GINA guidelines on asthma and beyond.

Clinical guidelines are systematically developed statements designed to help practitioners and patients make decisions regarding the appropriate health care for specific circumstances. Guidelines are based on the scientific evidence on therapeutic interventions. The first asthma guidelines were published in the mid 1980s when asthma became a recognized public health problem in many countries. The Global Initiative on Asthma (GINA) was launched in 1995 as a collaborative effort between the NHLBI and the World Health Organization (WHO). The first edition was opinion-based but updates were evidence-based. A new update of the GINA guidelines was recently available and it is based on the control of the disease. Asthma guidelines are prepared to stimulate the implementation of practical guidelines in order to reduce the global burden of asthma. Although asthma guidelines may not be perfect, they appear to be the best vehicle available to assist primary care physicians and patients to receive the best possible care of asthma.

Oral allergy syndrome.

The oral allergy syndrome (OAS) is a common adverse reaction to the ingestion of certain "trigger" foods and is especially prevalent in atopic individuals. Although rarely dangerous, the symptoms may concern patients. Severe forms of OAS may resemble or precede food-induced anaphylaxis. Thus, detection and recognition of OAS are important. New insights into the molecular mechanisms underlying OAS have elucidated earlier epidemiological observations that sensitivity to certain foods is related to reactivity to certain aeroallergens. This article reviews the clinical presentation, pathogenesis, and treatment of OAS.

Assessment of IgE allergen specificity among latex-allergic health care workers: review of IgE-binding components of various latex extracts.

BACKGROUND: Allergic reactions to natural rubber latex have increased during the past 10 years, especially in many health care workers who have high exposure to latex allergens both by direct skin contact and by inhalation of latex particles from powdered gloves. Development of satisfactory diagnostic methods to verify the presence of latex allergy in health care workers requires characterization of the immunoreactive proteins in latex products and identification of specific IgE antibodies in sensitized patients. A number of different latex preparations are now available for in vitro evaluations. OBJECTIVES: Utilizing different in vitro methods, this study examines IgE sensitization to components of latex in a selected population of hospital employees, employing a raw natural latex glove extract and various commercial latex extracts. METHODS: Two hundred hospital employees exposed to latex were evaluated using an allergy history questionnaire. To further identify sensitized patients, two different specific IgE tests and leukocyte histamine release tests were performed using a panel of latex extracts obtained from different manufacturers. Sodium dodecylsulfate polyacrylamide electrophoresis (SDS-PAGE) profiles were obtained. Sera from 34 subjects suspected to be latex-sensitized were IgE immunoblotted to assess the presence of IgE antibodies directed toward specific latex proteins. RESULTS: Thirty-four participants (17%) were considered sensitized to latex by a positive clinical history in conjunction with positive specific IgE tests (18 individuals) and/or positive histamine release tests (26 individuals). Significant extract differences in both the histamine release response profile and the frequency of positive test results were noted in the histamine release test. Significant individual differences in patients' latex epitope-specificity were found by IgE immunoblotting, substantiated by sodium dodecylsulfate polyacrylamide profiles revealing differences in protein band patterns among the various extracts. The IgE immunoblots indicated that the majority of patients reacted to proteins with molecular weights of 14, 21, 30 to 35, and 42 kD; the 30 to 35 kD protein being predominant. Seven subjects (22%) of the 34 considered to be latex-sensitized did not reveal binding of specific IgE in immunoblots. One latex extract (Stallergene) with the widest IgE-reacting protein repertoire identified the majority of subjects (63%) as latex sensitive by leukocyte histamine release and also provided the best quantitative histamine release test results. CONCLUSION: Only by testing with a combination of latex extracts were all sensitized individuals identified. This study demonstrates that currently several in vitro methods may be necessary to detect IgE sensitization to latex. Latex extracts to be employed in future skin tests must contain a wide epitope repertoire of IgE-binding proteins to identify all latex-sensitized individuals.

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.

Rpb7 can interact with RNA polymerase II and support transcription during some stresses independently of Rpb4.

Rpb4 and Rpb7 are two yeast RNA polymerase II (Pol II) subunits whose mechanistic roles have recently started to be deciphered. Although previous data suggest that Rpb7 can stably interact with Pol II only as a heterodimer with Rpb4, RPB7 is essential for viability, whereas RPB4 is essential only during some stress conditions. To resolve this discrepancy and to gain a better understanding of the mode of action of Rpb4, we took advantage of the inability of cells lacking RPB4 (rpb4Delta, containing Pol IIDelta4) to grow above 30 degrees C and screened for genes whose overexpression could suppress this defect. We thus discovered that overexpression of RPB7 could suppress the inability of rpb4Delta cells to grow at 34 degrees C (a relatively mild temperature stress) but not at higher temperatures. Overexpression of RPB7 could also partially suppress the cold sensitivity of rpb4Delta strains and fully suppress their inability to survive a long starvation period (stationary phase). Notably, however, overexpression of RPB4 could not override the requirement for RPB7. Consistent with the growth phenotype, overexpression of RPB7 could suppress the transcriptional defect characteristic of rpb4Delta cells during the mild, but not during a more severe, heat shock. We also demonstrated, through two reciprocal coimmunoprecipitation experiments, a stable interaction of the overproduced Rpb7 with Pol IIDelta4. Nevertheless, fewer Rpb7 molecules interacted with Pol IIDelta4 than with wild-type Pol II. Thus, a major role of Rpb4 is to augment the interaction of Rpb7 with Pol II. We suggest that Pol IIDelta4 contains a small amount of Rpb7 that is sufficient to support transcription only under nonstress conditions. When RPB7 is overexpressed, more Rpb7 assembles with Pol IIDelta4, enough to permit appropriate transcription also under some stress conditions.

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.

Wall hangings, hairs and the Holocaust.

Two wall hangings, from the time of the Second World War, were reportedly made from human hair. Laboratory examination of the hangings confirmed this fact. Fibers, holding the wall hangings together, and the weave of the hangings were also examined. Results and implications of the findings are discussed.

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.