Joe W. Ramsdell

Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma

BACKGROUND Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed. METHODS In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison). RESULTS The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003). CONCLUSIONS When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).

Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial

BACKGROUND Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid. METHODS In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967. FINDINGS After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures. INTERPRETATION In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine. FUNDING National Institutes of Health.

Estrogen replacement therapy and the risk of venous thrombosis

PURPOSE Estrogen replacement therapy is believed by many physicians to cause thrombophlebitis and to be contraindicated in women at risk for this disease. However, clinical data supporting this assumption are scant, and further investigation is required. PATIENTS AND METHODS We tested the estrogen-thrombophlebitis association in a case-control study. Charts of all consecutive women aged 45 years or older with a primary or secondary discharge diagnosis of thrombophlebitis, venous thrombosis, or pulmonary embolism were reviewed; 121 cases and 236 controls matched for age, year of admission, admitting service, and socioeconomic status were obtained. Hormone use and nonuse were validated in a subset of randomly selected women. RESULTS Cases and controls, whose average age was 65 years, did not differ significantly on matching variables or on current use of exogenous estrogen (5.1% of cases versus 6.3% of controls). Other analyses that variously excluded women with a past history of thrombosis, women less than 50 years of age, women with thrombosis occurring after admission, and women whose estrogen use was indeterminate also did not support an increased risk of thrombotic disease. Adjustment for the presence of independent thrombotic risk factors did not alter the odds ratio for estrogen use. CONCLUSION This case-control study of older women, unselected for other thrombotic risk factors, does not support the commonly held assumption that replacement estrogen increases the risk of venous thrombosis.

Asthma in the elderly: Current understanding and future research needs—a report of a National Institute on Aging (NIA) workshop

Asthma in the elderly is underdiagnosed and undertreated, and there is a paucity of knowledge on the subject. The National Institute on Aging convened this workshop to identify what is known and what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of asthma in the elderly. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger patients, but comorbid illnesses and the psychosocial effects of aging might affect the diagnosis, clinical presentation, and care of asthma in this population. At least 2 phenotypes exist among elderly patients with asthma; those with longstanding asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiologic mechanisms of asthma in the elderly are likely to be different from those seen in young asthmatic patients, and these differences might influence the clinical course and outcomes of asthma in this population.

Desert dust exposure is associated with increased risk of asthma hospitalization in children.

RATIONALE Desert dust particles, including quartz, which causes inflammatory responses in the airway in animal studies, are transported to widespread regions around the globe. Epidemiologically, areas impacted by desert dust storms, such as communities in the Middle East and the Caribbean, seem to have higher incidences of asthma than might be expected. OBJECTIVES We investigated the magnitude of association between airborne mineral dust concentration and hospitalization of children for asthma exacerbation by using Light Detection And Ranging (LIDAR) with a polarization analyzer for an exposure measurement, which can distinguish mineral dust particles from other particles. METHODS A case-crossover design was used. The exposure measurement was LIDARs nonspherical extinction coefficient. The outcome measurement was hospitalization of children aged 1 to 15 years for asthma exacerbation in eight principal hospitals in Toyama, a local area in Japan bordering the Japan Sea, during February to April, 2005 to 2009. MEASUREMENTS AND MAIN RESULTS During the study period, there were 620 admissions for asthma exacerbation, and 6 days with a heavy dust event (daily mineral dust concentration > 0.1 mg/m(3)). Conditional logistic regression showed a statistically significant association between asthma hospitalization and a heavy dust event. The crude odds ratio (OR) of the heavy dust event for hospitalization on the day was 1.88 (95% confidence interval [CI], 1.04-3.41; P = 0.037), and the OR of heavy dust event during the previous week was 1.83 (95% CI, 1.31-2.56; P = 0.00043). The OR adjusted by other air pollutant levels, pollen, and meteorological factors was 1.71 (95% CI, 1.18-2.48; P = 0.0050). CONCLUSIONS Heavy dust events are associated with an increased risk of hospitalizations for asthma.

Effect of medical records' checklists on implementation of periodic health measures

Recent re-evaluation of preventive health care has resulted in more limited and directed guidelines; nonetheless, physician compliance has remained poor. This study assessed whether an inexpensive reminder system of preventive care checklists would improve physician implementation of periodic health measures. Residents in internal medicine were randomly placed into two groups: one received a copy of the appropriate checklist with each patients medical record; the other did not. After one year, 200 randomly selected records were audited to determine the proportion of recommendations implemented for each patient. Residents who received checklists performed appropriate preventive health measures at a significantly higher rate than those who did not (0.56 +/- 0.26 versus 0.39 +/- 0.22, p less than 0.002). The actual use of the checklist to record the results was associated with an even higher rate of compliance compared with instances in which the checklists were provided but not used and instances in which checklists were not received (0.70 +/- 0.21 versus 0.44 +/- 0.24 and 0.39 +/- 0.22, respectively, p less than 0.002). These data suggest that a physicians use of simple checklists can provide an inexpensive and effective means of improving implementation of periodic health maintenance.

The clinical and genetic features of COPD-asthma overlap syndrome

Individuals with chronic obstructive pulmonary disease (COPD) and asthma are an important but poorly characterised group. The genetic determinants of COPD and asthma overlap have not been studied. The aim of this study was to identify clinical features and genetic risk factors for COPD and asthma overlap. Subjects were current or former smoking non-Hispanic whites or African–Americans with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40 years. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the non-Hispanic whites and African–American populations, and combined these results in a meta-analysis. More females and African–Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema and greater airway wall thickness compared to subjects with COPD alone. The non-Hispanic white GWAS identified single nucleotide polymorphisms in the genes CSMD1 (rs11779254, p=1.57×10−6) and SOX5 (rs59569785, p=1.61×10−6) and the meta-analysis identified single nucleotide polymorphisms in the gene GPR65 (rs6574978, p=1.18×10−7) associated with COPD and asthma overlap. Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD and asthma overlap is an important syndrome and may require distinct clinical management. We identified distinct clinical features and possible genetic risk factors for subjects with both COPD and asthma http://ow.ly/uWWBc

Adiponectin and Functional Adiponectin Receptor 1 Are Expressed by Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease

We screened bronchoalveolar lavage (BAL) fluids from COPD-E (chronic obstructive pulmonary disease-Emphysema) and control subjects using a 120 Ab cytokine array and demonstrated that adiponectin was highly expressed in BAL in COPD-E. An adiponectin ELISA confirmed that adiponectin was highly expressed in BAL in COPD-E compared with smokers and healthy control subjects. Immunohistochemistry studies of lung sections from subjects with COPD-E demonstrated that airway epithelial cells expressed significant levels of adiponectin and adiponectin receptor (AdipoR) 1 but not AdipoR2. In vitro studies with purified populations of human lung A549 epithelial cells demonstrated that they expressed both adiponectin and AdipoR1 (but not AdipoR2) as assessed by RT-PCR, Western blot, and immunohistochemistry. Lung A549 epithelial AdipoR1were functional as incubation with adiponectin induced release of IL-8, which was inhibited by small interfering RNA to AdipoR1. Using a mouse model of COPD, tobacco smoke exposure induced both evidence of COPD as well as increased levels of adiponectin in BAL fluid and increased adiponectin expression by airway epithelial cells. As adiponectin expression in adipocytes is dependent upon NF-κB we determined levels of adiponectin in tobacco smoke exposed CC10-Cretg/IkkβΔ/Δ mice (deficient in the ability to activate NF-κB in airway epithelium). These studies demonstrated that CC10-Cretg/IkkβΔ/Δ and wild-type mice had similar levels of BAL adiponectin and airway epithelial adiponectin immunostaining. Overall, these studies demonstrate the novel observation that adiponectin and functional AdipoR1are expressed by lung epithelial cells, suggesting a potential autocrine and/or paracrine pathway for adiponectin to activate epithelial cells in COPD-E.

Comparison of Physician-, Biomarker-, and Symptom-Based Strategies for Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma: The BASALT Randomized Controlled Trial

CONTEXT No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. OBJECTIVE To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma. DESIGN, SETTING, AND PARTICIPANTS A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. INTERVENTIONS For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. MAIN OUTCOME MEASURE The primary outcome was time to treatment failure. RESULTS There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). CONCLUSION Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00495157.

Nutritional Status of Free-Living Alzheimer’s Patients

Self-reported, dietary intake and biochemical estimates of thiamine, riboflavin, folate, vitamin B-12, protein, and iron were compared in 22, free-living elders by individuals who had senile dementia of the Alzheimers type (SDAT) and in 41 who were cognitively normal (CN). The two groups did not differ significantly in their intake of these nutrients or the number of deficiency states for intake (less than 67% RDA). Low serum transketolase (thiamin; p less than 0.055), red blood cell (RBC) folate (p less than 0.06), and serum vitamin B-12 (p less than 0.05) levels occurred more often in SDAT patients than in CN subjects. Individuals in both groups who used multivitamin supplements had significantly higher biochemical values for thiamine (p less than 0.03), riboflavin (p less than 0.01), and vitamin B-12 (p less than 0.003) than nonsupplement users. Because of the differences in vitamin B-12 and RBC folate levels between groups, a retrospective analysis was performed on a larger group of subjects drawn from a geriatric assessment clinic. Patients with SDAT had significantly lower serum vitamin B-12 (p less than 0.01) and lower RBC folate (p less than 0.03) values than CN subjects. Which mean values for vitamin B-12 and RBC folate were grouped by degree of impairment in SDAT subjects, vitamin B-12 was significantly lower in mildly and moderately impaired subjects than in those with normal cognition. Mean values for both nutrients did not differ significantly between severely impaired and CN subjects. There was a significant quadratic relationship between cognitive impairment and biochemical values for vitamin B-12.(ABSTRACT TRUNCATED AT 250 WORDS)