Background: Modern bronchodilators currently include the beta-2 agonists, methylxanthines, and anticholinergic agents. New developments surrounding beta-2 agonist therapy focus on downregulation of the beta-2 receptors, the pharmacogenetics of the beta-2 adrenergic receptor, and the possible influence of the microenvironment in the airways.Methods/Data base: Recent literature was reviewed to identify current clinical and research issues pertinent to Beta-2 agonist therapy in asthmatics. Using guinea pig lung membranes, the inhibition of I-125 cyanopindolol binding to beta-2 receptors mediated by sera and immunoglobulins from asthmatic and nonasthmatic sera was investigated. B82 fibroblasts transfected with the human beta-2 adrenergic receptor gene were also used to study functional inhibition of cyclic AMP production induced in culture by 10(-6M) isoproterenol in the presence of asthmatic sera, antibodies, and products of activated neutrophil and lymphocytes.Results: Recent literature suggests that tolerance to beta-2 agonist therapy is not uncommon and leukotriene receptor antagonists may be more effective bronchoprotectors for exercise-induced asthma (EIA). Chronic beta-2 agonist therapy may not be ideal for all patients. Significant inhibition of (ICYP)-C-125 ligand binding is mediated by asthmatic sera and normal sera and immunoglobulin fractions in in vitro studies. No functional inhibition of cyclic adenosine monophosphate (cAMP) was demonstrated by immunoglobulins. However, products of activated stimulated neutrophils markedly inhibited 10(-6n) Isoproterenol stimulated cAMP production by these cells. Effects on beta agonist induced cyclic AMP were mediated by activated lymphocytes. In addition to agonist mediated desensitization of beta-2 receptors via molecular mechanisms such as receptor phosphorylation, uncoupling from G proteins and sequestration, the inflammatory microenvironment may mediate significant inhibitory effects on the function of beta-2 receptors in asthmatic subjects. A physiological reserve or excess expression of beta-2 receptors may partially protect against such effects, but some cell types may be more vulnerable to the effects of inflammation in the airway microenvironment.Conclusions: The interplay between genetic, environmental, molecular and inflammatory factors on airway beta-2 receptor responsiveness in asthma is likely to be complex, but an understanding of these influences is necessary for optimizing beta-2 agonist therapy in asthmatics.
Background: Airway remodeling is an alteration in the size, mass, or number of tissue structural components that occurs during growth or in response to injury and/or inflammation. The primary inflammatory lesion consists of accumulation of CD4+ T-helper cell type 2 (Th2) lymphocytes and eosinophils in the airway mucosa. A first step in the control of the aberrant responses in airway diseases could be to identify in CD40-CD40L interaction one of the possible mechanism by which epithelial cells promote and sustain airway inflammation [10].Methods/Data base: A review of the literature and own studies.Results/Conclusions: The transformation of fibroblasts into myofibroblasts is a crucial step of airway remodeling and one of the principal aims of future studies might be its downregulation as early as possible. The real impact of upper airway remodeling still remains unclear and further investigations are needed.
Background: Although serum sickness-like reactions (SSLR) are rare in clinical practice, they have been documented to occur following the administration of many medications. The aim of this study is to describe the clinical features of serum sickness-like reactions and the characteristics of this type of presentation. Also, to determine which agents are associated with the development of serum sickness-like reactions in children admitted to a hospital in Tehran, Iran.Methods/Data base: This retrospective study was performed at the hospital of the Children's Medical Center by means of a review of medical charts of children admitted with serum sickness-like reactions during a period of 3 years. Twenty-three hospitalized children with serum sickness-like reactions were evaluated.Results: Of the 23 children with serum sickness-like reactions, 10 cases were related to penicillin drugs, 5 to trimethoprim-sulfamethoxazole, 4 to furazolidone, 2 to wasp stings, and a single case was due to ciprofloxacin and carbamazepine, respectively. Most of the patients (78.2%) were under 6 years of age and reactions began 5-20 days after exposure to causative agents. Two of the antibiotic-related cases had a history of prior exposure to the same antibiotic. All patients recovered within 1-7 days after withholding the offending agent and providing symptomatic relief.Conclusions: Serum sickness-like reactions to penicillin group drugs may be more common than reported in the literature. So physicians should be familiar with serum sickness reactions particularly as they relate to long-acting penicillin preparations, because accurate diagnosis in conjunction with cessation of drug exposure and prompt initiation of antiinflammatory treatment with corticosteroids can produce complete recovery. Also, clinicians should be aware of the possibility of serum sickness-like reactions associated with insect stings such as by wasps.
A 47-year-old African American female presented to the emergency department with increasing facial and upper lip swelling (angioedema) during the previous 12 h. There was no history of previous angioedema or urticaria. The patient's medications included hydrochlorothiazide 25mg and lisinopril 20 mg daily, the latter of which she had taken for 2 years. The lisinopril was discontinued, and she was treated with oral prednisone, diphenhydramine, and ranitidine. Her symptoms resolve completely over a 3-day period.
Background: Nasal congestion is a common problem in patients being treated with nasal positive airway pressure therapy. Although the problem is common, its treatment is challenging. We sought to evaluate the use of Breathe Right Strips((R)) (BRS)for improving nasal air flow in patients with obstructive sleep apnea (OSA) and rhinitis on positive pressure therapy.Methods/Data base: 40 patients that were part of a larger study assessing outcomes of positive airway pressure therapy in OSA patients with rhinitis were evaluated. Inclusion criteria were OSA, current treatment with nasal positive airway pressure., and at least one of the following: nasal itching, congestion, rhinorrhea, or postnasal drip. Patients were excluded if they had asthma, chronic obstructive pulmonary disease (COPD), congestive heart failure and previous sinus, air-way or throat surgery (except for adenoidectomy or tonsillectomy in the distant past). Patients were assessed between 1 and 4 PM and asked to perform both a peak expiratory flow (PEF) measurement and a nasal peak inspiratory flow (nPIF) measurement without and immediately after a BRS was applied. Patients were also tested to evaluate atopic status. Results were analyzed using a paired t-test.Results: nPIF and the respiratory index (RI, calculated as nPIF/PEF) increased by a mean of 23.2 L/min (p < 0.001) and 0.05 (p < 0.001), respectively. These improvements were also seen in patients when they were stratified by allergic vs. nonallergic disease.Conclusions: BRS improve nPIF and RI in patients with rhinitis on nasal positive airway pressure therapy for OSA. While other studies have shown similar findings in other populations, none have evaluated OSA patients on nasal positive airway pressure therapy, a situation in which nasal patency directly influences effectiveness of therapy. BRS may be a valuable adjunct to treatment of nasal symptoms in these patients. Further studies need to be done to assess the clinical utility of these findings.
Background: The only causal treatment against allergy is specific immunotherapy. However, specific immunotherapy is only available by the subcutaneous and sublingual route, even though oral application remains the most preferred route.Methods/Data base: A review of the literature. We discuss the mechanisms of sublingual and oral immunotherapy as well as strategies to overcome the digestive systems for the successful development for oral allergen immunotherapy. Promising current developments in oral allergen immunotherapy using microparticles that target M-cells are discussed in detail.Results/Conclusions: The main target for orally delivered vaccines are M cells in Peyer's patches. The upper limit for uptake via M cells appears to be 10 mu m , and within the 1-10 mu m range of microparticles, 1-2 mu m particles appear to be taken up preferentially as compared to larger particles. Particle uptake is not only influenced by size, but also by surface charge and hydrophobicity. The most widely used oral delivery system are the ones based on poly-D,L-lactide-co-glycolic acid (PLGA), but chitosan-particles and liposomes have also been used as carrier for allergen immunotherapy. PLGA represents a controlled release system which protects the entrapped allergens from degradation and allows a reduction of necessary booster shots or repetitions of oral intake. Allergen-loaded microparticles are able to counter-balance an allergic immune response when targeting M cells. Aleuria aurantia lectin (AAL) microparticles have been used successfully in murine trials and may be a potent candidate for successful oral immunotherapy in humans.
Background: Most patients with cutaneous hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit clinical tolerance to specific inhibitors (coxibs) of cyclooxygenase-2 (COX-2). However, a subset of such patients will develop urticaria or angioedema when exposed to coxibs. The mechanisms of urticaria and angioedema due to coxibs are presently unknown. In this paper we discuss the prevalence of skin reactions due to coxibs and possible mechanisms mediating such adverse manifestations.Methods/Data base: A total of 206 patients (female 144, male 62, mean age 31.1 +/- 13.7 years) with urticaria and/or angioedema due to nonselective NSAIDs were studied between September 1999 and September 2005. Drug pattern showed 167 crossreactors (81%) and 39 single-reactors (19%), with a cutaneous clinical pattern in 122 (59.2%), mixed reactions (respiratory/cutaneous) in 82 (39.8%), and systemic reactions only in 2 (0.9%). Oral provocation tests were carried out with preferential and specific COX-2 inhibitors. In addition, a PubMed search of published studies on the tolerance to specific COX-2 inhibitors in NSAID-hypersensitive subjects was performed.Results/Conclusions: Positive oral challenges with nimesulide were observed in 31% of studied patients, with meloxicam in 20.6%, with celecoxib in 18.4%, with etoricoxib in 11.2%, with valdecoxib in 10.3%, and with rofecoxib in 9.4%. While most NSAID-intolerant patients tolerated coxibs during oral challenges, a small subgroup of patients developed urticaria. Although there are few studies for valdecoxib and etoricoxib, these results are in agreement with the majority of published studies dealing with tolerability to rofecoxib (reaction rates 0-34.7%) and celecoxib (reaction rates 0-33.3%). Cutaneous reaction rates correlated with in vitro inhibition of COX-1 by different COX-2 inhibitors. Two possible mechanisms are proposed to explain urticaria induced by coxibs, an IgE-mediated allergic response, and inhibition of COX-1.
Background: Atopic eczema (AE) is a common chronic inflammatory skin disease that is part of the atopic syndrome and is frequently associated with asthma and allergic rhinoconjunctivitis. Aeroallergens like house-dust-mites, pollen, and animal epithelia represent important trigger factors in sensitised patients.Methods: While specific immunotherapy (SIT) is widely and most effectively used in allergy to insect venoms and allergic rhinitis. its use in AE is still controversially discussed. In a recent multicenter study it was shown in a double-blind controlled dose finding study that higher doses of allergens used for specific immunotherapy are effective in AE. A blind observer documented a higher decrease of scoring atopic dermatitis (SCORAD) points in patients treated with house dust mite allergen concentrations of 2000 and 20000 SQ-U compared to patients who belonged to the "active placebo group" who was treated with 20 SQ-U only.Results: A number of smaller clinical trials confirm that allergen-specific immunotherapy appears to be a promising approach for the treatment of patients with atopic eczema and clinically relevant sensitisation to house dust mites or other inhalant allergens which may lead to clinical improvement of eczema as well as subjective symptoms like pruritus and sleeplessness.Conclusions: Despite encouraging data the use of SIT as a therapeutic approach in the routine treatment of AE requires further evaluation.
Background: Sublingual immunotherapy (SLIT) is appropriate for home treatment of allergic rhinoconjunctivitis and allergic bronchial asthma. This study investigated patient acceptance and tolerability of a new SLIT treatment.Methods/Data base: This observational cohort study included 177 patients with allergic rhinoconjunctivitis and/or allergic bronchial asthma. Patients self-administered SLIT drops during an initial updosing and treatment phase, and an optional maintenance treatment phase. Patient acceptance and tolerability of SLIT were recorded through physician assessment and patients' diaries after each phase. Data are presented using summary statistics. Statistical estimates (chi(2) and U test) examined differences between age groups (<= 14 and >= 15 years).Results: 90.2% of patients completed the initial updosing and treatment phase; median treatment duration was 154 days. Adverse drug reactions were recorded in 14 patients, only I event was serious. Over 90% of patients and physicians rated the tolerability of SLIT as good or very good both in the initial phase and the maintenance phase. Patients' acceptance of SLIT treatment was high: Handling and once-daily dosing was particularly acceptable in the initial phase (50.9% and 47.9% of patients, respectively, rated their satisfaction as very good). The percentage of patients responding to different eye and nose symptoms ranged from 69.6% to 80.9%. The proportion of patients receiving any symptomatically effective medication decreased from 93.8% to 59.4% in patients aged <= 14 years, and from 91.2% to 61.4% in patients aged >= 15 years.Conclusions: This observational study reported a high level of patient acceptance and tolerability with SLIT treatment in a predominantly young population.
Background: Histological examination of biopsies from asthma obtained during bronchoscopy has highlighted the presence of increased vessel numbers and vascularity in the submucosa. We hypothesized that cytokines and chemokines may play an important role in angiogenesis associated with asthma and examined the effect of inhaled corticosteroids (ICS) on airway vascularity.Methods/Data base: We examined the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, and stromal cell-derived factor-1 (SDF-1) immunoreactivity in endobronchial biopsy specimens obtained from asthmatic patients and control subjects. The number of vessels and the vascular area per unit area on a histologic section were estimated by computerized image analysis after staining for type IV collagen in vessel walls.Results: The airways of asthmatic subjects had significantly more vessels and greater vascular area than controls. Asthmatic subjects exhibited higher VEGF and bFGF, angiogenin, and SDF-1 immunoreactivity in the submucosa than controls. Significant correlations were detected between vascular area and the number of each angiogenic factor-positive cells within the asthmatic airways. Furthermore using in situ hybridization methods, VEGF and its receptor mRNA(+) cells were over-expressed in asthma. Asthmatic patients treatment with ICS significantly reduced bronchial mucosal vascularity.Conclusions: These findings provide evidence that angiogenic factors may play an important role in angiogenesis of asthma, and ICS reduced vascularity during airway remodeling.
Background: Mouse, human, and rat mast cells have been shown to express major histocompatibility complex (MHC) II molecules and present antigens to specific T cells in vitro. The presence and detection of MHC class II molecules on mast cells remained elusive for many years. During the last two decades, a number of studies have made it clear, by combining biochemical, ultrastructural, and functional approaches, that MHC II molecules are indeed expressed, in some conditions, on mast cells from various species. This review reports on common as well as specific aspects of antigen-presenting function of mast cells.Methods/Data base: A review of the literature.Results/Conclusions: Although no evidence for antigen presenting function in vivo of mast cells is available, the assumption can be made that in some circumstances these cells may be involved in the initiation or the amplification of antigen-specific immune responses, however, it remains unclear whether mast cells truly present antigens directly to specific T lymphocytes or indirectly through professional antigen-presenting cells such as dendritic cells via exosomes.
A 64-year-old male, who moved to Florida from Jamaica 20 years ago, presented with a history for the past 5 years of blood eosinophilia between 1200 and 1900 cells/mm(3). In persistent eosinophilia, a number of differential diagnoses have to be considered. The patient was diagnosed as suffering from chronic strongyloidiasis. He was treated with one dose of ivermectin and tolerated it well. He is now asymptomatic with a normal eosinophil count.
Background: Until recently, airway remodeling has been considered to be a secondary phenomenon, developing later in the disease process as a consequence of persistent inflammation. The presence of airway inflammation and remodeling in children with asthma indicate that the remodeling process begins early in the disease process of asthma and occurs synchronously in ongoing and repeated airway inflammation rather than as a consequence of airway inflammation. Bronchial epithelial cell damage also occurs early in the course of childhood asthma, and injured and stressed epithelial cells trigger airway remodeling through activation of the epithelial-mesenchymal tropic unit. Therefore, the characteristic features of bronchial epithelial cells in asthmatics should be clarified. Early intervention with inhaled corticosteroids (ICS) before serious pathological changes occur, is expected to prevent the development of remodeling and improve asthma outcomes.Methods/Data base: A review of the current research and ideas regarding the mechanisms and assessment of airway inflammation and remodeling, as well as the effects of current and potential future therapeutics on airway remodeling, with a focus on bronchial epithelial cells.Results/Conclusions: Early intervention with ICS improves asthma-related symptoms and may partially prevent airway remodeling, however, the effects are not satisfactory. Therefore, therapeutic options, and how and when treatment can be effected should be investigated to reduce air-way inflammation and prevent the development of airway remodeling.
