International consensus on (ICON) pediatric asthma.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.

A new symptom-based questionnaire for predicting the presence of asthma.

BACKGROUND: Early diagnosis and treatment of asthma is important for improving health and minimizing the social and economic burden of the disease. A simple questionnaire would provide a convenient and timesaving tool to help physicians diagnose asthma. OBJECTIVE: The senior author developed a simple, pre-interview screening questionnaire--the Asthma Screening Questionnaire (ASQ)--consisting of 6 questions. The present report provides performance evidence that the ASQ is a reliable instrument for diagnosing asthma in adults. METHODS: Participants were asthmatics or controls, aged 18 to 65 years. All participants completed the questionnaire (self-administered and physician-administered), and underwent spirometry and a methacholine challenge test (if there was no reversibility during initial spirometry). Sensitivity, specificity, and positive and negative predictive values were calculated for each question, and the total scores of asthmatics were compared with those of controls. The degree of agreement between the self-administered and the physician-administered questionnaire was calculated. RESULTS: The main symptoms discriminating asthmatics from controls were cough more than average (88% vs 0%), cough from chest (72% vs 0%), shortness of breath with exercise (84% vs 16%), and chest tightness when lying down (72% vs 4%). A cutoff point of total score > or = 4 was associated with the highest combination of sensitivity (96%) and specificity (100%). Substantial agreement was observed between the self-administered and the physician-administered questionnaire (kappa statistic, 0.56-1.00; P<.0001). CONCLUSIONS: The ASQ is a simple, inexpensive, and efficient pre-interview screening tool to diagnose asthma.

Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription.

Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.

Recent findings in asthma likely to impact patient care.

The management of asthma is becoming increasingly complex as more pharmacologic agents become available and we gain increased understanding of the pathogenetic processes of asthma and the risks for potentially irreversible airway remodeling that might be increased by suboptimal management and interactions with concomitant disease states such as gastroesophageal reflux. Although physicians now have greater responsibility to make use of this increasing knowledge to provide more effective management for their asthma patients, they also have a greater opportunity to increase the overall quality of life of patients under their care.

Alternative treatments for severe, chronic asthma.

The current focus of treatment for chronic asthma is anti-inflammatory pharmaceuticals and minimizing of environmental factors that contribute to airway inflammation. Despite the development of increasingly potent inhaled glucocorticoids, certain select asthmatic patients require chronic systemic glucocorticoids for management. Several nonglucocorticoid, anti-inflammatory agents have been shown or suggested to be beneficial in the treatment of chronic asthma. The major purpose of using these agents has been to maximize airway function and to minimize the use of systemic glucocorticoids, with their attendant side effects. Some of these alternative anti-inflammatory agents are reviewed in this paper, with emphasis on clinical experience in the treatment of asthma. Additional double-blind, placebo-controlled studies are necessary to define the role of these agents in the management of chronic asthma.

Immunologic aspects of cardiovascular disease.

The spectrum of vasculitis is diverse, and numerous entities do not fit the aforementioned broad categories. Examples of these include Buerger's disease; vaso-occlusive vasculitis of the lower extremities associated with cigarette smoking; Behçet's disease, which is prevalent in the Orient and Middle East and is characterized by recurrent aphthous stomatitis, genital ulcerations, uveitis, meningoencephalitis, and phlebitis; and isolated central nervous system vasculitis, a rare disease with a poor prognosis that primarily affects intracranial arteries without a systemic acute-phase response. Improvement in the classification and definitive therapy of vasculitis awaits identification of etiologic agents and definition of host factors and the immune response responsible for the pathology.

Immunologic aspects of vasculitis and cardiovascular disease.

The immunologic cardiovascular diseases are a heterogeneous group of conditions. Many of these entities are associated with serious morbidity and mortality resulting from cardiac impairment, ischemic complications, or organ dysfunction, particularly of the kidneys, lung, and nervous system. The systemic nature of these conditions, coupled with vague symptoms and nonspecific initial physical findings, makes the differential diagnosis complicated. Research has identified specific mediators and primary origins in some conditions, with infections often being responsible. Immunosuppressive therapy, despite the potential complications, has improved the prognosis of some of the more serious immunologic cardiovascular diseases. Improvement in the treatment of immunologic cardiovascular diseases awaits identification of additional causes, improved definition of host factors that predispose an individual to develop these conditions, and better understanding of the immune dysregulation responsible for the progression of disease. The potential pathophysiologic role of immunologic mechanisms in common disorders such as congestive heart failure and atherosclerosis is intriguing and offers the possibility of novel therapies in these prevalent conditions.

Immunologic aspects of cardiovascular disease.

The current classification scheme of the diverse inflammatory cardiovascular diseases permits a clinical staging and facilitates prognostic assessment and therapeutic decision making. Ultimately, improvement in the classification of and definitive therapy for these conditions awaits better definition of the interaction among specific etiologic agents, host factors, and the immune system responsible for these diseases.

Preferential association of kappa IIIb light chains with monoclonal human IgM kappa autoantibodies.

The predominance of the relatively uncommon V region subgroup isotype kappa III among the light chains of human monoclonal (IgM kappa) anti-IgG antibodies, (i.e., rheumatoid factors), was further documented through sequence analyses of ten such autoantibodies isolated from IgM-anti-IgG cold-insoluble immune complexes (mixed cryoglobulins). The amino-terminal sequence of all ten kappa-chains was characteristic for kappa III proteins and virtually identical to that of a prototype kappa III light chain. Similar sequence identity was found for kappa-chains isolated from three IgM kappa autoantibodies that formed cold-insoluble immune complexes with low-density lipoprotein (LDL). The thirteen light chains were found to be virtually identical in sequence for the first framework region (FR); ten of these proteins sequenced through the first complementarity-determining region (CDR) and into the second FR were markedly similar. The second CDR of five proteins was almost identical in sequence to that of the prototype kappa III-chain. Concordance was also demonstrated between the structural classification of the light chains as kappa III and their immunochemical classification as members of this V region subgroup. Serologic analyses of light chains isolated from seven IgM kappa autoantibodies (six anti-IgG, one anti-LDL) and of one intact IgM kappa anti-LDL antibody showed that each had antigenic determinants common to kappa II proteins. These light chains also expressed the antigenic determinant(s) of a V-region sub-subgroup of kappa III proteins designated kappa IIIb. Our studies confirm the preferential association of kappa III (and kappa IIIb) light chains with IgM kappa anti-IgG antibodies and demonstrate a similar association for IgM kappa anti-LDL antibodies. The finding that these and other types of IgM kappa autoantibodies, e.g., cold agglutinins, have remarkably similar light chains suggests an inherent restriction in the immune response to self-antigens.

House dust mite, cat, and cockroach allergen concentrations in daycare centers in Tampa, Florida.

BACKGROUND: Allergen exposure in early childhood is a risk factor for sensitization and the development of asthma. Studies performed in Europe, New Zealand, and Singapore indicated the presence of indoor allergens in childcare centers and schools. However, the importance of indoor allergens in daycare centers in humid and warm regions of the world is not known. OBJECTIVE: To measure total mite counts, Der p 1, Der f 1, Fel d 1, and Per a 1 allergens in dust samples and mite allergen airborne concentrations in daycare centers in Tampa, Florida, United States. METHODS: Twenty daycare centers were surveyed for mite, cat, and cockroach allergens in Tampa, FL. One dust and two air samples (one during the day and one during the night) were collected in each center. Dust samples were extracted and analyzed for mite (Der p 1 and Der f 1), cat (Fel d 1), and cockroach (Per a 1) allergens. Mite airborne allergen concentrations were analyzed by RAST inhibition and expressed in standardized mite allergen units per m3 of air (AU/m3). RESULTS: Mites were identified in 15 samples, and concentrations ranged from 10 to 1,200 mites/g (298 +/- 355.2). The most prevalent mite species was Dermatophagoides pteronyssinus ( Der p 1). Der p 1 and/or Der f 1 were detected in 10 daycare centers. Der p 1 was detected in eight centers and ranged from I to 21.8 microg/g of dust (5.4 +/- 6.9); Der f 1 was detected in 3 centers and ranged from 0.2 to 2.1 microg/g of dust (1.3 +/- 0.9). Per a 1 and Fel d 1 were detected in all centers in small quantities; Per a 1 ranged from 8 to 1,806 ng/g (263.1 +/- 449.7) and Fel d 1 from 0.2 to 120 U/g of dust (16.6 +/- 31.7), respectively. Airborne mite allergen was detected in 18 centers and ranged from 0.01 to 2.7 AU/m3 during the day (0.2 +/- 0.6) and from 0.01 to 0.12 AU/m3 during the night (0.06 +/- 0.03), P = 0.001. CONCLUSIONS: Mite, cat, and cockroach allergens are present in daycare centers in Tampa, FL. Mite allergen concentrations exceeded levels that have been associated with sensitization and symptoms in allergic subjects in 40% of these centers.

Allergens of the imported fire ant.

A whole body extact (WBE) was prepared by saline extraction of ground imported fire ants (IFA). A serum pool from rabbits immunized with the WBE elicited 31 precipitates on crossed immunoelectrophoresis. Crossed radioimmunoelectrophoresis was performed with sera from 26 RAST IFA-positive subjects, 24 of whom were known for clinical hypersensitivity to IFA and two subjects, known to be hypersensitive to yellow jacket. Radiostaining was obtained to 14 precipitates, some of which were judged to be partially identical. Thus, six apparently different allergen groups could be identified. Two of these fulfilled arbitrary criteria of major allergens. Three of the IFA WBE allergens were easily identified in crossed immunoelectrophoresis of a commercially obtained IFA-venom preparation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the IFA WBE demonstrated protein bands with molecular weight ranging from 10,000 to 200,000 daltons. An immunoblotting technique with nitrocellulose paper strips revealed binding of human IgE from hypersensitive subjects to four different bands (either single bands or clusters of proteins of similar molecular weight) with molecular weights ranging from 13,000 to 42,000 daltons. It is a notable finding that these insect allergens thus were of a similar size as important aeroallergens.

Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticosteroid-dependent asthma.

BACKGROUND: This study compared the efficacy of weekly oral administration of methotrexate and placebo in treatment of 24 subjects with chronic glucocorticosteroid-dependent asthma. METHODS: The 33-week randomized, double-blind, placebo-controlled crossover trial compared once weekly 15 mg doses of methotrexate with placebo. At the time of entry, the subjects' mean dosage of prednisone was 23.8 mg/day (range, 12.5 to 85 mg) and glucocorticosteroid therapy had been used continuously for a mean duration of 78 months (range, 5 to 360 months). RESULTS: Of the 21 subjects who completed the study, 13 tolerated lower daily prednisone doses during methotrexate treatment compared with placebo. When treated with methotrexate, subjects required 14.2% less prednisone than when treated with placebo (p = 0.0447), their subjective symptom scores improved 21.4% (p < 0.05), and mean forced expiratory volume in 1 second values tended to improve. Mean serum theophylline levels did not change significantly between the methotrexate and placebo arms of the study. Adverse effects were minimal, with nausea and headache occurring twice as often during methotrexate therapy compared with placebo. CONCLUSION: Short-term, low-dose, pulse therapy with orally administered methotrexate results in a decrease in the daily glucocorticosteroid requirement in a majority of subjects with severe asthma and is accompanied by improvement in subjective symptom scores without unacceptable side effects or deterioration of pulmonary function.

Osteoporosis in the corticosteroid-treated patient with asthma.

Osteoporosis affects 40% of white women older than 45 years of age and 15% of white men older than 50 years of age, resulting in approximately 1.5 million annual fractures in the United States. Systemic corticosteroid therapy increases the probability of osteoporosis, even with alternate-day dosing and with dosages sufficiently low so as not to affect the hypothalamic-pituitary-adrenal axis. Inhaled corticosteroid therapy may affect bone density if high-dose therapy is given to select individuals. The potential of increasing osteoporosis with inhaled corticosteroid asthma therapy is a concern because of the availability of more potent inhaled corticosteroid agents and recommendations that inhaled corticosteroid therapy be initiated earlier in the course of asthma. This article provides suggestions, on the basis of the medical literature and consensus of the authors when specific information was not available, for assessing and treating osteoporosis in subjects with asthma. Suggested risk categories are "low risk" (inhaled corticosteroid dosage of < or =800 microg of heclomethasone dipropionate [BDP]/day in adults or < or =400 microg BDP or equivalent in children), "moderate risk" (inhaled BDP >800 microg/day in adults or >400 microg/day in children), and "high risk" (systemic corticosteroid therapy 4 times a year or daily or alternate-day systemic corticosteroid therapy). Dosage of nasal corticosteroid probably should be added to the orally inhaled corticosteroid for total burden of inhaled corticosteroid. Potential treatment strategies based on risk factors and bone density if indicated are offered to assist physicians treating patients with asthma.

Serum IgE and human immunodeficiency virus (HIV) infection.

Human immunodeficiency virus infection is characterized by a progressive depletion of helper T-lymphocytes and, like allergic diseases, is associated with altered T cell regulation. Total serum IgE was measured in 67 infected male subjects, 27 uninfected heterosexual male subjects, and 18 uninfected homosexual male subjects. The mean IgE level (132 IU/ml) of infected subjects with a helper T-lymphocyte number less than or equal to 200/mm3 was significantly greater than mean IgE levels of the uninfected heterosexual (38 IU/ml) and homosexual (35 IU/ml) groups. IgE levels were inversely related to both helper T cell and suppressor/cytotoxic T cell numbers but not to IgG or IgA levels. The increase in IgE was not a reflection of an increased prevalence of atopic disease (allergic asthma, allergic rhinitis, or atopic dermatitis) in the infected subjects. The elevation of IgE may be related to a difference among the groups in T cell production of IgE regulatory lymphokines.

House dust mite allergy in Florida. Mite survey in households of mite-sensitive individuals in Tampa, Florida.

This study evaluated the prevalence of positive house dust mite skin tests in a population of atopic individuals and identified the mite species present in mattress and house dust samples in homes of the Tampa Bay area. Four hundred consecutive individuals were evaluated for respiratory complaints and skin tested with standardized extracts of Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df). Two hundred forty individuals (60%) had a positive skin test to the mite extracts. Dust samples were collected in 40 homes of mite-allergic individuals and analyzed by light microscopy. Mite species were found in 53 of the 60 dust samples (20 mattresses and 40 carpets). Mite numbers ranged from 110-6200 mites/g of mattress dust and from 120-5500 mites/g of carpet dust. Eleven different mite species were identified and Blomia tropicalis (Bt), not previously identified in the United States, was found in 30% of the samples. Dp and Df wee the predominant species. These observations suggest that house dust mite allergy is common in the Tampa Bay area and that the house dust mite fauna comprises several mite species besides Dp and Df. Prospective studies in progress are designed to confirm the role of different mite species in house dust mite allergy.

Lack of effect of gold salts on acetylcholine or histamine contraction of canine tracheal and bronchial smooth muscle.

In vitro gold salt incubation with proximal and distal canine airway smooth muscle was compared to untreated canine airway muscle with respect to histamine and acetylcholine-induced contraction. Gold chloride and gold sodium thiomalate had no effect on either proximal or distal canine airway smooth muscle agonist-induced contraction. Gold chloride in concentrations greater than 10(-5) M had a direct contractile effect. These results differ from previous studies which showed an inhibition of the histamine response of guinea-pig tracheal smooth muscle following in vitro preincubation with gold salts. This difference suggests that the mechanism(s) of the beneficial effects of long-term gold salt therapy on human asthma cannot be reliably studied with short-term in vitro animal preparations without first assessing species differences with respect to the effects of therapeutic agents. Human airway smooth muscle preparations would be the best means of addressing this question.