Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma.

BACKGROUND: Benralizumab is a unique eosinophil-depleting monoclonal antibody that significantly reduces asthma exacerbations, improves lung function and asthma symptoms, and permits the reduction of maintenance oral corticosteroid dosage for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: To assess benralizumab's onset of action and efficacy by examining change in morning peak expiratory flow (PEF) after initiation of treatment in the phase 3 clinical trials SIROCCO, CALIMA, and ZONDA. METHODS: Mixed-model repeated-measures analysis was used to calculate PEF using daily least squares mean changes from baseline in morning PEF as well as differences between the benralizumab every 8 weeks (first 3 doses every 4 weeks) and placebo groups. A Bayesian nonlinear mixed-effects approach with an exponential relationship was used to model trial data to determine time to clinically meaningful improvement in morning PEF (defined as ≥25 L/min). RESULTS: Least squares mean morning PEF improvement from baseline was numerically greater by Day 2 after initiation of benralizumab therapy in all 3 trials. The Bayesian nonlinear mixed-effects model indicated that PEF improvement reached the clinically meaningful threshold within 3 weeks in SIROCCO and CALIMA and 2 weeks in ZONDA. CONCLUSION: In 3 phase 3 randomized clinical trials, benralizumab provided notable improvement in morning PEF 2 days after initiation and clinically meaningful improvements within 3 weeks for patients with severe, uncontrolled eosinophilic asthma. The rapid improvement in PEF demonstrated in these trials suggests that benralizumab's unique mechanism of action rapidly improves lung function for patients with severe, eosinophilic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01928771 (SIROCCO), NCT01914757 (CALIMA), and NCT02075255 (ZONDA).

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.

BACKGROUND: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. OBJECTIVE: We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers. METHODS: IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. RESULTS: Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. CONCLUSION: A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicentre studies.

Bronchial thermoplasty is an endoscopic therapy for severe asthma. The previously reported, randomised sham-controlled AIR2 (Asthma Intervention Research 2) trial showed a significant reduction in severe asthma exacerbations, emergency department visits and hospitalisations after bronchial thermoplasty. More "real-world" clinical outcome data is needed.This article compares outcomes in bronchial thermoplasty subjects with 3 years of follow-up from the ongoing, post-market PAS2 (Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma) study with those from the AIR2 trial.279 subjects were treated with bronchial thermoplasty in the PAS2 study. We compared the first 190 PAS2 subjects with the 190 bronchial thermoplasty-treated subjects in the AIR2 trial at 3 years of follow-up. The PAS2 subjects were older (mean age 45.9 versus 40.7 years) and more obese (mean body mass index 32.5 versus 29.3 kg·m-2) and took higher doses of inhaled corticosteroids (mean dose 2301 versus 1961 µg·day-1). More PAS2 subjects had experienced severe exacerbations (74% versus 52%) and hospitalisations (15.3% versus 4.2%) in the 12 months prior to bronchial thermoplasty. At year 3 after bronchial thermoplasty, the percentage of PAS2 subjects with severe exacerbations, emergency department visits and hospitalisations significantly decreased by 45%, 55% and 40%, respectively, echoing the AIR2 results.The PAS2 study demonstrates similar improvements in asthma control after bronchial thermoplasty compared with the AIR2 trial despite enrolling subjects who may have had poorer asthma control.

Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-ß-mediated collagen production in a murine asthma model.

Asthma is a disease of acute and chronic inflammation in which cytokines play a critical role in orchestrating the allergic inflammatory response. IL-13 and transforming growth factor (TGF)-ß promote fibrotic airway remodeling, a major contributor to disease severity. Improved understanding is needed, because current therapies are inadequate for suppressing development of airway fibrosis. IL-13 is known to stimulate respiratory epithelial cells to produce TGF-ß, but the mechanism through which this occurs is unknown. Here, we tested the hypothesis that reactive oxygen species (ROS) are a critical signaling intermediary between IL-13 or allergen stimulation and TGF-ß-dependent airway remodeling. We used cultured human bronchial epithelial cells and an in vivo mouse model of allergic asthma to map a pathway where allergens enhanced mitochondrial ROS, which is an essential upstream signal for TGF-ß activation and enhanced collagen production and deposition in airway fibroblasts. We show that mitochondria in airway epithelium are an essential source of ROS that activate TGF-ß expression and activity. TGF-ß from airway epithelium stimulates collagen expression in fibroblasts, contributing to an early fibrotic response to allergen exposure in cultured human airway cells and in ovalbumin-challenged mice. Treatment with the mitochondrial-targeted antioxidant, (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), significantly attenuated mitochondrial ROS, TGF-ß, and collagen deposition in OVA-challenged mice and in cultured human epithelial cells. Our findings suggest that mitochondria are a critical source of ROS for promoting TGF-ß activity that contributes to airway remodeling in allergic asthma. Mitochondrial-targeted antioxidants may be a novel approach for future asthma therapies.

Central nervous system influences in asthma.

Asthma is a biomedical disorder whose presentation can be markedly influenced by neurological and psychological factors. This chapter describes several approaches that provide insight into the role of psychological factors and brain function in asthma. These include the study of placebo responses and recent explorations using functional neuroimaging during the onset of asthma symptoms. Although the specific mechanisms involved remain uncertain, we are gaining an appreciation for some of the neurocircuitry that is involved. The insula and ACC may modulate inflammatory processes by their influence on neuroendocrine responses to stress, including highly studied effects on the HPA axis and its physiologic responses. However much we have recently learned, it is clear that further study of this topic is critical to fully explicate the role of the brain in asthma.

Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma.

BACKGROUND: Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. OBJECTIVE: We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. METHODS: BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.govNCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. RESULTS: One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV1 values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. CONCLUSIONS: These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting ß2-agonists.

Tim-1 regulates Th2 responses in an airway hypersensitivity model.

T-cell immunoglobulin mucin-1 (Tim-1) is a transmembrane protein postulated to be a key regulator of Th2-type immune responses. This hypothesis is based in part upon genetic studies associating Tim-1 polymorphisms in mice with a bias toward airway hyperrespon-siveness (AHR) and the development of Th2-type CD4(+) T cells. Tim-1 expressed by Th2 CD4(+) T cells has been proposed to function as a co-stimulatory molecule. Tim-1 is also expressed by B cells, macrophages, and dendritic cells, but its role in responses by these cell types has not been firmly established. Here, we generated Tim-1-deficient mice to determine the role of Tim-1 in a murine model of allergic airway disease that depends on the development and function of Th2 effector cells and results in the generation of AHR. We found antigen-driven recruitment of inflammatory cells into airways is increased in Tim-1-deficient mice relative to WT mice. In addition, we observed increased antigen-specific cytokine production by splenocytes from antigen-sensitized Tim-1-deficient mice relative to those from controls. These data support the conclusion that Tim-1 functions in pathways that suppress recruitment of inflammatory cells into the airways and the generation or activity of CD4(+) T cells.

Anti-inflammatory effects of the neurotransmitter agonist Honokiol in a mouse model of allergic asthma.

Chronic airway inflammation is a hallmark of asthma, an immune-based disease with great societal impact. Honokiol (HNK), a phenolic neurotransmitter receptor (γ-aminobutyric acid type A) agonist purified from magnolia, has anti-inflammatory properties, including stabilization of inflammation in experimentally induced arthritis. The present study tested the prediction that HNK could inhibit the chronic inflammatory component of allergic asthma. C57BL/6 mice sensitized to and challenged with OVA had increased airway hyperresponsiveness to methacholine challenge and eosinophilia compared with naive controls. HNK-treated mice showed a reduction in airway hyperresponsiveness as well as a significant decrease in lung eosinophilia. Histopathology studies revealed a marked drop in lung inflammation, goblet cell hyperplasia, and collagen deposition with HNK treatment. Ag recall responses from HNK-treated mice showed decreased proinflammatory cytokines in response to OVA, including TNF-α-, IL-6-, Th1-, and Th17-type cytokines, despite an increase in Th2-type cytokines. Regulatory cytokines IL-10 and TGF-ß were also increased. Assessment of lung homogenates revealed a similar pattern of cytokines, with a noted increase in the number of FoxP3(+) cells in the lung. HNK was able to alter B and T lymphocyte cytokine secretion in a γ-aminobutyric acid type A-dependent manner. These results indicate that symptoms and pathology of asthma can be alleviated even in the presence of increased Th2 cytokines and that neurotransmitter agonists such as HNK have promise as a novel class of anti-inflammatory agents in the treatment of chronic asthma.

Endotoxin inhalation alters lung development in neonatal mice.

BACKGROUND: Childhood asthma is a significant public health problem. Epidemiologic evidence suggests an association between childhood asthma exacerbations and early life exposure to environmental endotoxin. Although the pathogenesis of endotoxin-induced adult asthma is well studied, questions remain about the impact of environmental endotoxin on pulmonary responsiveness in early life. METHODS: We developed a murine model of neonatal/juvenile endotoxin exposures approximating those in young children and evaluated the lungs inflammatory and remodeling responses. RESULTS: Persistent lung inflammation induced by the inhalation of endotoxin in early life was demonstrated by the influx of inflammatory cells and pro-inflammatory mediators to the airways and resulted in abnormal alveolarization. CONCLUSIONS: Results of this study advance the understanding of the impact early life endotoxin inhalation has on the lower airways, and demonstrates the importance of an experimental design that approximates environmental exposures as they occur in young children.

Bronchial Thermoplasty in Patients With Severe Asthma at 5 Years: The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma Study.

BACKGROUND: Bronchial thermoplasty is a device-based treatment for subjects ≥ 18 years of age with severe asthma poorly controlled with inhaled corticosteroids and long-acting beta-agonists. The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) study collected data on patients with severe asthma undergoing this procedure. RESEARCH QUESTION: What are the 5-year efficacy and safety results in patients with severe asthma who have undergone bronchial thermoplasty? STUDY DESIGN AND METHODS: This was a prospective, open-label, observational, multicenter study conducted in the United States and Canada. Subjects 18 to 65 years of age who were taking inhaled corticosteroids ≥ 1,000 µg/d (beclomethasone or equivalent) and long-acting beta-agonists ≥ 80 µg/d (salmeterol or equivalent) were included. Severe exacerbations, hospitalization, ED visits, and medication usage were evaluated for the 12 months prior to and at years 1 through 5 posttreatment. Spirometry was evaluated at baseline and at years 1 through 5 posttreatment. RESULTS: A total of 284 subjects were enrolled at 27 centers; 227 subjects (80%) completed 5 years of follow-up. By year 5 posttreatment, the proportion of subjects with severe exacerbations, ED visits, and hospitalizations was 42.7%, 7.9%, and 4.8%, respectively, compared with 77.8%, 29.4%, and 16.1% in the 12 months prior to treatment. The proportion of subjects on maintenance oral corticosteroids decreased from 19.4% at baseline to 9.7% at 5 years. Analyses of subgroups based on baseline clinical and biomarker characteristics revealed a statistically significant clinical improvement among all subgroups. INTERPRETATION: Five years after treatment, subjects experienced decreases in severe exacerbations, hospitalizations, ED visits, and corticosteroid exposure. All subgroups demonstrated clinically significant improvement, suggesting that bronchial thermoplasty improves asthma control in different asthma phenotypes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01350336; URL: www. CLINICALTRIALS: gov.

Loss of Bardet-Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia.

Mutations in a group of genes that contribute to ciliary function cause Bardet-Biedl syndrome (BBS). Most studies of BBS have focused on primary, sensory cilia. Here, we asked whether loss of BBS proteins would also affect motile cilia lining the respiratory tract. We found that BBS genes were expressed in human airway epithelia, and BBS2 and BBS4 localized to cellular structures associated with motile cilia. Although BBS proteins were not required for ciliogenesis, their loss caused structural defects in a fraction of cilia covering mouse airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia. We discovered this same misshapen appearance in airway cilia from Bbs1, Bbs2, Bbs4, and Bbs6 mutant mice. The structural abnormalities were accompanied by functional defects; ciliary beat frequency was reduced in Bbs mutant mice. Previous reports suggested BBS might increase the incidence of asthma. However, compared with wild-type controls, neither airway hyperresponsiveness nor inflammation increased in Bbs2(-/-) or Bbs4(-/-) mice immunized with ovalbumin. Instead, these animals were partially protected from airway hyperresponsiveness. These results emphasize the role of BBS proteins in both the structure and function of motile cilia. They also invite additional scrutiny of motile cilia dysfunction in patients with this disease.

Moderate Intensity Exercise in Pre-manifest Huntington's Disease: Results of a 6 months Trial.

BACKGROUND: While it has been shown that aerobic exercise interventions are well tolerated in participants with the Huntington disease (HD) gene mutation, no study to date has tested whether an aerobic exercise intervention benefits brain structure and function in pre-manifest HD. OBJECTIVE: In this study we utilized magnetic resonance (MR) imaging techniques to assess the efficacy of moderate-to-vigorous exercise treatment relative to active stretching and toning control. METHODS: Forty pre-manifest participants with confirmed HD gene expansion were recruited into a two-arm intervention study that included a moderate-to-vigorous intensity home-based walking exercise intervention (N=34) and an active stretching and toning control intervention (N=6). Participants were assessed at baseline and after 26 weeks in one of the two study arms. RESULTS: 25 of the 34 (74%) participants assigned to the moderate-to-vigorous intensity group completed the intervention while 4 of the 6 (67%) participants in the stretching and toning intervention completed the study. The primary analyses compared the two arms of the study and found no statistical differences between the groups. Both groups were found to have improved their cardiorespiratory fitness as assessed by maximal oxygen uptake (VO2max). A secondary analysis combined the two arms of the study and there was a significant relationship (p<0.05) between change in VO2max and change in brain structure. CONCLUSIONS: Though this study did not show efficacy for the exercise intervention, secondary results suggest that aerobic exercise interventions increasing cardiorespiratory fitness may be a potential way to slow progression in pre-manifest HD.

Toll-like receptor 9 activation with CpG oligodeoxynucleotides for asthma therapy.

Prokaryotic DNA has long been recognized as immunostimulatory. In the last decade the role played by CpG motifs (nucleotide sequence motifs centered on a cytosine-guanine dinucleotide) in bacterial and viral DNA has been elucidated. CpG motifs are detected by the innate immune pattern recognition receptor Toll-like receptor (TLR) 9, the ligation of which activates multiple signal cascades in responding cells. A restricted pattern of TLR9 expression to certain dendritic cells and B cells appears to provide relative specificity in responses, especially in comparison to other TLR ligands. TLR9 activation induces a Th1-like pattern of cytokine release which led to interest in the use of synthetic CpG oligodeoxynucleotides (CpG ODN) for the prevention and treatment of Th2-associated atopic disorders such as asthma. Interestingly, Th1 cytokines do not appear to be necessary for a therapeutic response in preclinical models of atopic asthma. Additional potential mechanisms of action include induction of regulatory-type responses (involving interleukin-10 release), and expression of indoleamine 2,3-dioxygenase. CpG ODN have been shown to prevent and reverse antigen-induced eosinophilic airway inflammation in animal models; human trials are ongoing with encouraging early results when used as a ragweed vaccine adjuvant in allergic upper airway disease.

Immunotherapy of asthma using CpG oligodeoxynucleotides.

Asthma and other atopic disorders have increased in prevalence and severity over the past three decades. Reduced risk of atopic disease associated with early life exposure to infections and microbes has raised the possibility that pathogen-associated molecular patterns (PAMPs) may confer protection against allergic disorders, a concept that has been named the "Hygiene Hypothesis". This relationship is most likely mediated through the induction of specific patterns of anti-atopic immune responses that follow engagement of innate immune mechanisms. Bacterial DNA is one such immunostimulatory microbe-associated ligand, whose properties can be mimicked by oligodeoxynucleotides (ODN) containing unmethylated cytosine-guanine dinucleotides in specific base sequences (CpG motifs), motifs characteristic of prokaryotic DNA that have been suppressed in eukaryotic DNA. Based initially on observations that CpG ODN induced Th1-type patterns of immune responses, we proposed that CpG ODN might represent a novel therapeutic strategy for the prevention and treatment of atopic disorders. Current understanding suggests multiple mechanisms of action of CpG ODN, but our initial hypothesis has been supported by extensive studies demonstrating, in animal models, efficacy in both incipient and established atopic asthma. These preclinical studies are now being translated into clinical trials exploring this new approach to immunotherapy for atopic disease.

Health effects of airborne exposures from concentrated animal feeding operations.

Toxic gases, vapors, and particles are emitted from concentrated animal feeding operations (CAFOs) into the general environment. These include ammonia, hydrogen sulfide, carbon dioxide, malodorous vapors, and particles contaminated with a wide range of microorganisms. Little is known about the health risks of exposure to these agents for people living in the surrounding areas. Malodor is one of the predominant concerns, and there is evidence that psychophysiologic changes may occur as a result of exposure to malodorous compounds. There is a paucity of data regarding community adverse health effects related to low-level gas and particulate emissions. Most information comes from studies among workers in CAFO installations. Research over the last decades has shown that microbial exposures, especially endotoxin exposure, are related to deleterious respiratory health effects, of which cross-shift lung function decline and accelerated decline over time are the most pronounced effects. Studies in naïve subjects and workers have shown respiratory inflammatory responses related to the microbial load. This working group, which was part of the Conference on Environmental Health Impacts of Concentrated Animal Feeding Operations: Anticipating Hazards-Searching for Solutions, concluded that there is a great need to evaluate health effects from exposures to the toxic gases, vapors, and particles emitted into the general environment by CAFOs. Research should focus not only on nuisance and odors but also on potential health effects from microbial exposures, concentrating on susceptible subgroups, especially asthmatic children and the elderly, since these exposures have been shown to be related to respiratory health effects among workers in CAFOs.

Safety assessment of inhaled xylitol in subjects with cystic fibrosis.

BACKGROUND: Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration, thus enhancing innate immunity. We tested the safety and tolerability of aerosolized iso-osmotic xylitol in subjects with cystic fibrosis. METHODS: In this pilot study, 6 subjects with cystic fibrosis and an FEV1>60% predicted underwent a baseline spirometry followed by exposures to aerosolized saline (10 ml) and 5% xylitol (10 ml). Serum osmolarity and electrolytes were measured at baseline and after xylitol exposure. Spirometry, oxygen saturation and respiratory symptom questionnaire using visual analog scale were tested at baseline and after each exposure. Sputum for cytokine analysis was collected after saline and xylitol nebulizations. RESULTS: There was no change in FEV1 after xylitol exposure compared with baseline or normal saline exposure (p=0.19). Laboratory values and respiratory symptoms were not affected by xylitol inhalation. The mean IL-8 level in the sputum was similar with saline and xylitol exposures (3.5+/-0.5 vs. 3.5+/-0.6 ng/ml). CONCLUSIONS: A single dose inhalation of aerosolized iso-osmotic xylitol was well tolerated by subjects with cystic fibrosis. Future studies of long term safety are required.

A four-dimensional computed tomography comparison of healthy and asthmatic human lungs.

The purpose of this study was to explore new insights in non-linearity, hysteresis and ventilation heterogeneity of asthmatic human lungs using four-dimensional computed tomography (4D-CT) image data acquired during tidal breathing. Volumetric image data were acquired for 5 non-severe and one severe asthmatic volunteers. Besides 4D-CT image data, function residual capacity and total lung capacity image data during breath-hold were acquired for comparison with dynamic scans. Quantitative results were compared with the previously reported analysis of five healthy human lungs. Using an image registration technique, local variables such as regional ventilation and anisotropic deformation index (ADI) were estimated. Regional ventilation characteristics of non-severe asthmatic subjects were similar to those of healthy subjects, but different from the severe asthmatic subject. Lobar airflow fractions were also well correlated between static and dynamic scans (R2>0.84). However, local ventilation heterogeneity significantly increased during tidal breathing in both healthy and asthmatic subjects relative to that of breath-hold perhaps because of airway resistance present only in dynamic breathing. ADI was used to quantify non-linearity and hysteresis of lung motion during tidal breathing. Non-linearity was greater on inhalation than exhalation among all subjects. However, exhalation non-linearity among asthmatic subjects was greater than healthy subjects and the difference diminished during inhalation. An increase of non-linearity during exhalation in asthmatic subjects accounted for lower hysteresis relative to that of healthy ones. Thus, assessment of non-linearity differences between healthy and asthmatic lungs during exhalation may provide quantitative metrics for subject identification and outcome assessment of new interventions.

Safety of incremental inhaled lipopolysaccharide challenge in humans.

BACKGROUND: Inhalation of environmental endotoxin is important in the pathogenesis of asthma and other environmental airway diseases. Inhaled airway challenge using lipopolysaccharide in humans has been performed for over 20 years to assess the airway response to endotoxin. However, there are no published data on the short-term safety of endotoxin inhalation protocols. OBJECTIVE: To characterize the safety and tolerability of incremental inhaled lipopolysaccharide challenge in humans. PATIENTS AND METHODS: We performed a retrospective analysis of data obtained from 119 subjects who underwent inhaled challenge with up to 41.5 mug of lipopolysaccharide. We measured pulmonary function, temperature, mean arterial pressure, heart rate, and systemic symptoms for 3 h after challenge. RESULTS: Fever occurred in 30% of subjects and was associated with a higher cumulative dose of lipopolysaccharide. Reduced mean arterial pressure occurred in 21% of subjects and was dose-related. There was no association between fever or decreased mean arterial pressure and airway responsiveness to inhaled lipopolysaccharide. Common symptoms reported by subjects included: chills (64%), malaise (56%), cough (56%), chest tightness (49%), headache (43%), and myalgias (27%). None of the subjects experienced delayed discharge or a serious adverse event. CONCLUSIONS: Inhaled lipopolysaccharide causes dose-related systemic responses that include fever, reduced blood pressure, and constitutional symptoms that are not associated with the airway response to inhaled lipopolysaccharide. Systemic responses to inhaled lipopolysaccharide should be expected and subjects undergoing inhaled lipopolysaccharide challenge in the research setting should be carefully monitored for non-pulmonary adverse events for several hours after challenge.

School proximity to concentrated animal feeding operations and prevalence of asthma in students.

STUDY OBJECTIVES: Asthma prevalence and severity are rising in industrialized nations. Studies supporting the hygiene hypothesis suggest that being raised on a farm protects against atopy and, often, asthma. In rural United States, however, an increased rate of asthma has been found among schoolchildren. We hypothesized that the rural US environment may not be protective against airway inflammation, perhaps due to environmental effluents from a relatively high number of concentrated animal feeding operations (CAFOs). We compared the prevalence of asthma in two Iowa elementary schools, one adjacent to a CAFO, and the other distant from any large-scale farming operations. DESIGN: Cross-sectional questionnaire-based study. SETTING: Two rural Iowa elementary schools: the study school is located one-half mile from a CAFO, and the control school is distant from any large-scale agricultural operation. PARTICIPANTS: Children, kindergarten through grade 5, who attended either the study school or the control school. RESULTS: Children in the study school had a significantly increased prevalence of physician-diagnosed asthma (adjusted odds ratio, 5.71; p = 0.004). Although this group was more likely to live on a farm and have parents who smoke, these potentially confounding variables did not account for increased prevalence in a multivariate model. No difference in measures of asthma severity was found between the two populations. Because different sets of physicians are responsible for the medical care of the groups of children, it is possible that physician bias is responsible for the different prevalence of asthma diagnoses. This was not explored in the study. CONCLUSIONS: This study supports a role for exposure to rural environmental toxicants in the etiology of asthma, and suggests a need for further study of this relationship.