Predicting worsening asthma control following the common cold.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

Recertification in internal medicine: a program of continuous professional development. Task Force on Recertification.

In 2000, the American Board of Internal Medicine (ABIM) introduced a second-generation recertification process that builds on the current knowledge-centered program by adding assessments of clinical and communication skills, clinical performance, and medical outcomes. The three-part process, called a program of continuous professional development, includes innovative self-evaluation exercises, documentation of essential knowledge, and confirmation of satisfactory qualifications and professional and community good standing. The program introduces the principles of continuous quality improvement; deemphasizes the summary nature of the traditional secure examination; and is designed to be a more continuous, less saltatory process for maintaining clinical competence. With the continuous professional development program, ABIM believes that it has taken a substantial step toward creating a recertification process that meets its goal of being valuable, doable, tolerable, and affordable" while maintaining the high standards expected of an accountable profession.

The allergist in the new millennium.

Allergy and immunology emerged as a distinct research area and clinical specialty in the early 20th century. As the 21st century approaches, the evolution of clinical and academic life in American medicine produces unique challenges for this field and its practitioners, educators, and investigators. How we reached our current state and a personal view of the future for the clinician and the academician in this field are discussed.

Asthma in a Vietnamese refugee population.

Asians and Pacific Islanders comprise a large and growing minority group in the United States, yet data on health status specific to these populations are scant. We conducted an epidemiologic study of asthma in a Vietnamese refugee population to estimate prevalence, evaluate risk factors, and better understand treatments of asthma among Vietnamese individuals. One hundred twenty-four asthma cases were identified from a population of 2,536 new Vietnamese refugees in San Diego (prevalence = 49 per 1,000; 4.9%). Two nonasthmatic control groups of Vietnamese refugees, matched for age and gender with the asthma cases, were recruited for a case-control study, using a questionnaire administered in Vietnamese. Vietnamese asthmatic individuals used both Western and non-Western therapies. Most subjects used traditional health practices, such as coining, cupping, and oil inhalation. As compared with current-refugee controls, the asthmatic subjects used significantly more bleeding (OR: 3.40; 95% CI: 1.06 to 10.80) and herbal ingestion (OR: 1.87; 95% CI: 1.08 to 3.19). As compared with former-refugee controls, the asthmatic subjects used significantly more oil inhalation (OR: 2.58; 95% CI: 1.45 to 4.85), bleeding (OR: 8.64, 95% CI: 1.02 to 73.70), and herbal ingestion (OR: 1.93; 95% CI: 1.02 to 3.67). The presentation and recognition of asthma among the Vietnamese subjects were similar to those in other populations. This information may be helpful in designing culture-specific health-education programs.

A 12-week dose-ranging study of fluticasone propionate powder in the treatment of asthma.

Fluticasone propionate (FP) administered via metered-dose inhaler is a potent corticosteroid effective in the treatment of asthma. To evaluate the efficacy and safety of FP powder administered via a breath-activated inhaler (Diskhaler), a multicenter, double-blind, randomized, placebo-controlled, parallel-group study was conducted in adolescent and adult patients (n = 331) with mild-to-moderate asthma previously treated with beta 2-agonist therapy alone. Patients received FP powder 50, 100, or 250 micrograms or placebo twice daily for 12 weeks. FP-treated patients compared with placebo-treated patients had significantly (p < 0.001) greater improvements in morning predose forced expiratory volume in 1 sec (21-22% increase vs. 9%). Improvement in morning peak flow rate were also significantly (p < 0.001) greater with FP than with placebo (8-10% increase vs. 2% increase). There was also a significant overall treatment difference in the frequency of inhaled albuterol use (p < 0.001) and number of nighttime awakenings due to asthma (p = 0.005). There were no statistically significant difference among the FP treatment groups in any outcome measure. Physicians' global assessments also indicated significant (p < 0.001) differences in efficacy, with 67-74% of FP-treated patients rated as having "effective" or "very effective" treatment compared with 41% of placebo-treated patients. Significant beneficial effects of FP were observed in lung function and diary card parameters after just 1 week of treatment. Adverse events were similar across treatment groups and primarily related to local irritation. Effect on hypothalamic-pituitary-adrenal axis function was minimal. In summary, all three dosages of inhaled FP powder were well tolerated and improved various asthma-related variables. Improvements in pulmonary function, beyond those achieved with beta 2-agonist therapy alone, were maintained for the duration of the 12-week study.

Immunopharmacologic profile of nedocromil sodium.

Nedocromil sodium, a pyranoquinolone, was specifically designed as an agent to suppress allergic inflammation. Nedocromil sodium significantly affects not only the early-phase of allergen-induced responses, but also expression of late-phase inflammation, even when administered after the onset of early-phase responses. Nedocromil sodium also limits bronchoconstriction induced by nonallergic factors, including cold air and sulfur dioxide at dosages lower than required with cromolyn sodium. Nedocromil sodium is more potent than cromolyn sodium in preventing mast cell degranulation in selective animal models. In addition, nedocromil sodium limits leukotriene C4 production by calcium ionophore-stimulated eosinophils and also limits the activity of platelet activating factor to induce neutrophil generation of superoxides. Diurnal variation of peak flow rates in asthmatics and requirement for both beta 2-agonists and inhaled beclomethasone have been noted to be reduced in several trials employing nedocromil sodium, suggesting that its in vivo activity parallels its in vitro activity as an anti-inflammatory agent.

Asthma symptoms and airway hyperresponsiveness are lower during treatment with nedocromil sodium than during treatment with regular inhaled albuterol.

In a double-blind, double-dummy, multicenter study, 212 patients with asthma whose symptoms were not controlled by as-needed use of inhaled bronchodilators were randomized to receive either 4 mg of nedocromil sodium or 180 micrograms of albuterol four times daily for 12 weeks. Asthma symptom scores (daytime asthma, nighttime asthma, morning chest tightness, and cough) and peak expiratory flow rate were recorded daily on diary cards. Bronchial hyperresponsiveness was assessed by changes in diurnal variation in peak expiratory flow rate and by methacholine inhalation challenge. Statistically significant differences were found between groups favoring nedocromil sodium for relief of day and nighttime asthma and morning chest tightness. Patients treated with nedocromil sodium also had significantly lower diurnal variation in peak expiratory flow rate compared with patients treated with albuterol. Compared with patients treated with albuterol, patients treated with nedocromil sodium showed a greater improvement in cough and a decreased sensitivity to methacholine challenge. Patients in both groups reduced their as-needed albuterol use. Regular treatment with nedocromil sodium therefore led to greater asthma symptom control and reduced bronchial responsiveness compared with regular treatment with albuterol. The study also showed that more frequent use of a beta 2-agonist (for symptom relief or not) did not improve asthma control. Both drugs were well tolerated.

Mast cells and airway inflammation in asthma.

A number of new observations have added to our understanding of mast cell biology and the relevance of this cell to the genesis of asthma. The purpose of this review has been to highlight this new information and to refer the reader to extensive reviews where previously documented and well-known data are available. Of particular current interest is the knowledge that mast cell growth and differentiation is regulated by a specific molecule, stem cell factor, which interacts with a receptor on the surface of the mast cell (a tyrosine kinase) and that mast cell phenotype may be modulated by exposure to stem cell factor as well as to a host of inflammatory cytokines. In addition to the ability to release vasoactive/spasmogenic mediators characterized by histamine, the slow-reacting substance of anaphylaxis (sulfidopeptide leukotrienes), platelet-activating factor, and adenosine, the mast cell can release a unique family of enzymes and generate a cassette of cytokines with critically important pro-inflammatory potential. The enzymes that are unique to the mast cell can potentiate a number of inflammatory events central to asthma, including fibroblast activation, mucus secretion, smooth muscle contraction, and neuropeptide degradation, while the cytokines may directly influence the influx, persistence, and activity of inflammatory cells, particularly eosinophilis and basophils, through the ability of the cytokines to modulate endothelial expression of leukocyte adhesion receptors and to prevent target cell apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)

A review of some recent clinical studies with nedocromil sodium.

Clinical trials reported in these proceedings have shown that nedocromil sodium is an effective antiasthmatic agent. Preclinical studies and the results of the worldwide clinical study program have also shown that nedocromil sodium is a very safe drug. Although it is anticipated that a new drug will perform better than placebo, perhaps a more critical assessment of efficacy is how the drug compares with other currently used agents. Nedocromil sodium has been directly compared with all of the antiasthmatic medications currently used in the United States including theophylline, beta-adrenergic agents, inhaled corticosteroids, and cromolyn sodium. The results of these studies indicate that for the treatment of mild-to-moderate asthma, nedocromil sodium provides a safe and clinically effective antiinflammatory addition to the physician's armamentarium of antiasthma drugs.

Cytokines in symptomatic asthma airways.

To determine whether cytokines are generated in vivo in subjects with asthma, we have measured cytokine levels (tumor necrosis factor [TNF], granulocyte-macrophage-colony-stimulating factor [GM-CSF], interleukin [IL]-1 alpha, IL-1 beta, IL-2, IL-4, and IL-6) in the airways of subjects with symptomatic (N = 24) and asymptomatic (N = 9) asthma with immunoassays (GM-CSF, IL-1 alpha, IL-1 beta, IL-2, and IL-4) or bioassays (TNF and IL-6) and the polymerase chain reaction (IL-1 beta and TNF). Significant levels of TNF (578 +/- 917 pg/ml versus 24 +/- 29 pg/ml) (p = 0.01), GM-CSF (24 +/- 41 pg/ml versus less than 8 pg/ml) (p = 0.02), and IL-6 (225 +/- 327 pg/ml versus 7 +/- 12 pg/ml) (p = 0.01), but not IL-1 alpha or IL-4, were detected in the bronchoalveolar lavage fluid (BALF) of patients with symptomatic compared with BALF of patients with asymptomatic asthma. Levels of IL-1 beta (266 +/- 270 pg/ml versus less than 20 pg/ml) (p = 0.001) and IL-2 (1.4 +/- 2.8 ng/ml versus less than 0.3 ng/ml) (p = 0.05) in BALF in patients with symptomatic compared with that in BALF levels in patients with asymptomatic asthma suggested activation of alveolar macrophages and T cells. Thus, in episodes of asthma, several cytokines, including TNF, GM-CSF, IL-1 beta, IL-2, and IL-6 are detectable in BALF.

Cetirizine therapy for seasonal allergic rhinitis: alternative dosage schedules.

A double-blind, placebo-controlled clinical trial was undertaken for two weeks to evaluate three dosing schedules for administration of cetirizine in patients with seasonal allergic rhinitis. Average severity scores from the patients' ratings for sneezing and nasal itching were significantly reduced in all three cetirizine groups (10 mg QAM or QHS and 5 mg BID), compared with placebo. The effectiveness of cetirizine in once-daily dosing schedules indicates that significant antihistaminic activity is delivered over a full 24 hours. The possibility for flexibility in dosing combined with its relatively short half-life and low incidence of adverse effects make cetirizine an important second-generation H1-antihistamine for the management of seasonal allergic rhinitis.

Evidence of ongoing mast cell and eosinophil degranulation in symptomatic asthma airway.

To assess whether mast cell and eosinophil (EOS) degranulation occurs in the airway of subjects with moderately symptomatic asthma, we have measured levels of preformed mast cell-derived mediators (histamine and tryptase) and EOS-derived mediators (major basic protein and EOS-derived neurotoxin) in bronchoalveolar lavage fluid (BALF) obtained from patients with symptomatic (N = 14) and asymptomatic asthma (N = 9) and patients without asthma (N = 6). Both the FEV1 (1.52 +/- 0.33 L:55% +/- 15% of predicted FEV1) and the forced expiratory flow at 50% (FEF50) (1.11 +/- 0.62 L/sec:26% +/- 14% of predicted FEF50) in the patients with symptomatic asthma were significantly lower than the corresponding values for FEV1 (3.16 +/- 0.45 L:86% +/- 10% of predicted FEV1) and the FEF50 (4.04 +/- 1.54 L/sec:71% +/- 25% of predicted FEF50) in the patients with asymptomatic asthma. Levels of histamine (4.8 +/- 5.0 ng/ml versus 0.2 +/- 0.2 ng/ml) (p = 0.05), EOS-derived neurotoxin (420.6 +/- 959.4 ng/ml versus 12.6 +/- 7.7 ng/ml) (p = 0.05), major basic protein (31.4 +/- 46.6 ng/ml versus less than 9 ng/ml) (p = 0.05), and percent EOSs (10.6% +/- 7.0% versus 1.1% +/- 0.9% of BAL cells) (p = 0.0006) were all significantly elevated in BALF from symptomatic compared to asymptomatic patients with asthma. The elevated levels of tryptase (13.2 +/- 14.8 ng/ml versus 3.9 +/- 3.9 ng/ml) in BALF from symptomatic compared to asymptomatic patients with asthma approximated, but did not reach, statistical significance. Spontaneous histamine release from BAL mast cells of symptomatic patients with asthma was 46% +/- 5% compared to 5% +/- 2% in asymptomatic patients with asthma. In response to antihuman IgE, histamine release from BAL mast cells recovered from asymptomatic patients with asthma increased to 25% +/- 10%, whereas in BAL mast cells of symptomatic patients with asthma, no anti-IgE potentiation of histamine release occurred. This study suggests that mast cell and EOS degranulation is ongoing in the airway of patients with moderately symptomatic asthma.

The response to human rIL-1, rIL-2, and rTNF in the middle ear of guinea pigs.

Human recombinant interleukin 1 (rIL-1), interleukin 2 (rIL-2), or tumor necrosis factor (rTNF) were injected transtympanically into the middle ear of normal guinea pigs. Effusion volume and cellular content were determined after sacrifice and rapid dissection of the ear. By 24 hours, rIL-2 (100 U) had produced a cellular effusion (77% to 92% polymorphonuclear neutrophil leukocytes), which cleared by 72 hours. rTNF (10 U) yielded a cellular effusion (12% to 67% lymphocytes) at 24 hours, which cleared by 48 hours. rIL-1 (100 U) did not produce significant effusion when compared to control. rIL-2 and rTNF cause an inflammatory effusion in the middle ear. To the extent they are generated in the middle ear during otitis media, these cytokines have the potential to contribute to the pathogenesis of otitis media with effusion.

Double-blind comparison of cetirizine and placebo in the treatment of seasonal rhinitis.

The efficacy and safety of cetirizine were evaluated in 419 patients with seasonal allergic rhinitis. Using a 4-way, double-blind randomization schedule, patients were given a 1-week course of once daily cetirizine (5, 10, or 20 mg) or placebo. Patient and physician efficacy ratings corresponded, indicating superiority of cetirizine to placebo (P less than .05) in reducing symptom severity scores for sneezing, rhinorrhea, ocular pruritus, nasal pruritus, watering of the eyes, and redness of the eyes. All cetirizine doses achieved higher efficacy ratings (72.7%, 79.2%, and 75.7%, respectively) than placebo (52.9%; P less than .05) by the physician's global assessment. Cetirizine was well tolerated, with sedation being the most common adverse experience, increasing in frequency at higher doses. A dose-response relationship was evident for selected symptoms, and the once daily 5-mg dose was found to be an effective minimum dose.

Calcium mobilization in activated mast cells monitored by flow cytometric analysis.

Changes in intracellular calcium levels induced in mast cells by either antigen or ionomycin were monitored using flow cytometry and the calcium binding dye indo-1. Both stimuli increased calcium levels in responsive cells by a similar amount, but not all cells examined were responsive to antigen. Antigen-induced increases in intracellular calcium levels could be completely blocked by the calcium antagonist TMB-8. Flow cytometry appears to be a useful method for monitoring mast cell calcium concentrations, as it provides the capability to study large numbers of individual cells.

Mast cell biology.

Mast cells are the repository for histamine in the body. They influence the pathophysiology of allergic diseases, such as rhinitis, urticaria, and asthma; regulate bone formation and integrity; help repair and maintain connective tissue; promote wound healing; and probably contribute to the development and preservation of the endothelium and small blood vessels. Although they are found in all human tissue, mast cells are most prevalent at the interface between the host and its environment, that is, in the skin and in the mucosa of the upper and lower respiratory tracts and the gastrointestinal tract. Recent evidence suggests that two types of mast cells exist: (1) the connective tissue type, found primarily but not exclusively in loose connective tissue and skin, and (2) the mucosal type, found primarily in gastrointestinal mucosa and peripheral airways. The factors that produce this differentiation are not fully known. Although both mast cell types have IgE receptors that can be activated by allergens, differences between the two types exist in their responses to nonallergic signals, the mediators they release, their proteoglycan constituents, and the makeup of their granular enzymes. The importance of these biochemical differences to cellular functioning remains to be investigated.

Mast cells and pulmonary fibrosis. Identification of a histamine releasing factor in bronchoalveolar lavage fluid.

As elevated bronchoalveolar lavage (BAL) fluid histamine levels are noted in patients with pulmonary fibrosis (PF), we assayed BAL fluid from 16 patients with PF for the presence of a histamine releasing factor (HRF). HRF activity was assayed by measuring release of the preformed mast cell-derived mediators, histamine, or beta-hexosaminidase (beta-hex) from a purified population of IL-3 dependent mouse bone marrow derived mast cells (MBMMC) or human blood basophils. Mean BAL cell free histamine levels in the patients with PF was 1226 +/- 1349 pg/ml, whereas BAL histamine levels in a comparison group of six non-PF patients was 118 +/- 60 pg/ml. HRF was significantly elevated in BAL fluid of patients with PF (mean beta-hex release 24.5 +/- 12.9%; range 6.8 to 52.4%) compared to the non-PF group of patients (mean beta-hex release 7.9 +/- 7.7%; range 1.8 to 20.7%). The PF HRF not only degranulated MBMMC, but also induced the generation of the arachidonic acid metabolite leukotriene C4 from MBMMC (24.6 +/- 4.2 ng leukotriene C4/10(6) MBMMC). The PF HRF did not appear to be a cytokine previously identified in BAL fluid of patients with PF (i.e., platelet derived growth factor or insulin growth factor-1) or a human cytokine able to degranulate human basophils (i.e., IL-1, or granulocyte-macrophage-CSF) as these recombinant human cytokines did not induce MBMMC beta-hex release. Physicochemical characterization of the HRF revealed that it was relatively heat stable, pronase sensitive and on Sephadex G-75 and G-200 column chromatography had an apparent molecular mass of 30 to 50 kDa. The ability of PF BAL to induce beta-hex release from MBMMC was not dependent on IgE as unsensitized or lactic acid treated MBMMC release similar amounts of beta-hex compared to MBMMC sensitized with IgE. Thus, BAL fluid of patients with PF contains an HRF that induces beta-hex release from MBMMC via an IgE-independent mechanism. The presence of the HRF could explain elevated BAL histamine levels in patients with PF.