E at the same time; in both cases, there was an inverse relationship between the serum concentration used for passive sensitization and the concentration of antigen or antibody required for histamine release. There is a rough correlation (r_s = 0.42; P<0.01) between the serum IgE concentration and the response of leucocytes from allergic donors to anti-IgE and an excellent correlation (r_s = 0.82; P<0.01) between the response of the cells to ragweed antigen E and anti-IgE. There is also a strong parallel between the mechanism of direct, antigen mediated histamine release and the reversed reaction induced by anti-IgE. Both appear to be non-serum requiring, non-cytotoxic, secretory-like responses which are inhibited by theophylline, cyclic AMP and colchicine. These data suggest that cell bound IgE is of major importance in the in vitro anaphylactic response and that the direct and reversed in vitro anaphylactic reactions both operate through cell-bound IgE and share a common reaction mechanism.     

Detection of allergen-specific IgE in tears of grass pollen-allergic patients with allergic rhinoconjunctivitis

Background Allergic conjunctivitis is a common symptom amongst Type I (IgE-mediated) allergic diseases; and mosl frequently seen as rhinoconjunctivitis. However, the site of production and the significance of allergen specific IgE needs further elucidation. Objective We investigated whether the presence of IgE in tears of grass pollen allergic patients correlated with disease and clinical symptoms, whether the IgE binding pattern to the different grass pollen antigens was diflferent in sera and tears, and whether IgA antibodies to grass pollen allergens were present in tears. Finally, we looked whether specific IgE was produced locally or was exudated from serum. Methods Sera from 44 grass pollen allergic patients suffering from either allergic rhinitis (n=11) or allergic rhinoconjunctivitis (n= 33) and from healthy controls (n= l) were used for the experiments. Binding of specific IgE and IgA antibodies to the differyent groups of grass pollen allergens (Phleum pratense) was evaluated by means of immunobtotting. Results Specific IgE was detected in sera as well as in tears of allergic patients, whereby tear-derived allergen-specific IgE exerted similar specificities to the corresponding IgE from serum. The correlation between symptoms of ocular allergy and the presence of allergen-specific IgE in tears was highly significant (P 0.0001). In contrast, only a poor correlation was found between specific and/or total IgE in sera and the manifestation of ocular allergy (P = 0.73). Conclusion Allergen-specific IgE antibodies in tears seem to be produced locally rather than exsudated from serum. IgE in tears seems to be responsible for allergic conjunctivitis. IgA in tears cannot exert a protective function since the IgA antibodies recognize different antigens in a grass pollen (Phleum pratense) extract than IgE antibodies. The highly significant correlation between allergic conjunctivitis and the presence of specific tear IgE emphasizes the diagnostic value of immunoblots with tear IgE, especially in cases in which serum provides inconclusive results.     

The inhibitory effect of serum factors on measurement of IgE aspergillus antibodies by RAST

The RAST value obtained in the A. fumigalus system, from sera of patients with allergic bronchopulmonary aspergillosis (ABPA) is dependent not only on the reagin titre but also on blocking factors that depress the RAST score. These factors are primarily specific for A. fumigatus and can be removed by an A. fumigatus immuno-adsorbent. However, some blocking activity could be found in normal sera even after absorption with an A, fumigates immunoadsorbent and seems to be non-specific. All of these blocking factors influence the specificity of the RAST, and complicate the comparison of the quantitation of IgE antibodies in different sera. The use of discs rather than cellulose particles and the use of dilute sera result in a RAST assay more proportional to the specific IgE antibodies to A. fumigates.     

Cryptogenic pulmonary eosinophilia

The clinical and immunological features of fifteen cases of cryptogenic pulmonary eosinophilia are reported. There were ten women (mean age 35·4 years) and five men (mean age 42 years). Eight gave a previous history of asthma and seven had none. Thirteen of the fifteen patients had negative skin test to common allergens. Many features of a systemic illness were present in the asthmatic and non-asthmatic groups including anaemia, weight loss, fever and a grossly raised ESR. An absolute polymorphonuclear leucocytosis was frequent as well as the obligatory increase in blood eosinophils used as one of our criteria for inclusion. Hepatomegaly (three cases), splenomegaly (four cases) and hilar node enlargement (one case) were seen in the group without asthma. Evidence of renal involvement or necrotizing vasculitis was notably absent and the response to small doses of corticosteroids was dramatic. Immunologically the striking feature was a disproportionate increase in blood eosinophils compared with only minor elevations in the total serum IgE levels. This stands in contrast to patients with bronchopulmonary aspergillosis and helminth infestation. Studies of cytophilic antibodies using histamine liberation after challenge with antibodies to immunoglobulin sub-classes in six patients showed a marked increase in IgG₂ and lesser increases of IgE and IgG₃. No evidence of antibodies specific to A. fumigatus was found. The amount of cytophilic antibody was also in contrast to that found in bronchopulmonary aspergillosis.     

Incidence of immediate sensitivity to Aspergillus fumigatus in a North American asthmatic population

Allergic bronchopulmonary aspergillosis might be less frequent in North America because the incidence of immediate sensitivity by asthmatics to A. fumigatus is less. In order to check this hypothesis, 200 asthmatics were skin tested with two extracts of A. fumigatus which had been shown to produce positive reactions in fifty patients who had allergic aspergillosis. Of the asthmatics, 21.5% reacted to the commercial extract by prick testing and 39% by intradermal testing. Using an extract kindly provided by Professor Pepys, 19.5% reacted to a concentration of 1 mg/ml and 31.5% to 10 mg/ml. By the prick method, 21.5% reacted to both extracts. Specific IgE was measured with one of the extracts and a good correlation (r= 0.48) was found with the size of the prick reaction. The increase in specific IgE was reflected in the increase of total IgE (r= 0.84). The authors conclude that the incidence of immediate sensitivity to A. fumigatus in asthmatic patients in North America is at least equal to that found in the U.K.     

Specific serum IgE antibodies to bacterial antigens in allergic lung disease*

A radio-allergosorbent test (RAST) to measure specific IgE antibodies in man to whole bacterial cells of Streptococcus pneumoniae, Staphylococcasaureus and Haemophilus influenzae was developed to investigate different well-defined lung diseases (chronic bronchitis, allergic bronchopulmonary aspergillosis (ABPA), bronchial asthma, allergic rhinitis, cystic fibrosis) and also in urticaria as compared with non-atopic blood donors, in addition, total IgE values and skin prick tests were assessed in these patients. The ABPA group gave the highest specific IgE RAST scores to all three bacteria. whilst the chronic bronchitis and cystic fibrosis groups also gave raised RAST scores withH. influenzae. There was a positive correlation between the patients' Sta. aureus and Str. pneumoniae immediate-type skin reactions and their RAST scores and total serum IgE concentrations, but there was only a low incidence of immediate-type skin test positivity to H. influenzae.     

Sensitization to Aspergillus species in the congenital neutrophil disorders chronic granulomatous disease and hyper-IgE syndrome

Background: Hyper-IgE syndrome (HIE) and chronic granulomatous disease (CGD) are congenital immunodeficiency diseases with increased susceptibility to bacterial and fungal infections. Both carry significant morbidity and mortality rates because of invasive infections by Aspergillus species. We encountered 2 patients, one with HIE and one with CGD, in whom detection of sensitization to Aspergillus species preceded the diagnosis of immunodeficiency. With high-dose systemic corticosteroids for allergic bronchopulmonary aspergillosis (ABPA), an inflammatory disorder caused by sensitization to Aspergillus species, pulmonary abscesses developed in the patient with HIE, and the patient with CGD succumbed to an overwhelming Aspergillus species–induced pneumonia. Objective: We sought to assess the prevalence of sensitization to Aspergillus fumigatus and the presence of diagnostic criteria for ABPA in patients with CGD and HIE. Methods: We measured A fumigatus –specific serum IgE, IgG, and precipitating antibodies as indicators for A fumigatus sensitization in the sera of 18 patients with neutrophil disorders (7 with HIE and 11 with CGD). Hospital records were reviewed for the presence of other diagnostic criteria for ABPA (asthma, elevated total serum IgE concentration, and radiographic abnormalities). Results: Twelve (67%) of 18 patients were sensitized to A fumigatus , as evidenced by precipitating A fumigatus –specific antibodies. Six (33%) of 18 patients had serologic evidence of ABPA. Five of those 6 patients had radiologic abnormalities consistent with a diagnosis of ABPA. One patient with HIE also had asthma, thus fulfilling minimal essential criteria for concurrent ABPA. Conclusions: Patients with HIE syndrome and CGD have a high incidence of sensitization to Aspergillus species. A clinical picture indistinguishable from ABPA may coexist or emerge in patients with CGD or HIE and create a major management dilemma because systemic corticosteroids may accelerate tissue damage and invasive fungal infections. It is important to distinguish individuals with congenital neutrophil disorders from uncomplicated classic ABPA. (J Allergy Clin Immunol 1999;1265-72.)     

Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils

Background Rapid clinical tolerance can be induced over several hours by very fast bee venom immunotherupy (VIT) protocols. Objective To investigate the mechanisms underlying VIT we examined the changes of blood basophil responsivetiess during VIT. Methods Seven bee venom allergic patients with a history of severe systemic reactions after a bee sting were investigated. A cumulative dose of 111.1 μg bee venom (BV) was administered sc over 3.5 h under intensive care conditions according to an ultra-rush protocol. The release of histamine and the formation of leukotrienes in response to BV, major BV allergen Phospholipase A₂ (PLA), IgE receptor cross-linking with the use of monoclonal antibodies against IgE and IgE receptor, as well as IgE independent activation in response to C5a were determined in vitro before and after ultra-rush VIT. Results We demonstrated a decrease of total histamine in peripheral blood leucocytes just after VIT. Histamine release in response to all the stimuli used is not affected by ultra-rush VIT, if expressed as per cent release of total histamine. However, the absolute amount of product released in response to stimulation was decreased, particularly with allergen (BV, PLA). We also found a significant reduction of LTC4 formation after VIT in samples stimulated with specific allergen (BV, PLA). Conclusion Blood basophils are a target for VIT, which induces impaired release of both preformed and newly generated mediators. However, we believe the basic mechanisms of rapid clinical tolerance induced by ultra-rush VIT remain to be investigated.     

Automated specific IgE assay with recombinant allergens: evaluation of the recombinant Aspergillus fumigatus allergen I in the Pharmacia CAP System

Background We report the results of a study comparing the recombinant Aspergiilus fumigatus allergen I (rAsp f I) to commercial A. jumigatus extracts in serological assays, Pharmacia CAP System and skin tests. Objective The study was designed to test the feasibility of using recombinant allergens in an automated serology system for determination of allergen-specific IgE. Methods Patients with allergic bronchopulmonary aspergillosis (ABPA), asthmatics with A. fumigatus allergy and control subjects, who included allergic asthmatics without allergy to A. fumigatus and healthy subjects, were investigated. All subjects were characterized with respect to their total IgE level, radio allergosorbent test to A. fumigatus and skin test reactivity to both commercial A. fumigatus extracts and recombinant rAsp f I protein. Results All patients with ABPA (n = 30) showed positive skin test reactions with commercial A. fumigatus extracts, and 24 were sensitized to r Asp f I by the same criterion. The 10 patients with asthma and A. fumigatus allergy showed positive skin reactions to at least one commercial extract, and five reacted to r Asp f I. AU control subjects (H= 19) scored negatively in skin tests to A. fumigatus extracts and r Asp f I, and showed no detectable rAsp f I-specific IgE. ImmunoCAP carrying immobilized r Asp f I were evaluated using sera from all individuals described and the results compared with those obtained with the r Asp f I-specific ELISA for IgE. The data obtained with the two r Asp f I-specific detection systems correlated closely (r= 0.997) and were in perfect agreement with the skin test results. Conclusion The data show that r Asp f I can be used as immobilized allergen in the Pharmacia CAP System indicating the feasibility of using recombinant allergens for an automated serological diagnosis of allergic diseases. However, every recombinant allergen needs to be evaluated individually for its performance if applied to a new diagnostic technology.     

IgE antibody-specific activity in human allergic disease

IgE antibody concentration, affinity, clonality and specific activity (also known as the allergen-specific IgE to total IgE ratio) influence the translation of IgE responses into clinically evident allergic symptoms following allergen exposure. Reported IgE-specific activity levels >3–4% place allergic individuals undergoing anti-IgE (Omalizumab^®) therapy at a disadvantage for poor resolution of their allergy symptoms following manufacturer’s recommended dosing schemes. We investigated the hypothesis that the specific activity of the IgE antibody response is highly variable with respect to age, allergen specificity and an individual’s total serum IgE level. Second, we investigated whether the IgE-specific activity level influences the extent and rate of loss of effector cell mediator release. IgE-specific activity distributions were plotted against age, allergen specificity and total serum IgE using 18,950 paired total IgE and allergen-specific IgE antibody data obtained from the analysis of sera from 3,614 allergic subjects and covering 182 allergen specificities. The fraction of specific IgE antibody of the total serum IgE was dependent on age of the individual, epitope specificity (clonality) and total serum IgE. The youngest group of allergic individuals with the lowest total serum IgE levels tended to have the highest allergen-specific IgE to total IgE ratios. Hymenoptera venom (54%), peanut (33%) and milk (27%) were the three allergen specificities that elicited the highest frequency of IgE-specific activities >4% among sensitized individuals. A prospective double-blind, placebo-controlled clinical study involving anti-IgE treatment of cat-allergic subjects showed IgE-specific activity was remarkably constant over the 16-week course of treatment, despite the up to 8-fold rise in total serum IgE following repetitive Omalizumab^® administration. Changes in specific and total IgE levels paralleled each other in patients receiving anti-IgE therapy. The fastest rate of reduction in cat allergen-induced basophil histamine release following anti-IgE therapy was observed when the cat-specific IgE to total IgE ratio was <2.5%. This reflected the more rapid loss of surface cat-specific IgE antibody with anti-IgE therapy in allergic individuals who displayed a more diverse IgE antibody repertoire. We conclude that IgE-specific activity is an age-, IgE heterogeneity- and total serum IgE-dependent variable that influences the magnitude of effector cell mediator release, and by inference, ultimate allergic symptom induction.