The natural history of exercise-induced anaphylaxis: survey results from a 10-year follow-up study.

BACKGROUND: Exercise-induced anaphylaxis (EIA) is a unique physical allergy that is triggered by exertion, the clinical spectrum and modifying factors of which have been previously studied. At the time of initial description, it was postulated that other factors contributed to this disorder. OBJECTIVE: We sought to determine the clinical course and potential modifying factors in EIA. METHODS: In 1993, we conducted a cross-sectional analysis of 671 individuals with exercise-associated symptoms for more than a decade using a validated 75-item questionnaire. Subjects met criteria for EIA if they had anaphylactic symptoms, including hypotension or upper airway obstruction, urticaria, or angioedema with physical exertion but without a passive increase in core body temperature. RESULTS: Of 365 (54%) questionnaire respondents, 279 (87%) met criteria for EIA (199 females and 80 males). At the time of study entry, subjects with EIA (mean age, 37.5 years; range, 13 to 77 years) had an average of 10.6 years of symptoms, which were most frequently triggered by aerobic activities such as jogging or brisk walking (78% and 42%, respectively). On average, subjects reported that the frequency of attacks had decreased (47% of subjects) or stabilized (46% of subjects) since onset. One hundred (41%) subjects reported being completely free of attacks in the past year. Subjects reduced their attacks by avoiding exercise during extremely hot or cold weather (44%), avoiding ingestion of certain foods before exercise (37%), and restricting exercise during their allergy season (36%) or humid weather (33%). The most common pharmacologic agents used to manage symptoms were H1 antagonists (56%) and/or epinephrine (31%). However, 28% used no treatment at all. CONCLUSION: EIA is an episodic condition in which the frequency of attacks tends to stabilize or decrease over time. Improvement appears to result from individual modification of exercise and avoidance of known environmental and ingestible precipitants.

Exercise-induced anaphylaxis (EIA).

EIA is a unique physical allergy with increasing incidence as the exercising population increases. Clinical features are indistinguishable from IgE-mediated anaphylaxis in which the offending allergens are known (food or insect stings). Recognition of the association with exercise is crucial. A wide variety of exercises can induce the symptoms, including brisk walking. Symptoms may not be always reproduced by the same amount and type of exercise in a given patient suggesting that associated factors are also needed. Food is an associated factor recognized with increasing frequency, and in the last 5 yr, wheat has been the most frequently associated. Avoidance of the known associated factors, such as food or nonsteroidals, induces a long-lasting remission of EIA. Treatment does not differ from that of anaphylaxis of any other cause. General recommendations for patients with EIA include avoidance of exercise 4-6 h after eating, avoidance of aspirin and nonsteroidals before exercise, and avoidance of all associated conditions known to trigger attacks in each particular patient. Discontinuation of exercise at the earliest warning symptom is critical.

Chlorofluorocarbon-free inhalers: are we ready for the change?

Chlorofluorocarbons (CFCs) damage stratospheric ozone permitting enhanced levels of ultraviolet B radiation to reach the Earth's surface. As a result, production of CFCs is now banned under the Montreal Protocol with the exception of their temporary continued use in pressurized metered dose inhalers used to treat those with airway disorders. Replacement propellants have now been identified and shown to be safe and a major exercise is under way to reformulate the commonly used aerosolized medicines with the new propellants. The new products are now undergoing clinical trials and the first reformulated beta-agonist and corticosteroid inhalers have reached the marketplace. The majority of the current products will have been changed over to the new types over the next 3 yrs, and each country will adapt a transition strategy to oversee this process. The politicians, the environmentalists, the pharmaceutical industry and the regulatory authorities have fulfilled their part in this changeover, and respiratory interested health professionals now need to address what this means for them and their patients so that there may be a seamless transition for the millions of people who use inhaled medicines worldwide.

Characterisation of asthma management in the Fallon Community Health Plan from 1988 to 1991.

In order to characterise asthma management in a managed care setting, we identified 10,301 patients who were diagnosed with asthma between 1 January 1988 and 31 December 1991 at a group model health maintenance organisation in central Massachusetts, US. We obtained for these patients automated utilisation files containing data on medications, hospitalisations, emergency room visits, office visits, and estimated costs of these services. The medication dispensed to the greatest proportion of patients was beta 2 agonists either by inhalation (56%) or orally (21%). Theophylline was dispensed to 23% of the patients. Maintenance therapy was inhaled anti-inflammatory medication was uncommon, as inhaled corticosteroids (17%) and sodium cromoglycate (cromolyn sodium) [8%] were dispensed to fewer patients than other asthma medications. Among patients who had been hospitalised in the previous year, 36% were presently receiving inhaled corticosteroids, and among patients who used at least one beta 2 agonist metered-dose inhaler per month, 49% were presently receiving inhaled corticosteroids. Economic analyses showed that only 8% of the patients had either a hospital admission or an emergency room visit, but hospital costs among these patients accounted for 25% of the total costs of asthma care. In addition, the top 10% most expensive patients accounted for 42% of the total cost of asthma care. We conclude that a substantial proportion of patients at increased risk of a severe attack, by virtue of having a recent hospitalisation, do not receive maintenance anti-inflammatory therapy, and that hospitalisations among a relatively small proportion of asthma patients contribute significantly to the cost of asthma care.

Fluticasone propionate aerosol: efficacy in patients with mild to moderate asthma. Fluticasone Propionate Asthma Study Group.

BACKGROUND: This double-blind, randomized, parallel-group, placebo-controlled study investigated the efficacy and tolerability of fluticasone propionate aerosol (25, 50, or 100 mg bid for 12 weeks) administered as primary maintenance therapy to patients whose mild to moderate asthma was inadequately controlled by as-needed use of an inhaled beta-agonist. RESULTS: At all clinic visits, fluticasone propionate compared with placebo was associated with significant (P<.05) improvement in pulmonary function indexed by forced expiratory volume in 1 second (FEV1) as well as fewer night awakenings and less use of rescue albuterol. Values for patient-measured morning peak expiratory flow rates (PEFR) were significantly (P<.05) higher and the use of rescue albuterol was significantly (P<.05) lower beginning 3 to 5 days after initiation of therapy in the groups treated with fluticasone propionate, compared with the placebo group. Maximal improvement in FEV1 was achieved during the second week of treatment and maintained throughout the course of therapy. Differences among the three fluticasone propionate dosing groups for these efficacy measures were not statistically significant. The incidence of adverse events was similar across groups. CONCLUSIONS: These data indicate that fluticasone propionate aerosol is an effective and well-tolerated treatment for asthma and significantly improves pulmonary function within days of initiation of treatment in patients whose asthma is inadequately controlled with as-needed beta-agonists.

[Exercise-induced urticaria and anaphylaxis]. / Anstrengungsinduzierte Urtikaria und Anaphylaxie.

AIM: The study was designed to characterise more exactly the complex syndrome of exercise-induced urticaria and anaphylaxis in order to obtain guidelines for their management. METHODS: 30 patients (18 women and 12 men with physical exercise-induced urticaria and anaphylaxis were investigated by questionnaire. The following items were of particular interest: age and sex; age at first manifestation; type, duration and intensity of the precipitating activity; type, duration and sequence of symptoms; prophylactic or therapeutic measures as cofactors. RESULTS: Initial symptoms occurred at an average age of 22 (7-50) years. Atopy was present in 70%. Jogging (60%), ball games (40%) and walking (27%) were the most frequent precipitating activities. On each occasion symptoms began a few minutes to hours after the start of the exercise. During a typical episode an average of eight symptoms were observed, most frequently affecting the skin (pruritus, angiooedema, erythema and urticaria), dyspnoea and gastrointestinal manifestations. Syncope occurred in nine patients: before they lost consciousness they noted at least two prodromal symptoms. The most common co-factors were humid-warm weather, severe sweating and eating certain foods shortly before the exercise. Prophylactic measures were quite different between individuals. CONCLUSION: Providing detailed information on how to avoid possible cofactors and manage prodromal symptoms should be at the forefront of looking after such patients, most of whom lead a rather active life.

A cluster of mutations within a short triplet repeat in the C1 inhibitor gene.

Mutations in the C1 inhibitor gene that result in low functional levels of C1 inhibitor protein cause hereditary angioneurotic edema. This disease is characterized by episodic edema leading to considerable morbidity and death. Among 60 unreported kindred with the disease, four patients were discovered to have mutations clustered within a 12-bp segment of exon 5 from nucleotide 8449 to nucleotide 8460. This short segment of DNA contains three direct repeats of the triplet CAA and is immediately preceded by a similar adenosine-rich sequence (CAAGAACAC). These triplet repeats make this region susceptible to mutation by a slipped mispairing mechanism. There are two other short triplet repeat elements in the coding region for this gene, but they have not become mutated in any kindred examined. This suggests that the apparent enhanced mutation rate in this region of exon 5 may be influenced by DNA structural characteristics.

Allergen-specific immunotherapy: a role for T-cell anergy.

T cells induce both a specific and nonspecific effect during an allergic immune response. Antigen receptors on T cells recognize peptide fragments of foreign proteins associated with products of the major histocompatibility complex expressed on the membranes of antigen-presenting cells. The recognition event triggers T-cell activation, secretion of lymphokines, and the isotypic switch from IgG to IgE synthesis, which is mediated by IL-4. This cascade results in sensitization of the mast cell, elaboration of various mediators, and local tissue inflammation. The interaction of the antigen-presenting cell and T cell holds implications for therapeutic modulation of the allergic response by the antigen. Animal studies have demonstrated that peptides containing T-cell epitopes can be used to control the immune response. Peptides delivered with adjuvants cause stimulation, whereas peptides delivered without adjuvants result in specific T-cell anergy or tolerance. Soluble peptide can be used to induce tolerance to the peptide and to protein molecules containing that peptide. The administration of peptides containing T-cell epitopes to allergic individuals may thereby represent an important component of the next generation of allergen-specific immunotherapy.

The National Asthma Education Program. Expert panel report guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute.

The significant worldwide increase in asthma-related severity and mortality has evoked increasing concern from the medical community. To enhance early recognition and appropriate therapeutic intervention of asthma, the National Heart, Lung, and Blood Institute's National Asthma Education Program convened an expert panel to develop guidelines for the diagnosis and treatment of asthma. The guidelines discussed in this article emphasize that airway inflammation is a central characteristic of asthma. Appropriate therapy must include four components: the use of objective measures of lung function to assess the severity of asthma and to monitor the course of therapy, comprehensive pharmacologic therapy that includes medications to reverse and prevent the underlying airway inflammation and to relieve the bronchoconstriction, environmental control measures to avoid or control factors that precipitate asthma exacerbations, and patient education to foster a partnership among the patient, the patient's family, and the clinician.

Physical allergies.

Allergic responses that occur as a result of exposure to physical stimuli are discussed. Most of these conditions are mediated by vasoactive substances, resulting in urticaria and/or angioedema. Susceptible individuals who engage in athletic activities may place themselves at particular risk for these problems. The physical allergies include cholinergic urticaria, exercise-induced anaphylaxis, cold urticaria, dermatographism, solar urticaria, and aquagenic urticaria. Management of these conditions includes patient education, selective avoidance, antihistamines, and, in some cases, induction of tolerance.

Exercise-induced anaphylaxis.

Exercise-induced anaphylaxis (EIA) is a unique form of physical allergy that has been recognized with increasing frequency in recent years. The hallmarks of this syndrome are generalized pruritus with a flushing sensation, a feeling of warmth, and the development of urticaria in association with vigorous physical exertion. These symptoms tend to occur variably with exercise, but not with passive warming. Most patients report typical giant urticarial eruptions. Skin mast cells degranulate, and serum histamine increases during symptomatic attacks. Treatment is often problematic, but cessation of exercise with onset of symptoms and self-administration of epinephrine are recommended.

Cetirizine: antiallergic therapy beyond traditional H1 antihistamines.

For three decades, traditional H1 antihistamines have been used in the treatment of allergic diseases. They are effective in reducing histamine-related symptoms, but the use of such agents has been limited by sedation and anticholinergic side effects. These adverse effects are fewer with the recently introduced H1 antihistamines. One of these, cetirizine, a human metabolite of hydroxyzine, is characterized by its high selectivity for the H1 receptor site and its reliable and consistent inhibition of histamine-induced allergic reactions. It also blocks eosinophil infiltration to the site of allergen-induced cutaneous reactions. Cetirizine has proved effective in the treatment of seasonal and perennial allergic rhinitis and urticaria. It is excreted primarily by renal mechanisms. It is well tolerated by elderly patients. Cetirizine has a low rate of penetration of the blood-brain barrier, and it has minimal central nervous system impairment. Furthermore, it can be given once a day. Cetirizine's low incidence of sedation and anticholinergic side effects contribute to its high profile of safety. In this article the characteristics, pharmacology, pharmacokinetics, and mode of action of cetirizine are reviewed.

Hypodense eosinophils and interleukin 5 activity in the blood of patients with the eosinophilia-myalgia syndrome.

The recent recognition of the eosinophilia-myalgia syndrome (EMS) associated with the ingestion of L-tryptophan prompted an analysis of the peripheral blood eosinophil phenotypes and of the serum eosinophil hematopoietins in this disorder. Five patients with an illness characterized by the abrupt onset of aching skeletal muscles, edema, thickening and induration of the skin, and marked blood eosinophilia associated with L-tryptophan ingestion provided eosinophils, serum, or both, for evaluation. Gradient sedimentation density analysis of the peripheral blood eosinophils from four of these patients revealed that 43 +/- 13% (mean +/- SEM) of the cells had converted to the abnormal (hypodense) sedimenting phenotype. When normodense eosinophils from the reference donors were cultured for 3 days in medium supplemented with increasing concentrations of serum from the patients with EMS, their viability increased in a dose-dependent manner to 45%, which was significantly augmented over the effect of normal serum. This eosinophil viability-sustaining activity was inhibited by 76 +/- 7% (mean +/- SEM; n = 3) by the addition of anti-interleukin 5 (IL-5) but not by neutralizing antibodies monospecific for either granulocyte/macrophage colony-stimulating factor (GM-CSF) or IL-3. IL-5, an eosinophilopoietic factor, converts normodense peripheral blood eosinophils in vitro to a hypodense sedimenting form with extended viability and augmented biologic responses to activating stimuli. Thus, the presence of IL-5 in the sera of patients with EMS may contribute to the development and maintenance of the eosinophilia and may regulate the conversion of the peripheral blood eosinophils to the hypodense phenotype with augmented pathobiologic potential.

Characterization of cellular dermal infiltrates in human cutaneous mastocytosis.

Biopsies of lesional and nonlesional skin from 14 patients with localized cutaneous or associated systemic mastocytosis were examined by ultrastructural and immunohistochemical techniques. Mast cells within lesions of the dermis were highly variable between patients with regard to cell number and extent of degranulation, although lesional sites consistently contained more mast cells than did nonlesional sites. Two mast cell patterns were identified based upon granule morphology. In biopsies from 8 patients, the majority of granules contained electron-dense amorphous zones; crystalline lattices; and indistinct, incomplete solid scrolls forming parallel lamellae. In biopsies from 6 patients, in addition to these granules, there were also granules composed of electron-dense amorphous zones, reticulated matrices, and/or distinct scrolls with lucent cores interrupted by dense spheres. The granule morphology for the first group (N = 8) was identical with that seen in the preponderant type of skin mast cell of 6 normal control subjects, whereas the granule morphology of the second group (N = 6) displayed an abnormal ultrastructural phenotype for skin that included granule types normally found not only in skin but also in intestinal lamina propria and lung. For individual patients, the patterns of granule ultrastructure were consistent between clinically nonlesional and lesional skin. A minority of cells in both patient groups appeared primitive ultrastructurally, exhibiting rudimentary, Golgi-associated progranules; monocyte-like morphologic characteristics; and mitotic activity. Moreover, when mast cells in lesional skin were screened for a limited panel of surface antigens, they displayed common patterns of reactivity (M718+, HLA-DR/DQ+, CD4+), and in a selected case, immunoelectron microscopy confirmed the presence of these antigens on mast cell plasma membranes. Dermal mast cells from normal donors (N = 6) lack these epitopes. These observations suggest that infiltrates in cutaneous mastocytosis may exhibit phenotypic characteristics not only of cutaneous mast cells, but in some patients also of mucosal mast cells. In either circumstance, the mast cells may display antigenic determinants common to monocyte/macrophages. Concordance of granule phenotype between lesional and clinically uninvolved skin of individual patients furthers the notion that even localized mastocytosis reflects covertly defective systemic mast cell homeostasis.