Guiding principles for use of newer biologics and bronchial thermoplasty for patients with severe asthma.

BACKGROUND: Severe asthma poses significant disease-related and economic burdens in the United States. Challenges in practice include how to define "severe asthma" for a given patient, knowing which are the right tests to perform and when, and having a better understanding of a patient's asthma phenotype. Furthermore, current guidelines do not address a clear, practical approach to treatment that is based on a patient's asthma phenotype. OBJECTIVE: To develop a consensus on the definition of severe asthma, the role of biomarkers and phenotyping severe asthma, and the use of newer biologic therapies and bronchial thermoplasty to help guide practicing clinicians. METHODS: A roundtable meeting was convened with a panel of severe asthma experts to discuss areas in practice that are not adequately addressed by current guidelines, specifically phenotype-guided treatment. RESULTS: We describe a consensus on the definition of severe asthma, asthma phenotyping with the use of available biomarkers, and guiding principles for newer biologic therapies and bronchial thermoplasty. CONCLUSION: To optimize therapy and improve outcomes such as daily symptoms, quality of life, exacerbations, and hospitalizations, a clear picture of a patient's asthma phenotype is needed to guide therapy. Determining asthma phenotypes is the foundation of precision medicine for this persistent, often difficult-to-treat disease.

Small airways disease and severe asthma.

The small airways of the lungs are commonly affected in pediatric and adult asthma. Small airways disease has been related to asthma control, severity, and risk of exacerbation. Diagnosis of small airways disease can be best made through evaluation of surgical lung specimens. Noninvasive techniques including spirometry, plethysmography, nitrogen washout, impulse oscillometry, and cross-sectional imaging have been utilized to assess and infer the extent of small airways disease in asthma and can be used longitudinally to assess response to treatment. Patients with small airways disease seem to benefit from inhaled asthma medications that have improved capacity to reach the distal lung compartment. This is especially important for patients with severe asthma, who rely upon high doses of inhaled corticosteroid and bronchodilators for asthma control. This review will describe the techniques which may be utilized to assess small airways disease, discuss the prevalence and characteristics of small airways disease in severe asthma, and highlight how small airway disease may complicate severe asthma treatment.

Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States.

BACKGROUND: Although anaphylaxis is recognized as an important life-threatening condition, data are limited regarding its prevalence and characteristics in the general population. OBJECTIVE: We sought to estimate the lifetime prevalence and overall characteristics of anaphylaxis. METHODS: Two nationwide, cross-sectional random-digit-dial surveys were conducted. The public survey included unselected adults, whereas the patient survey captured information from household members reporting a prior reaction to medications, foods, insect stings, or latex and idiopathic reactions in the previous 10 years. In both surveys standardized questionnaires queried anaphylaxis symptoms, treatments, knowledge, and behaviors. RESULTS: The public survey included 1,000 adults, of whom 7.7% (95% CI, 5.7% to 9.7%) reported a prior anaphylactic reaction. Using increasingly stringent criteria, we estimate that 5.1% (95% CI, 3.4% to 6.8%) and 1.6% (95% CI, 0.8% to 2.4%) had probable and very likely anaphylaxis, respectively. The patient survey included 1,059 respondents, of whom 344 reported a history of anaphylaxis. The most common triggers reported were medications (34%), foods (31%), and insect stings (20%). Forty-two percent sought treatment within 15 minutes of onset, 34% went to the hospital, 27% self-treated with antihistamines, 10% called 911, 11% self-administered epinephrine, and 6.4% received no treatment. Although most respondents with anaphylaxis reported 2 or more prior episodes (19% reporting ≥5 episodes), 52% had never received a self-injectable epinephrine prescription, and 60% did not currently have epinephrine available. CONCLUSIONS: The prevalence of anaphylaxis in the general population is at least 1.6% and probably higher. Patients do not appear adequately equipped to deal with future episodes, indicating the need for public health initiatives to improve anaphylaxis recognition and treatment.

Advances in inhaled corticosteroid pharmacology.

Inhaled corticosteroids have been the backbone of asthma therapy for the past 20 plus years. Although they have, for the most part, been effective in controlling asthma symptoms and preventing exacerbations, not all patients are universally responsive to their beneficial effects. In addition, several recent studies have failed to demonstrate a disease-modifying effect of inhaled corticosteroids, with clinically indicated doses failing to prevent long term deterioration in lung function and potential airway "remodeling". Furthermore, it is apparent that possible side effects are still a concern with currently available formulations. Steroid characteristics, which might improve the therapeutic index of this class of medicine by enhancing efficacy while minimizing side effects, are explored, with special emphasis on the molecule, ciclesonide.

Mometasone furoate nasal spray: a review of safety and systemic effects.

The development of corticosteroids that are delivered directly to the nasal mucosa has alleviated much of the concern about the systemic adverse effects associated with oral corticosteroid therapy. However, given the high potency of these drugs and their widespread use in the treatment of allergic rhinitis, it is important to ensure that intranasal corticosteroids have a favourable benefit-risk ratio. One agent that typifies the systemic safety found in the majority of intranasal corticosteroids is mometasone furoate nasal spray, a potent and effective treatment for seasonal and perennial allergic rhinitis and nasal polyposis. Mometasone furoate does not reach high systemic concentrations or cause clinically significant adverse effects. Results from pharmacokinetic studies in adults and children suggest that systemic exposure to mometasone furoate after intranasal administration is negligible. This is probably because of the inherently low aqueous solubility of mometasone furoate, which allows only a small fraction of the drug to cross the nasal mucosa and enter the bloodstream, and because a large amount of the administered drug is swallowed and undergoes extensive first-pass metabolism. There is no clinical evidence that mometasone furoate nasal spray suppresses the function of the hypothalamus-pituitary-adrenal axis when the drug is administered at clinically relevant doses (100-200 microg/day); consequently, mometasone furoate nasal spray has not been associated with growth inhibition in children. The safety and tolerability of mometasone furoate nasal spray have been rigorously assessed in clinical trials involving approximately 4,500 patients, with epistaxis, headache and pharyngitis being the most common adverse effects associated with treatment in adolescents and adults. The clinical effectiveness of mometasone furoate nasal spray, coupled with its agreeable safety and tolerability profile, confirms its favourable benefit-risk ratio.

Optimal management of community-acquired acute bacterial rhinosinusitis: the allergist's perspective.

OBJECTIVES: To characterize the antibiotic resistance seen in community-acquired respiratory tract infections (RTIs) and determine which characteristics to look for in an antibiotic to improve clinical outcomes and decrease the potential for development of resistance. DATA SOURCES: Using MEDLINE, we performed a search of articles published from 1966 to 2004 to evaluate the current literature on the subject of antibiotic resistance and strategies to overcome it. Additional cited references, such as abstracts, were also identified. STUDY SELECTION: Relevant original research articles, reviews, and published abstracts were selected for inclusion in this review. RESULTS: Several factors were identified that should be considered when choosing empiric antibiotic therapy for community-acquired RTIs with the goal of improving clinical outcomes while minimizing the risk of resistance. These factors include spectrum of activity, bactericidal vs bacteriostatic activity, chemical structure, elimination half-life, and potency. CONCLUSIONS: The results of these studies support the use of targeted antibiotic agents that, based on structural and chemical properties, are optimized to have a low potential to induce resistance. This approach to antimicrobial therapy appears to be the most suitable for patients with acute bacterial rhinosinusitis and other community-acquired RTIs.

Clinical applications of exhaled nitric oxide for the diagnosis and management of asthma: a consensus report.

BACKGROUND: Patients with asthma routinely exhibit elevated levels of fractionated exhaled nitric oxide (FE(NO)), and this observation has led to studies investigating FE(NO) as a potential marker of airway inflammation. FE(NO) has been shown to enhance the diagnosis of asthma, detect deterioration in control of patients with asthma, and monitor response to anti-inflammatory therapy. OBJECTIVES: The aim of this work was to determine if FE(NO) measurement provides a noninvasive, well-tolerated, and standardized technique to monitor airway inflammation, and if it has the potential to complement standard asthma monitoring tools (eg, symptom diaries, control questionnaires, and pulmonary function testing) and to improve asthma control and patient outcomes. METHODS: Thirteen experts in the diagnosis and treatment of asthma met to discuss the use of FE(NO) in the diagnosis and management of patients with asthma. Participants were selected by Aerocrine, a medical, technical company with headquarters in Stockholm, Sweden, in consultation with their medical education partner Cadent Medical Communications located in Irving, Texas, to represent a diversity of specialists, including both clinicians and investigators, in the fields of allergy, immunology, and pulmonology. All participants were nominally compensated for their time to attend this closed scientific roundtable discussion. The meeting was supported by an educational grant from Aerocrine. This report represents the overall consensus reached by the participants on the clinical applicability of this technique. RESULTS: Our understanding of asthma has expanded so that investigators are now focusing on inflammation in addition to airway obstruction and hyper-reactivity. Whereas patient history, symptoms, and pulmonary function testing can assist in diagnosing asthma, they are not direct measures of the extent of airway inflammation. Elevated FE(NO) levels have been shown to reflect airway inflammation and to occur together with other conventional markers used to detect inflammation. Studies have confirmed increased levels of FE(NO) in both adults and children with asthma. In most studies, FE(NO) was found to be elevated 2- to 3-fold compared with normal controls. There are many determinants of FE(NO) levels, however, and factors other than inflammation must be considered when FE(NO) measurement is used to diagnose and monitor asthma. FE(NO) measurement alone is not sufficient for diagnosing or monitoring asthma, but it can be a valuable addition to current clinical tools. CONCLUSIONS: FE(NO) measurement is a noninvasive and reproducible test that is a surrogate measure of airway inflammation in patients with asthma. The test has demonstrated utility in diagnosing and managing asthma and in predicting response to therapy and, therefore, may be an important tool to incorporate into clinical care.

Properties of the ideal corticosteroid therapy.

Currently, inhaled corticosteroids (ICSs) are the most effective long-term control therapy for persistent asthma. However, patients show a variable response to ICSs and some exhibit glucocorticoid resistance. At recommended doses, there is little evidence to suggest that ICSs can either prevent or reverse the chronic airflow limitation that develops in some asthma patients. Could an improvement in the therapeutic index and greater accessibility of the drug to peripheral airways improve patient outcomes? Can a more potent ICS overcome glucocorticoid resistance or prevent airway remodeling? An optimal response could be achieved by modifying the drug's pharmacokinetic and pharmacodynamic profile, thus maximizing potency while minimizing adverse effects, creating the "ideal" ICS. Increasing lung deposition by modifying the drug formulation, increasing the fraction of respirable particles and receptor binding affinity, and heightening lipophilicity to facilitate passage of the drug into airway cells all play a role in improving efficacy. Could a drug that undergoes lipid conjugation increase the time the drug remains in the lungs, potentially allowing for once-daily dosing? Improvements in drug safety can be achieved by optimizing half-life and plasma clearance, limiting oropharyngeal deposition by on-site activation in the lungs, and increasing plasma protein binding to reduce the amount of free drug in systemic circulation. Ciclesonide, a novel ICS currently being developed for the treatment of persistent asthma, achieves many of these positive properties. The delivery of this relatively high-potency drug to strategic areas of inflammation, without the development of significant adverse effects, ideally will lead to improved asthma outcomes.

The role of nonsedating antihistamines in asthma therapy.

There is well-established evidence that histamine plays a significant role as a chemical mediator in asthma. However, although antihistamines are commonly used for the treatment of allergic rhinitis, their use in asthma has been somewhat controversial. Mechanistically, their application for asthma appears logical. In addition to their effects at the histamine receptor, antihistamines, in a dose-dependent fashion, inhibit the release of preformed mediators such as histamine and mediators synthesized de novo including the metabolities of arachidonic acid from mast cells and basophils. Antihistamines also show, in a concentration-dependent manner, anti-inflammatory and immunomodulatory activity through their effects on epithelial cells, endothelial cells, macrophages, eosinophils, and T lymphocytes. Clinically, there appears to be a link between allergic rhinitis and asthma such that treatment of the upper airway has been shown to benefit lower airway disease. Of interest is that although antihistamines have been shown to reduce asthma symptoms and improve quality of life, generally, they have not, at doses sufficient to control rhinitis, improved objective measures of lung function. This could potentially be achieved, in a fashion similar to that observed in concentration-dependent in vitro studies, by using higher medication levels. However, most antihistamines, both first- and second-generation, cannot be used above recommended doses without causing unacceptable side effects including sedation and psychomotor function impairment. As newer antihistamines with improved therapeutic indices have been developed, asthma studies can and must be conducted to evaluate high-dose therapy with the potential of reaping the anti-inflammatory and immunomodulatory effects of these drugs.

A preliminary retrospective treatment and pharmacoeconomic analysis of asthma care provided by allergists, immunologists, and primary care physicians in a teaching hospital.

Allergy immunology specialists (AIs) differ from primary care physicians (PCP) in their treatment of asthma. A limited retrospective chart review of several visits over a 1-year period in 1997 evaluating the quality of asthma care by AIs vs. PCPs was conducted in an academic center. Data concerning quality, effectiveness and cost of asthma care was randomly collected from 15 AIs and 15 PCPs from charts at 3-month intervals over a 1-year period. Information obtained from data collection forms revealed that asthma patients evaluated by AIs had more visits and received a greater quantity of medication compared to those treated by PCPs. All 15 patients with persistent asthma followed by AIs were treated with inhaled corticosteroids at each visit in contrast to only 80% of those treated by PCPs. The total numbers of controller medications (i.e., inhaled corticosteroids, salmeterol, cromolyn, and theophylline) that were utilized, as recommended, by the National Asthma Expert Panel (NAEP) of the National Heart, Lung, and Blood Institute (NHLBI) guidelines were 70 by AIs vs. 24 by PCPs over three visits. Cromolyn was prescribed five times over three visits by AIs and not at all by PCPs. Recognition and treatment of coexisting allergic rhinitis was evident in only 13% of patients treated by PCPs as compared to 80% in those treated by AIS. (p < 0.0001). However, all patients treated by AIs were skin tested to explore the presence of allergic triggers, while no patients treated by PCPs were evaluated for IgE-mediated reactions. Treatment cost for allergic rhinitis was therefore higher, at $2039, for AIs as compared to $741 for PCPs. There were no peakflow values in charts obtained from PCPs. However, all charts from AIs had peakflow values, which improved during the course of therapy in 33% of patients. Total medication costs for asthma were higher for AIs @ $5,646.30 vs. $1,932.25 for PCPs. Total medication costs for allergic rhinitis plus asthma were higher for AIs @ $7615 vs. $2681 for PCPs. However, patients treated by AIs had more severe asthma and required more frequent visits. Ipratropium bromide was prescribed a total of four times over several visits by PCPs vs. only once by AIs. In comparing asthma care between AI specialists and PCPs, it was found that AI specialists treat more severe asthmatics, provide more frequent follow-up visits, utilize peak flow rates, prescribe more controller medications, and more often recognize and treat comorbid conditions such as allergic rhinitis that impact on asthma care. Thus, although treatment costs for AIs are higher, these costs are justified by a quality of care that is more consistent with national (NHLBI) guidelines.