Mechanisms of IgE Inflammation

The prevalence of diseases such as allergic asthma and rhinitis continues to increase in the United States, affecting millions of people. It is well-established that allergy contributes to the pathogenesis of most asthma, especially in children and young adults. Despite current therapy (eg, inhaled corticosteroids, anti-leukotrienes, and bronchodilators), patients with moderate to severe asthma remain symptomatic and experience frequent exacerbations of disease requiring oral corticosteroids, emergency department treatments, and hospitalizations. Allergic diseases are traditionally referred to as immediate or type 1 hypersensitivity reactions, with IgE as a critical factor. IgE is involved in allergic inflammation, especially in early-phase response, but it may also be involved in the late-phase allergic response. A direct correlation between serum IgE levels and asthma exists. As logarithm IgE values increase, asthma prevalence increases linearly, even in patients who are categorized as having nonallergic asthma. In addition, there is a significant, although low association in allergic rhinitis with IgE levels and positive skin test reactivity to pollens. Recent advances in our understanding of the role of IgE in allergic inflammation have led to the development of a monoclonal antibody to IgE that reduces IgE levels, thereby reducing allergic inflammation. This review aims to provide an overview of the basic science of the IgE molecule and the clinical efficacy of anti-IgE therapy in allergic and asthmatic diseases.     

Age effects on objective measures of atopy in adult asthma and rhinitis.

A cross-sectional survey of 132 adult men referred to the outpatient allergy clinic at the West Los Angeles Veterans Affairs Medical Center was performed to assess age effects on allergic disease in the elderly. Total serum immunoglobulin E (IgE), immediate hypersensitivity skin testing, and serum eosinophil count were measured in all subjects. Subjects were stratified by age into one of five groups for comparison. In asthma, prevalence of allergy skin test reactivity and mean total serum IgE levels did not decline with advancing age, suggesting that IgE-dependent mechanisms continue to be significant in elderly patients with asthma. In subjects with rhinitis, prevalence of allergy skin test reactivity and mean total serum IgE did decline among elderly subjects relative to younger subjects. However, the prevalence of allergic rhinitis did not decline in the elderly. This suggests that although allergic rhinitis is common in elderly patients, nonallergic causes of rhinitis may become more prevalent with advancing age.     

Lack of Correlation between Nonspecific Nasal and Bronchial Reactivity in Allergic Rhinitis Subjects

A link between allergic rhinitis and asthma has long been suspected, allergic rhinitis being considered a precursor of asthma. The hypothesis is that if such a link exists, then nonspecific nasal and bronchial reactivity are already correlated in acute rhinitis patients. To test for this correlation, we compared nonspecific nasal and bronchial reactivity in two groups of rhinitis subjects: 37 rhinitis pollinosis patients tested during the pollen season and 35 rhinitis pollinosis patients tested outside the pollen season. We also assessed how smoking affects this link. In each subject, allergy, nonspecific nasal, and nonspecific bronchial reactivity were tested, and smoking was categorized. We found no correlation between nonspecific nasal and bronchial reactivity in the two nonasthmatic rhinitis groups. During active allergic inflammation (pollinosis season) no shift toward a stronger link between upper and lower airways can be found compared with the latent period (out of pollinosis season). Unexpectedly, among smokers we found a significant relationship between nonspecific nasal and bronchial reactivity. Thus, there is not yet sufficient evidence for a straightforward link between nasal and bronchial hyperreactivity in nonasthmatic pollinosis rhinitis subjects. The development of asthma seems to be crucial for this link. Accepted for publication: 30 November 1998     

Allergy shots: Taking the sting out of allergic asthma

People with allergic rhinitis, or hay fever, often experience the nuisance and discomfort of sneezing, a runny nose, itchy and watery eyes, and nasal congestion. For some people, this affliction is seasonal; for others it occurs year-round. To make matters worse, allergic rhinitis is closely associated with asthma. For people who have asthma and allergic rhinitis, the allergies often trigger asthma symptoms. An estimated 50% of asthma in adults and a whopping 80% in children is triggered by allergies. People who have allergic rhinitis but do not have asthma may be more likely to develope it. An estimated 20% of all children with allergic rhinitis will develop asthma within the next 8 to 10 years.     

What is new in antiimmunoglobulin E asthma therapy.

Omalizumab, a recombinant humanized monoclonal antibody, is the first therapeutic agent specifically targeting immunoglobulin E (IgE). It has been investigated extensively in the treatment of patients with allergic diseases and is approved in the United States for the treatment of patients with moderate-to-severe persistent asthma. In this setting, omalizumab reduced the frequency and incidence of asthma exacerbations and asthma control was well maintained, even though patients significantly reduced their dose of inhaled corticosteroid. Importantly, omalizumab has been shown to reduce asthma exacerbations in high-risk patients (e.g., with previous intubation and hospitalization) and to reduce the level of severe asthma exacerbations (those resulting in emergency treatment and hospitalization). Responder analysis shows that omalizumab provides the greatest benefit in patients with more severe asthma, and this has been confirmed by recent studies establishing the efficacy of omalizumab in patients whose asthma is poorly controlled despite receiving the best standard care in medication. Omalizumab also has proved to be effective in patients with seasonal and perennial allergic rhinitis and to improve quality of life for patients with asthma or rhinitis. As expected with a systemic anti-IgE agent, omalizumab was shown to be effective in the treatment of patients with concomitant asthma and allergic rhinitis. The efficacy of omalizumab in a range of allergic diseases reaffirms the importance of IgE in the pathogenesis of these conditions and establishes the potential benefit to be obtained by inhibiting IgE, especially in patients with more severe and comorbid allergic diseases.     

Management of asthma with anti-immunoglobulin E: a review of clinical trials of omalizumab

Immunoglobulin E (IgE) is a key mediator of the inflammatory reactions that are central to the pathogenesis of allergic diseases such as asthma and rhinitis. The recognition of the importance of IgE in allergic disease led to the development of omalizumab, a humanized monoclonal anti-IgE antibody that binds free circulating IgE and prevents the interaction between IgE and high-affinity (FcepsilonRI) and low-affinity (FcepsilonRII) IgE receptors on inflammatory cells. By removing free IgE, omalizumab also markedly downregulates the expression of high-affinity receptors on basophils, mast cells and dendritic cells. Several studies have shown that omalizumab effectively reduces the risk of exacerbations and hospitalization and improves symptom control, lung function and quality of life in patients with severe persistent allergic asthma. Importantly, omalizumab has been shown to be effective in patients with poorly controlled severe persistent allergic asthma, a group of patients with few effective additional treatment options. In addition, omalizumab has been shown to provide effective relief from the symptoms of allergic rhinitis (including patients with concomitant asthma). Patients with uncontrolled severe persistent allergic asthma are a challenging and difficult-to-treat population for whom omalizumab might represent an important new treatment option. In addition, omalizumab may provide a means to address comorbid allergic disease in patients with asthma. Further investigation is also warranted to explore potential applications of omalizumab in occupational asthma.     

Human basophil releasability. VI. Changes in basophil releasability in patients with allergic rhinitis or bronchial asthma.

We evaluated basophil releasability in two groups of allergic patients with positive skin tests to Dermatophagoides pteronyssinus major allergen (Der p l) (29 adults with bronchial asthma and 17 with allergic rhinitis) and in 31 age-matched normal donors. Both basophil reactivity (maximal percent histamine release) and basophil sensitivity (the concentration that causes 50% of maximal percent histamine release: HC50) to Der p l in patients with asthma were similar to those in patients with allergic rhinitis. On the contrary, basophil reactivity to anti-IgE was significantly higher in patients with asthma (58.0 +/- 3.6%) than in patients with allergic rhinitis (46.3 +/- 5.2%; p less than 0.05). Both groups of patients showed an increased releasability compared to control subjects (27.3 +/- 4.6%; p less than 0.001), whereas there were no significant differences in basophil sensitivity to anti-IgE among the three groups of donors. Differences were also found with respect to basophil reactivity and sensitivity to f-met peptide, whereas no differences appeared when basophils from the three groups of donors were challenged with the Ca2+ ionophore A23187. There was a significant correlation between basophil reactivity and sensitivity to Der p l and to anti-IgE in both asthmatic and allergic rhinitis patients. A significant correlation was found between basophil reactivity and sensitivity to anti-IgE and serum IgE level only in patients with bronchial asthma, whereas no correlations were found in patients with allergic rhinitis. There was no correlation between in vivo mast cell releasability and in vitro basophil releasability in response to Der p l in either group of allergic patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Targeting immunoglobulin E as a novel treatment for asthma

Omalizumab is a recently developed monoclonal anti-IgE antibody. Clinical trials have demonstrated its efficacy in patients with moderate-to-severe and severe or poorly controlled allergic asthma, in patients with seasonal and perennial allergic disease, and in subjects with concomitant asthma and allergic rhinitis. Patients with more severe asthma appear to obtain the greatest benefit from omalizumab therapy. Omalizumab is well tolerated and has a good safety profile. Anti-inflammatory activity has been shown in both allergic asthma and allergic rhinitis. These results confirm the importance of IgE in allergic disease and support the rationale behind the development of a therapeutic anti-IgE antibody. Omalizumab is a significant addition to current asthma treatments and shows great promise as a therapy for allergic rhinitis, in particular for those patients with concomitant allergic disease.     

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变应性鼻炎(AR)与支气管哮喘均是上、下气道的一种慢性炎症性疾病,在流行病学、病理生理学和治疗方法上存在相似性和相关性,在临床上被称为"同一气道,同一疾病"。AR增加支气管哮喘患者的症状和就诊的需求,不利于支气管哮喘控制,AR对支气管哮喘的影响(ARIA)推荐对AR和支气管哮喘要进行联合诊断并同时治疗。     

Etiopathogenesis and Management of Perennial Allergic Rhinitis

Perennial allergic rhinitis is an inflammatory disorder characterized by symptoms of nasal congestion, rhinorrhea, sneezing, and itching. The prevalence of allergic rhinitis is quite common and affects 20% or more of various populations. Some patients with allergic rhinitis are symptomatic only during the pollen season, while many others are allergic to multiple allergens including indoor allergens such as house dust mites, animal dander, cockroaches, and fungi, which lead to perennial symptoms. Immunoglobulin (Ig)-E is the proximate cause of perennial allergic rhinitis. Circulating IgE antibodies bind to the high affinity IgE receptor on mast cells and basophils. IgE antibodies, bound to the receptors crosslinked by allergen, initiate the secretion of inflammatory mediators including histamine, leukotrienes, and cytokines. These mediators can induce both acute and chronic changes that result in symptoms of allergy. Many therapies are approved for the treatment of allergic rhinitis including intranasal corticosteroids, antihistamines with or without decongestants, and nasal cromolyn sodium (sodium cromoglicate). Allergen avoidance is the mainstay of therapy for many patients but is not always practical. For those patients who have not responded to appropriate medications, allergen specific immunotherapy may also be effective.A number of studies with omalizumab have shown that it is effective in the treatment of seasonal allergic rhinitis induced by pollen such as ragweed and birch pollen. Omalizumab is a molecularly cloned humanized monoclonal antibody inhibiting human IgE. It binds specifically to the region of the IgE molecule that binds to the IgE receptor on the mast cell or basophils. Because omalizumab cannot bind IgE molecules that are already bound to the surface receptors on mast cells and basophils, it does not stimulate secretion of mediators from these cells. Omalizumab does not appear to stimulate an immune response against itself. It rapidly reduces free serum IgE levels by over 95% when administered at therapeutic doses and also results in the reduction of IgE receptors on mast cells and basophils. The combined effects of reduction of both free IgE in serum and the receptor density on the mast cells or basophils results in decreased allergen-stimulated mediator release. Preliminary studies in the treatment of perennial allergic rhinitis supports omalizumab's efficacy and safety. The compound has been well tolerated. Aside from urticarial reactions, adverse effects appear to be minimal. Omalizumab is the first of several new immune-based specifically targeted molecules that may prove to be extremely valuable in the treatment of perennial allergic rhinitis, as it is often unresponsive to traditional therapies.     

Anti-IgE antibodies for the treatment of asthma

PURPOSE OF REVIEW: Allergic asthma is a hypersensitivity reaction initiated by immunologic mechanisms mediated by IgE antibodies. IgE plays a central role in the initiation and propagation of the inflammatory cascade and thus the allergic response. Targeting factors involved in the allergic response, such as IgE, is a novel strategy for new therapies. Attenuating allergic disease by specifically inhibiting IgE and the development of the monoclonal anti-IgE antibody, omalizumab, were major breakthroughs in asthma management. RECENT FINDINGS: Several studies have shown that omalizumab has significant anti-inflammatory effects and that it may act on multiple components of the inflammatory cascade. Specific binding of IgE by omalizumab reduces both the early allergic response and the late allergic response and symptoms of IgE-mediated allergy. The long-term clinical efficacy of omalizumab has been demonstrated along with improvements in quality of life. As add-on therapy in severe asthma, omalizumab reduces the requirement for inhaled corticosteroids and improves disease control. Clinical studies have shown that the patients who benefit most from omalizumab therapy are those at high risk of exacerbations, those with poorly controlled and/or severe asthma, and those with IgE-mediated comorbidities. SUMMARY: Omalizumab is a significant addition to current asthma treatments and shows great promise as a therapy for allergic asthma and for patients with concomitant allergic rhinitis. This is particularly true for difficult-to-treat patients with moderate to severe allergic asthma who have poorly controlled disease on conventional therapies, experience severe adverse effects secondary to high-dose or prolonged corticosteroid treatment, have frequent exacerbations, and/or are at high risk of hospitalization. Future studies will continue to investigate the anti-inflammatory mechanisms of anti-IgE therapy. Because many of these mechanisms are common to all IgE-mediated allergic diseases, the efficacy of omalizumab in other allergic diseases should be further explored.     

Role of Allergen Sensitization in Older Adults

There is a common perception among physicians and patients that allergic diseases are not relevant in older adults. There is also recognition that innate and adaptive immune functions decline with aging. It is the function of a variety of immune cells in the form of allergic inflammation that is a hallmark of allergic diseases. In fact, there is a fairly consistent observation that measures of allergic sensitization, such as skin prick testing, specific IgE, or total IgE, decline with age. Nonetheless, the association between allergic sensitization and allergic diseases, particularly asthma and allergic rhinitis, remains robust in the older adult population. Consequently, an appropriate evaluation of allergic sensitivities is warranted and indicated in older asthma and rhinitis patients to provide optimal care for the individual and minimize any resultant morbidity and mortality.     

Omalizumab: Anti-IgE Therapy in Allergy

Omalizumab is a humanized, monoclonal anti-IgE antibody that binds specifically to circulating IgE molecules, thus interrupting the allergic cascade. Omalizumab has been shown to be highly effective in treating children and adults with moderate to severe allergic asthma. Beyond this indication, the mode of action itself suggests that omalizumab is not only an antiasthmatic drug but also a promising therapeutic option for various allergic conditions, including allergic rhinitis, food allergy, urticaria, allergic bronchopulmonary aspergillosis, insect hypersensitivity, and atopic dermatitis. However, data from double-blind, placebo-controlled clinical trials are only available for allergic rhinitis and moderate to severe bronchial asthma. The aim of this review is to discuss the current clinical data as well as possible further indications of omalizumab treatment.     

Omalizumab and the treatment of allergic rhinitis

Anti-IgE therapy affects mechanisms in the allergic response that are IgE-dependent or IgE-mediated and common to both allergic asthma and allergic rhinitis. Clinical trials of omalizumab in the treatment of patients with allergic rhinitis or comorbid allergic rhinitis and moderate to severe allergic asthma have recorded significant reductions in symptom severity scores of both conditions. This novel therapy has increased the knowledge base concerning IgE-mediated allergic responses, and, in keeping with its actions established in the treatment of asthma, appears to be useful in the treatment of moderate to severe allergic rhinitis, as well.     

广州地区儿童呼吸道变态反应性疾病常见变应原的流行病学分析

目的 了解广州地区呼吸道变态反应性疾病儿童常见变应原,为预防和治疗儿童变应性疾病提供科学依据.方法 选择2006年2月至2007年3月在广州医学院第一附属医院儿科门诊符合支气管哮喘(简称哮喘)和(或)变应性鼻炎(简称鼻炎)的广州地区5岁以上患儿183例,其中男132例,年龄(8.2-4-0.2)岁;女51例,年龄(7.8士0.4)岁;哮喘并鼻炎者105例,哮喘患儿58例,仅鼻炎患儿20例.所有对象均进行皮肤变应原点刺试验(SPT)及血清总IgE、特异性IgE和嗜酸粒细胞计数.结果 在人选的183例患儿中,SPT阳性(≥1个变应原阳性)157例(85.8%),各变应原阳性率为5.5%～75.4%,变应原中以屋尘螨致敏的阳性率最高,达79.8%,其次为粉尘螨与热带螨,分别为72.7%与65.0%,其余变应原阳性率依次为:狗毛48.6%,美洲大蠊47.0%,猫毛34.4%,德国小蠊29.5%,霉菌类19.7%,花粉类15.9%,艾蒿7.7%,豚草5.5%.螨过敏阳性患儿有146例,常合并其他一种或多种变应原阳性(115例,78.8%),而螨过敏阴性患儿(37例,20.2%)中仅有11例(29.7%)合并其他一种或多种变应原阳性(x2=33.099,P<0.001),差异有统计学意义.各年龄组发病率特点:高龄组(>7岁)SPT阳性率为82.3%,高于低龄组(≤7岁)(79.3%),两组间SPT阳性率的差异有统计学意义(P<0.05).在吸入变应原种类的比较中,高龄组在螨类过敏阳性率、猫毛与狗毛阳性率、蟑螂阳性率均高于低龄组,差异有统计学意义(P<0.05);两组在霉菌类及花草类阳性率的差异无统计学意义.哮喘并鼻炎、哮喘、鼻炎3组患儿均以螨类过敏最为常见,3组间除蟑螂SPT阳性率差异有统计学意义外(P<0.05),螨类、动物皮毛类、霉菌及花草类的变应原阳性率差异均无统计学意义.结论 过敏性因素是儿童呼吸系统变态反应性疾病发病的重要诱发因素,在广州地区哮喘和(或)鼻炎儿童可以通过SPT检查明确过敏原,最常见的变应原是屋尘螨、粉尘螨及热带螨.随着年龄增长,呼吸道变态反应性疾病患儿对吸入性变应原更为敏感.鼻炎、哮喘、哮喘并鼻炎患儿有共同的变应原.研究不同年龄段变态反应性疾病患者的变应原特征,有助于对疾病的早期诊断和早期干预.     

Immunotherapy for House Dust Mite Sensitivity: Where Are the Knowledge Gaps?

House dust mites (HDMs) are found in the environments where human habitation exists. Their density is dependent on environmental relative humidity; therefore, higher populations are present in areas of the world with higher humidity levels, e.g., coastal areas and tropics. To date, 24 HDM allergens have been identified. Many of these represent digestive enzymes since HDM feces are the major source of allergen exposure. IgE- medicated sensitization to HDM allergens is an important factor in the pathogenesis of allergic diseases since it is the most common aeroallergen detected by skin testing or in vitro IgE assays. Sensitization to HDM allergens often occurs early in life and appears to play an important role in the progression from allergic rhinitis to asthma (the so-called Allergic March) in children. HDM sensitization is also associated with asthma across all age groups. Efforts to control environmental exposure to HDM allergens have often proven to be unsuccessful. While medications can improve symptoms, only immunotherapy currently provides disease-modifying effects in allergic rhinitis and asthma. Several systemic reviews and meta-analysis indicate that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective in the treatment of allergic rhinitis and asthma for HDM sensitivity. In this report, we review recent studies and the evidence for the use of HDM SCIT and SLIT. Fundamental gaps in knowledge are identified which could lead to improved approaches to HDM allergy.     

Discriminant analysis in allergic rhinitis and asthma: methacholine dose-response slope allows a good differentiation between mild asthma and rhinitis

Asthma and rhinitis frequently coexist in allergic patients, but nasal symptoms may predominate, leading to asthma underdiagnosis and undertreatment. Discriminant analysis obtains the best differentiation between groups using one or one set of variables. Our aim was to identify the laboratory test [allergen exposure, total and specific serum IgE, lung function, blood eosinophils and, bronchial response and sensitivity to methacholine (Mth) and allergen] or combination of them that allowed the best differentiation between mild asthma and allergic rhinitis. A cross-sectional analysis was performed in 86 Dermatophogoides pteronyssinus allergic rhinitis patients, who were classified according to clinical data as rhinitis plus mild asthma (n = 62) or "pure" rhinitis (n = 24). Bronchial symptoms had been exhaustively evaluated during a 2-years pre-inclusion period. Patients underwent skin tests and bronchial challenge with Mth and allergen. The exposure to D. pteronyssinus allergen (Der pl) was quantified in dust samples. Dose-response curves with Mth [until the FEV1 fell by 40% or the maximal dose (200 mg/ml) was inhaled] were attained. We developed multiple models of discriminant analysis in order to evaluate the capacity of the above variables to differentiate groups. Asthma patients had higher total and specific IgE levels and a greater sensitivity (PD20 values) and response [dose-response slope (DRS)] to both Mth and allergen. The model entering these variables was the one that correctly classified more patients (79.2%). The discriminative power of the model that only included Mth-DRS values was similar to the above (78.8%). Bronchial response to Mth is quantitatively different in allergic rhinitis patients who display mild asthma symptoms when compared to those that only report rhinitis, suggesting a distinct bronchial intrinsic behavior. The utilization of complete dose-response curves with Mth allows a good separation between mild asthma and "pure" rhinitis patients and might be useful in the diagnosis of mild asthma. Whether the early detection and treatment of these patients prevents the development of symptomatic asthma needs further evaluation.     

Absence of relationships between tuberculin responses and development of adult asthma with rhinitis and atopy

OBJECTIVE: To investigate the relationship between tuberculin skin responses and the development of adult asthma, rhinitis, and atopy. METHODS: Two hundred fourteen patients with mild-to-moderate asthma accompanied with rhinitis and 220 normal volunteers underwent a medical history, chest radiography, allergen skin-prick testing (SPT), bovine Mycobacterium tuberculosis vaccine (BCG) scar identification, purified protein derivative (PPD) tuberculin skin testing, serum-total and serum-specific IgE measurements, and bronchial provocation (provocative dose of histamine causing a 20% fall in FEV(1) [PD(20)]). RESULTS: Thirty-one normal volunteers (14.1%) and 168 asthma-rhinitis subjects (78.5%) had one or more positive skin test results (p < 0.0001). Neither the presence of a BCG scar nor a history of BCG vaccination had a significant effect on atopy in either group. The rate of PPD positivity had no statistical difference between atopy and nonatopy in both groups. In multivariate logistic regression analysis, the odds ratio for tuberculin reactivity was not related to the level of serum-total IgE nor to the level of serum-specific IgE to Dermatophagoides pteronyssinus (DP) and Dermatophagoides farinae (DF), skin response to DP and DF, and PD(20). Overall, no significant correlations were found between tuberculin skin reactivity and log serum-total IgE or PD(20). CONCLUSION: There is no relationship between history of tuberculosis infection, tuberculin responses, and development of adult bronchial asthma, allergic rhinitis, and atopy. Our study suggests that the protection provided by intradermal BCG vaccination in infants to prevent atopic diseases may be limited in early childhood, when a substantial memory of cellular immune modulation still exists.     

Novel clinical and serological aspects in non-allergic asthma

BACKGROUND: We have recently observed that skin reactivity to autologous serum injection is common in patients with non-allergic asthma. However, clinical significance of skin reactivity to autologous serum remains to be defined. OBJECTIVE: To evaluate the possible relation between skin reactivity to autologous serum and clinical and laboratory characteristics in a series of patients with non-allergic asthma. METHODS: Fifty-five patients with non-allergic asthma underwent in vivo autologous serum skin test (ASST) and in vitro basophil histamine release assay using basophils from a normal donor. Clinical and laboratory characteristics including peripheral blood eosinophilia, antinuclear antibodies and total IgE concentration were evaluated. As control, ASST was performed in 10 allergic asthmatic patients, 10 patients with allergic rhinitis and 10 normal subjects. RESULTS: ASST was positive in 29/55 non-allergic asthmatics (53%), whereas it was negative in all 30 control subjects (P<0.001). The sera of 6 out of 51 patients induced in vitro histamine release from autologous basophils. The sera from two patients induced histamine release from membrane IgE-stripped basophils. A significant predominance of female sex (83%) and a high incidence of antinuclear antibodies (ANA) positivity (55%) were found among ASST-positive patients. CONCLUSION: These findings indicate that ASST is positive in about half patients with non-allergic asthma and that a proportion of patients (16%) has functional evidence of circulating histamine-releasing factors. In addition, predominance of female sex and frequent ANA positivity are in line with an autoimmune basis of non-allergic asthma.