Is there a place for intrinsic asthma as a distinct immunopathological entity?

Allergic asthma is usually diagnosed on the basis of the medical history, recurrent airway obstruction, bronchial hyperresponsiveness and the presence of an underlying allergic diathesis as assessed by skin provocation, variably increased eosinophil numbers in the blood and sputum, and the detection of allergen-specific immunoglobulin E (IgE). Based on the above criteria many cases of asthma can be diagnosed. In addition, increased total IgE, specific IgE and increased blood or sputum eosinophils may also help to differentiate between asthma and chronic obstructive pulmonary disease (COPD). There are, however, individuals who fulfil most diagnostic criteria for asthma, but have neither a detectable skin test reactivity to common allergens nor an increased total or specific IgE, despite a raised eosinophil count in the blood and/or sputum. In 1940 RACKEMANN [1] introduced the term "intrinsic" asthma in order to emphasize that this type is distinct from allergic extrinsic asthma with respect to the absence of an obvious precipitating exogenous cause. Since then, intrinsic asthma has been the subject of numerous reports and additional features related to the nonatopic variant were established. For instance, intrinsic asthmatics characteristically have a later onset of symptoms with a more severe clinical course of the disease than those with allergic asthma. Further, there is usually no family history of asthma or allergy and the female sex appears to be affected more often. In addition, a respiratory flu-like disease or cold often precedes the development of symptoms in intrinsic asthma. Finally, nasal polyps and aspirin sensitivity seems to occur more frequently in the nonatopic form of the disease. Due to its operational definition and continuous incidence, the terms intrinsic and nonallergic asthma have established themselves in clinical practice, referring to those asthmatic patients without an apparent underlying allergic disorder. Although widely accepted by many clinicians, the existence of intrinsic asthma has been questioned by others with respect to epidemiological data and the role of allergens in the pathogenesis of asthma. For instance, based on the relationship between total serum IgE levels and airway hyperreactivity, it has been suggested that virtually all patients suffering from asthma have an atopic component [2, 3]. Indeed, apart from the subtle clinical and laboratory differences mentioned above, there are no data available to date which allow a clear distinction between intrinsic and extrinsic asthma. Even more important to the ongoing discussion, neither the putative aetiologic agent nor the underlying immunopathogenesis of intrinsic asthma have yet been established. Therefore, much hope rests on recent advances in modern immunological and molecular techniques that may help to solve this controversy. In recent years, a number of studies have demonstrated that an immunological distinction between extrinsic and intrinsic asthma may indeed exist. For instance, both CD4+ and CD8+ T-lymphocytes in the blood of nonatopic asthmatics persistently express the cellular activation markers including interleukin (IL)-2R human leucocyte antigen (HLA)-DR, and very late activation antigen (VLA)-1 surface antigens throughout the year even during symptom-free periods [4, 5, 6], whereas Tcells obtained from subjects with atopic asthma show increased absolute numbers of CD4+IL-2R+ T-cells. Moreover, CD45RO+ "memory" T-cells are prominent in nonatopic subjects with asthma [5, 6]. Further analysis of both blood and bronchoalveolar lavage cells as well as bronchial biopsies from patients with allergic asthma revealed a predominant activation of T-helper (Th)2-like T-lymphocytes, producing IL-4 and IL-5 but no IL-2 or interferon (IFN)-γ [6, 7, 8]. In contrast, nonallergic asthmatics appear to have a more pronounced T-cell activation pattern, and the analysis of the cytokine profile demonstrates significantly raised levels of IL-5 and IL-2 but not IL-4, a cytokine pattern incompatible with a pure Th2-like cell response [6]. Since IL4 is required for Th2-like cell differentiation and is intimately involved in the regulation of IgE production, the low levels of this cytokine in intrinsic asthma would be a reasonable explanation for the lack of elevated IgE concentrations in this group of asthmatic patients. The hypothesis that intrinsic asthma is, in fact, a distinct immunopathological entity was, at least in part, supported by the demonstration that stimulated peripheral blood T-cells from atopic children secrete significantly more IL-4 and less IFN-γ than those obtained from nonatopic asthmatics and normal controls [9]. Moreover, the production of IL-4 closely correlated with the total serum IgE concentration, suggesting that increased synthesis of IL-4 by T-cells may be required for the development of allergic asthma but not for asthma per se. Taken together, the results provided by the above studies suggest that intrinsic asthma differs from the atopy-associated form of the disease with regard to both EDITORIAL