Clinical and Experimental Allergy

Despite considerable research, the aetiology of asthma and allergic disease remains poorly understood. The International Study of Asthma and Allergies In Childhood (ISAAC), was founded to maximize the value of epidemiological research into asthma and allergic disease by establishing a standardized methodology and facilitating international collaboration. It has achieved its specific aims which are to describe the prevalence and severity of asthma, rhinitis and eczema in children living in different centres and to make comparisons within and between countries; to obtain baseline measures for assessment of future trends in the prevalence and severity of these diseases; and to provide a framework for further aetiological research into genetic, lifestyle, environmental and medical care factors affecting these diseases.

 The ISAAC design comprises three phases. Phase One used simple core written questionnaires for two age groups, and was completed in 156 collaborating centres in 56 countries and a total of 721 601 children participated. In the 13–14 years age group 155 centres from 56 countries participated, of which 99 centres completed a video questionnaire. For the 6–7 years age group there were 91 collaborating centres in 38 countries. ISAAC Phase One has demonstrated a large variation in the prevalence of asthma symptoms in children throughout the world including hitherto unstudied populations. It is likely that environmental factors were responsible for major differences between countries. The results provide a framework for studies between populations in contrasting environ‐ments which are likely to yield new clues about the aetiology of asthma. ISAAC Phase Two will investigate possible aetiological factors, particularly those suggested by the findings of Phase One. ISAAC Phase Three will be a repetition of Phase One in the year 2000 to assess trends in prevalence.

Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and bronchiectasis. There are estimated to be in excess of four million patients affected world‐wide. The importance of recognizing ABPA relates to the improvement of patient symptoms, and delay in development or prevention of bronchiectasis, one manifestation of permanent lung damage in ABPA. Environmental factors may not be the only pathogenetic factors because not all asthmatics develop ABPA despite being exposed to the same environment. Allergic bronchopulmonary aspergillosis is probably a polygenic disorder, which does not remit completely once expressed, although long‐term remissions do occur. In a genetically predisposed individual, inhaled conidia of A. fumigatus germinate into hyphae with release of antigens that activate the innate and adaptive immune responses (Th2 CD4⁺ T cell responses) of the lung. The International Society for Human and Animal Mycology (ISHAM) has constituted a working group on ABPA complicating asthma (www.abpaworkinggroup.org), which convened an international conference to summarize the current state of knowledge, and formulate consensus‐based guidelines for diagnosis and therapy. New diagnosis and staging criteria for ABPA are proposed. Although a small number of randomized controlled trials have been conducted, long‐term management remains poorly studied. Primary therapy consists of oral corticosteroids to control exacerbations, itraconazole as a steroid‐sparing agent and optimized asthma therapy. Uncertainties surround the prevention and management of bronchiectasis, chronic pulmonary aspergillosis and aspergilloma as complications, concurrent rhinosinusitis and environmental control. There is need for new oral antifungal agents and immunomodulatory therapy.

Despite its well‐known association with IgE‐mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half‐molecules (i.e. a heavy and attached light‐chain) exchange. This process, also referred to as ‘Fab‐arm exchange’, results usually in asymmetric antibodies with two different antigen‐combining sites. While these antibodies are hetero‐ bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T‐helper type 2 (Th2) cells, the IgG4 response is largely restricted to non‐microbial antigens. This Th2‐dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE‐mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen‐blocking effect at the mast cell level and/or at the level of the antigen‐presenting cell (preventing IgE‐facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL‐10 and other anti‐inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non‐activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti‐inflammatory cytokines triggering an overwhelming expansion of IgG4‐producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen‐specific IgG4 indicates that anti‐inflammatory, tolerance‐inducing mechanisms have been activated. The existence of the IgG4 subclass, its up‐regulation by anti‐inflammatory factors and its own anti‐inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.

Background Patients with severe asthma are often inadequately controlled on existing anti‐asthma therapy, constituting an unmet clinical need.

Objective This randomized, double‐blind, placebo‐controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti‐IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma.

Methods After a run‐in period when an optimized fluticasone dose (1000 μg/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo (n=120) at intervals of 2 or 4 weeks. The study comprised a 16‐week add‐on phase of treatment followed by a 16‐week fluticasone‐reduction phase. Short‐/long‐acting β₂‐agonists were allowed as needed.

Results Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% (P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a 50% dose reduction (P=0.001). Fluticasone dose reduction to 500 μg/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo‐treated patients (P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma‐related quality of life compared to placebo.

Conclusion Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use.

Background: A previous study has shown a twofold increase in prevalence of asthma and allergic rhinitis (AR) in Swedish recruits during the 1970s. The increase was higher in more northerly colder regions.

Objectives To follow up the previously found trend to increasing prevalences with time as well as the climatic variations within the country.

Methods: The prevalences of asthma, allergic rhinitis and eczema were assessed using two questionnaire studies, 12 years apart (1979 and 1991) with identical questions about the diseases. The study comprised representative samples of children from the Göteborg area on the south‐western coast (in 1979: 7‐year‐olds, n= 4255, in 1991: 7‐year‐olds, n= 1649) and in Kiruna, a mining town in the northernmost inland mountains (in 1979: 7‐year‐olds, n= 427, in 1991: 7‐9‐year‐olds, n= 832). In 1991 there was also a personal interview and a skin‐prick test (SPT) on subsamples.

Results: The prevalence of all these diseases present over the last year had roughly doubled over the 12‐year period. On both occasions, most symptoms were more prevalent in the northern area. In 1991, the prevalence of one or more symptoms in Goteborg was 23.8% and 32.5% and in Kiruna 29.9% and 44.8% in the questionnaire and the interview, respectively.

Conclusion: Asthma, AR and eczema increase continuously in prevalence in Sweden and the climatic distribution of the prevalences suggests possible major risk factors to be found in a closed indoor climate.