Severe Asthma and Biological Therapy: When, Which, and for Whom

Asthma is a heterogeneous chronic inflammatory disease of the airways that affects approximately 300 million people worldwide. About 5–10% of all asthmatics suffer from severe or uncontrolled asthma, associated with increased mortality and hospitalization, reduced quality of life, and increased health care costs. In recent years, new treatments have become available, and different asthma phenotypes characterized by specific biomarkers have been identified. Biological drugs are currently indicated for patients with severe asthma that is not controlled with recommended treatments. They are mostly directed against inflammatory molecules of the type 2 inflammatory pathway and are effective at reducing exacerbations, maintaining control over asthma symptoms, and reducing systemic steroid use, which is associated with well-known adverse events. Although biological drugs for severe asthma have had a major impact on the management of the disease, there is still a need for head-to-head comparison studies of biologics and to identify new biomarkers for asthma diagnosis, prognosis, and response to treatment. Identifying novel biomarkers could facilitate the development of therapeutic strategies that are precisely tailored to each patient’s requirements

Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD

SummaryBackgroundCombining maintenance medications with different mechanisms of action may improve outcomes in COPD. In this study we evaluated the efficacy and safety of fluticasone/salmeterol (FSC) (250/50 mcg twice daily) when added to tiotropium (18 mcg once daily) (TIO) in subjects with symptomatic moderate to severe COPD.MethodsThis was a 24-week, randomized, double-blind, parallel group, multi-center study. Subjects 40 years or older with cigarette smoking history ≥10 pack-years and with the diagnosis of COPD and post-bronchodilator FEV1 ≥40 to ≤ 80% of predicted normal and FEV1/FVC of ≤0.70 were enrolled. Following a 4-week treatment with open-label TIO 18 mcg once daily, subjects were randomized in a double-blind fashion to either the addition of FSC 250/50 DISKUS twice daily or matching placebo. The primary efficacy endpoint was AM pre-dose FEV1 and secondary endpoints included other measures of lung function, rescue albuterol use, health status and exacerbations.ResultsThe addition of FSC to TIO significantly improved lung function indices including AM pre-dose FEV1, 2 h post-dose FEV1, AM pre-dose FVC, 2 h post-dose FVC and AM pre-dose IC compared with TIO alone. Furthermore, this combination was superior to TIO alone in reducing rescue albuterol use. However, there were no significant differences between the treatment groups in health status or COPD exacerbations. The incidence of adverse events was similar in both groups.ConclusionsThe addition of FSC to subjects with COPD treated with TIO significantly improves lung function without increasing the risk of adverse events. NCT00784550

An Official American Thoracic Society Workshop Report: Evaluation and Management of Asthma in the Elderly

Asthma in the elderly (>65 yr old) is common and associated with higher morbidity and mortality than asthma in younger patients. The poor outcomes in this group are due, in part, to underdiagnosis and undertreatment. There are a variety of factors related to aging itself that affect the presentation of asthma in the elderly and influence diagnosis and management. Structural changes in the aging lung superimposed on structural changes due to asthma itself can worsen the disease and physiologic function. Changes in the aging immune system influence the cellular composition and function in asthmatic airways. These processes and differences from younger individuals with asthma are not well understood. Phenotypes of asthma in the elderly have not been clearly delineated, but it is likely that age of onset and overlap with chronic obstructive pulmonary disease impact disease characteristics. Physiologic tests and biomarkers used to diagnose and follow asthma in the elderly are generally similar to testing in younger individuals; however, whether they should be modified in aging has not been established. Confounding influences, such as comorbidities (increasing the risk of polypharmacy), impaired cognition and motor skills, psychosocial effects of aging, and age-related adverse effects of medications, impact both diagnosis and treatment of asthma in the elderly. Future efforts to understand asthma in the elderly must include geriatric-specific methodology to diagnose, characterize, monitor, and treat their disease

Age-Related Differences in Health-Related Quality of Life in COPD

OBJECTIVE: Younger persons with COPD report worse health-related quality of life (HRQL) than do older individuals. The factors explaining these differences remain unclear. The objective of this article was to explore factors associated with age-related differences in HRQL in COPD. METHODS: Cross-sectional analysis of participants with COPD, any Global Initiative for Chronic Obstructive Lung Disease grade of airflow limitation, and ≥ 50 years old in two cohorts: the Genetic Epidemiology of COPD (COPDGene) study and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). We compared St. George's Respiratory Questionnaire (SGRQ) scores by age group: middle-aged (age, 50-64) vs older (age, 65-80) adults. We used multivariate linear modeling to test associations of age with HRQL, adjusting for demographic and clinical characteristics and comorbidities. RESULTS: Among 4,097 participants in the COPDGene study (2,170 middle-aged and 1,927 older adults) SGRQ total scores were higher (worse) among middle-aged (mean difference, -4.2 points; 95% CI, -5.7 to -2.6; P < .001) than older adults. Age had a statistically significant interaction with dyspnea (P < .001). Greater dyspnea severity (modified Medical Research Council ≥ 2, compared with 0-1) had a stronger association with SGRQ score among middle-aged (β, 24.6; 95% CI, 23.2-25.9) than older-adult (β, 21.0; 95% CI, 19.6-22.3) participants. In analyses using SGRQ as outcome in 1,522 participants in SPIROMICS (598 middle-aged and 924 older adults), we found similar associations, confirming that for the same severity of dyspnea there is a stronger association with HRQL among younger individuals. CONCLUSIONS: Age-related differences in HRQL may be explained by a higher impact of dyspnea among younger subjects with COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764 and No.: NCT01969344; URL: www.clinicaltrials.gov

A Simplified Score to Quantify Comorbidity in COPD

Importance Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes. Materials and Methods Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS. Results Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341). Conclusions Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD

Inhaled ciclesonide versus inhaled budesonide or inhaled beclomethasone or inhaled fluticasone for chronic asthma in adults: a systematic review

BACKGROUND: Ciclesonide is a new inhaled corticosteroids licensed for the prophylactic treatment of persistent asthma in adults. Currently beclomethasone dipropionate, budesonide and fluticasone propionate are the most commonly prescribed inhaled corticosteroids for the treatment of asthma but there has been no systematic review comparing the effectiveness and safety ciclesonide to these agents. We therefore aimed to systematically review published randomised controlled trials of the effectiveness and safety of ciclesonide compared to alternative inhaled corticosteroids in people with asthma. METHODS: We performed literature searches on MEDLINE, EMBASE, PUBMED, the COCHRANE LIBRARY and various Internet evidence sources for randomised controlled trials or systematic reviews comparing ciclesonide to beclomethasone or budesonide or fluticasone in adult humans with persistent asthma. Data was extracted by one reviewer. RESULTS: Five studies met the inclusion criteria. Methodological quality was variable. There were no trials comparing ciclesonide to beclomethasone. There was no significant difference between ciclesonide and budesonide or fluticasone on the following outcomes: lung function, symptoms, quality of life, airway responsiveness to a provoking agent or inflammatory markers. However, the trials were very small in size, increasing the possibility of a type II error. One trial demonstrated that the combined deposition of ciclesonide (and its active metabolite) in the oropharynx was 47% of that of budesonide while another trial demonstrated that the combined deposition of ciclesonide (and its active metabolite) in the oropharynx was 53% of that of fluticasone. One trial demonstrated less suppression of cortisol in overnight urine collection after ciclesonide compared to fluticasone (geometric mean fold difference = 1.5, P < 0.05) but no significant difference in plasma cortisol response. CONCLUSION: There is very little evidence comparing CIC to other ICS, restricted to very small, phase II studies of low power. These demonstrate CIC has similar effectiveness and efficacy to FP and BUD (though equivalence is not certain) and findings regarding oral deposition and HPA suppression are inconclusive. There is no direct comparative evidence that CIC causes fewer side effects since none of the studies reported patient-based outcomes

Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures

Samples of human and rat skin in short-term organ culture exposed to ALA or a range of hydrophobic derivatives were examined for their effect on the accumulation of protoporphyrin IX (PpIX) measured using fluorescence spectroscopy. With the exception of carbobenzoyloxy-D-phenylalanyl-5-ALA-ethyl ester the data presented indicate that, in normal tissues, ALA derivatives generate protoporphyrin IX more slowly than ALA, suggesting that they are less rapidly taken up and/or converted to free ALA. However, the resultant depot effect may lead to the enhanced accumulation of porphyrin over long exposure periods, particularly in the case of ALA-methyl ester or ALA-hexyl ester, depending on the applied concentration and the exposed tissue. Addition of the iron chelator, CP94, greatly increased PpIX accumulation in human skin exposed to ALA, ALA-methyl ester and ALA-hexyl ester. The effect in rat skin was less marked.</p

InforMing the PAthway of COPD Treatment (IMPACT Trial) Single-Inhaler Triple Therapy (Fluticasone Furoate/Umeclidinium/Vilanterol) Versus Fluticasone Furoate/Vilanterol and Umeclidinium/Vilanterol in Patients With COPD: Analysis o the Western Europe and North America Regions

Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by airflow limitation and progressive respiratory symptoms.1 Global public health trends estimate that the COPD burden will continue to rise, with COPD deaths estimated to increase to 4.4% of all deaths in Europe and 6.3% in the World Health Organization-defined region of the Americas by 2060.2 There are differences in the COPD burden in different regions reflecting variations in etiology,3,4 disease severity,5 symptoms,6 medication use,7 and health care systems and utilization.7 These differences may help inform therapeutic strategies to optimize therapeutic approaches to reducing symptoms and exacerbation risk.1 In the global InforMing the PAthway of COPD Treatment (IMPACT) trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates and improved lung function and health-related quality of life versus FF/VI or UMEC/VI dual therapy in patients ≥40 years of age with symptomatic COPD and a history of exacerbations.8 Within trial populations, regional differences such as patient characteristics, treatment patterns, access to care and cultural/socioeconomic factors may dictate treatment choices and influence disease severity and progression in particular geographical locations. For example, a meta-analysis conducted in 2015 comprising 123 studies between 1990 and 2010 found that the overall prevalence of COPD as well as the rate of increase was higher in the Americas (including both North and South America) compared with Europe.9 Furthermore, a cross-sectional study assessing the burden of COPD symptoms in the United States and Europe found variations between patients across countries who had experienced at least 1 symptom of COPD.10 In Europe, patients with more frequent symptoms were more likely to experience worsening of symptoms and unexpected hospitalization. Whereas in the United States, patients with more frequent symptoms were not only more likely to experience worsening of symptoms but also longer lasting symptoms and a longer length of exacerbations.10 A further difference was that treatment adherence was higher in the United States than Europe, however, adherence was consistent across patients in Europe when assessed by modified Global initiative for chronic Obstructive Lung Disease (GOLD) 2014 groups11 but varied in the United States with adherence highest in the GOLD Group C and lowest in Group A.10 Therefore, it is important to evaluate how overall population results pertain to patients treated in particular regions. As IMPACT is one of the largest trials conducted in patients with COPD to date, we have the unique opportunity to analyze study outcomes in patients enrolled in Western Europe and North America, the 2 main regions from an enrollment perspective

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis