Asthma and respiratory physiology: Putting lung function into perspective

Juan Carlos Ivancevich Tuesday, 29 July 2014 11:42

Respirology

Giuseppe Francesco Sferrazza Papa,Giulia Michela Pellegrino and Riccardo Pellegrino. Article first published online: 24 JUL 2014 DOI: 10.1111/resp.12355 © 2014 Asian Pacific Society of Respirology

Bronchial asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation and remodelling. The hypothesis that the illness is inflammatory in nature has recently been challenged by studies showing that airway smooth muscle (ASM) plays a more important role than previously thought. For example, it is now known that in asthma patients, ASM proliferates more and faster than in healthy subjects, carries intrinsic defects and exhibits impaired relaxation, increased velocity of shortening, plastic adaptation to short length and perturbed equilibrium of actin-to-myosin during cycling. Similar conclusions can be drawn from studies on airway mechanics. For instance, in asthma, abnormal ASM contributes to limiting the response to deep lung stretching and accelerates the return of bronchial tone to baseline conditions, and contributes to increased airway stiffness. Upon stimulation, ASM causes airway narrowing that is heterogeneous across the lung and variable over time. This heterogeneity leads to patchy ventilation. Experimental studies have shown that patchy ventilation may precipitate an asthma attack, and inability to maintain bronchial tone control over time can predict the occurrence of bronchospastic attacks over a matter of a few days. To improve our knowledge on the pathogenesis of asthma, we believe that it is necessary to explore the disease within the framework of the topographical, volume and time domains of the lung that play an important role in setting the severity and progression of the disease. Application of the forced oscillation technique and multiple breath nitrogen washout may, alone or in combination, help address questions unsolvable until now.

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Long-acting beta-agonists plus inhaled corticosteroids safety: a systematic review and meta-analysis of non-randomized studies

Juan Carlos Ivancevich Tuesday, 22 July 2014 14:28
Open Access
 
Research

Gimena HernándezMónica AvilaÀngels PontOlatz GarinJordi AlonsoLaurent Laforest,Christopher J Cates and Montserrat Ferrer

Respiratory Research 2014, 15:83  doi:10.1186/1465-9921-15-83

Published: 19 July 2014
 

Abstract (provisional)

Background

Although several systematic reviews investigated the safety of long-acting beta-agonists (LABAs) in asthma, they mainly addressed randomized clinical trials while evidence from non-randomized studies has been mostly neglected. We aim to assess the risk of serious adverse events in adults and children with asthma treated with LABAs and Inhaled Corticosteroids (ICs), compared to patients treated only with ICs, from published non-randomized studies.

Methods

The protocol registration number was CRD42012003387 (http://www.crd.york.ac.uk/Prospero). Literature search for articles published since 1990 was performed in MEDLINE and EMBASE. Two authors selected studies independently for inclusion and extracted the data. A third reviewer resolved discrepancies. To assess the risk of serious adverse events, meta-analyses were performed calculating odds ratio summary estimators using random effect models when heterogeneity was found, and fixed effect models otherwise.

Results

Of 4,415 candidate articles, 1,759 abstracts were reviewed and 220 articles were fully read. Finally, 19 studies met the inclusion criteria. Most of them were retrospective observational cohorts. Sample sizes varied from 50 to 514,216. The meta-analyses performed (69,939-624,303 participants according to the outcome considered) showed that odds ratio of the LABAs and ICs combined treatment when compared with ICs alone was: 0.88 (95%CI 0.69-1.12) for asthma-related hospitalization; 0.75 (95%CI 0.66-0.84) for asthma-related emergency visits; 1.02 (95%CI 0.94-1.10) for systemic corticosteroids; and 0.95 (95%CI 0.9-1.0) for the combined outcome.

Conclusions

Evidence from observational studies shows that the combined treatment of LABAs and ICs is not associated with a higher risk of serious adverse events, compared to ICs alone. Major gaps identified were prospective design, paediatric population and inclusion of mortality as a primary outcome.

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Differential serum protein markers and the clinical severity of asthma

Super User Thursday, 26 June 2014 19:03
 

Authors: Norbert Meyer,1,2 Sarah Janine Nuss,1 Thomas Rothe,1 Alexander Siebenhüner,1 Cezmi A Akdis,2Günter Menz1

Published Date April 2014 Volume 2014:7 Pages 67 - 75

DOI: http://dx.doi.org/10.2147/JAA.S53920
1Hochgebirgsklinik Davos, Davos-Wolfgang, Switzerland; 2Swiss Institute of Allergy and Asthma Research (SIAF), Davos Platz, Switzerland

Background: Asthma is a heterogeneous disease characterized by different clinical phenotypes and the involvement of multiple inflammatory pathways. During airway inflammation, many cytokines and chemokines are released and some are detectable in the sera.
Objective: Serum chemokines and cytokines, involved in airway inflammation in asthma patients, were investigated.
Methods: A total of 191 asthma patients were classified by hierarchical cluster analysis, including the following parameters: forced expiratory volume in 1 second (FEV1), eosinophil cationic protein (ECP) serum levels, blood eosinophils, Junipers asthma symptom score, and the change in FEV1, ECP serum levels, and blood eosinophils after 3 weeks of asthma therapy. Serum proteins were measured by multiplex analysis. Receiver operating characteristic (ROC) curves were used to evaluate the validity of serum proteins for discriminating between asthma clusters.
Results: Classification of asthma patients identified one cluster with high ECP serum levels, increased blood eosinophils, low FEV1 values, and good FEV1 improvement in response to asthma therapy (n=60) and one cluster with low ECP serum levels, low numbers of blood eosinophils, higher FEV1 values, and no FEV1 improvement in response to asthma therapy (n=131). Serum interleukin (IL)-8, eotaxin, vascular endothelial growth factor (VEGF), cutaneous T-cell-attracting chemokine (CTACK), growth-related oncogene (GRO)-α, and hepatocyte growth factor (HGF) were significantly different between the two clusters of asthma patients. ROC analysis for serum proteins calculated a sensitivity of 55.9% and specificity of 75.8% for discriminating between them.
Conclusion: Serum cytokine and chemokine levels might be predictors for the severity of asthmatic inflammation, asthma control, and response to therapy, and therefore might be useful for treatment optimization.

Keywords: asthma, cluster, phenotype, serum cytokines
 
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Gene - Gene Interactions Among MCP Genes Polymorphisms in Asthma

Juan Carlos Ivancevich Thursday, 10 July 2014 15:25
Allergy Asthma Immunol Res. 2014 Jul;6(4):333-340. English.
Published online 2014 April 07.  http://dx.doi.org/10.4168/aair.2014.6.4.333 
Copyright © 2014 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease
   
 
June-Hyuk Lee and Choon-Sik Park
Respiratory and Allergy Medicine, Interanl Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.

 Correspondence to: Choon-Sik Park, MD, PhD, Respiratory and Allergy Medicine, Interanl Medicine, Soonchunhyang University Bucheon Hospital, 170 Jomaru-ro, Wonmi-gu, Bucheon 420-021, Korea. Tel: +82-32-621-5105; Fax: +82-32-621-5016; Email: This email address is being protected from spambots. You need JavaScript enabled to view it.  
 

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

Purpose

Monocyte chemoattractant proteins (MCPs) are important cytokines that involved in cellular activation and releasing of inflammatoy mediators by basophils and eosinophils in allergic disease. Some MCP gene variants implicate in asthma and monoclonal antibody for MCP-3 blocks allergic inflammations in the patients with asthma. Detection of interactions between gene and environment or between genes for complex disease such as asthma is important. We searched for an evidence of genetic effect of single nucleotide polymorphisms (SNPs) of MCP genes as well as gene - gene interactions involved in asthma.

Methods

Four hundreds asthmatics and four hundreds normal controls were enrolled. Asthma was defined as a positive bronchodilator response or positive methacholine provocation test with compatible clinical symptoms. Seven MCP gene SNPs (2 SNPs in MCP-1, 1 in MCP-2, and 4 in MCP-3) were included. Association analyses between SNP and asthma, and the tests for gene - gene interaction were performed.

Results

Strong linkage disequilibria were found among 7 MCP gene polymorphisms. There was no SNP that showed a significant association with asthma among 7 SNPs of 3 MCP genes. No haplotype was associated with asthma, either. The combination of MCP1-2518G>AMCP2+46A>C, and MCP3+563C>T was the best predictive model for asthma as compared to the control in tests for gene - gene interaction. The MCP1-2518G>A and MCP2+46A>C was the second best predictive combination and this had the highest synergistic interaction effect on the subject's status than any other combination of polymorphisms. Complete linkages were not associated with the gene - gene interactions models.

Conclusions

MCP gene polymorphisms probably interact with each other; thus, these findings may help in developing a possible genetic marker to predict asthma.

The role of macrolides in asthma: current evidence and future directions

Super User Wednesday, 25 June 2014 14:45
The Lancet Respiratory Medicine
 
The Lancet Respiratory Medicine, Early Online Publication, 17 June 2014
doi:10.1016/S2213-2600(14)70107-9 Cite or Link Using DOI
This article can be found in the following collections: Infectious Diseases (Anti-infective therapy); Respiratory Medicine (Asthma)
 

The role of macrolides in asthma: current evidence and future directions

Ernie H C Wong MBBS a b c dJames D Porter MSc a b cMichael R Edwards PhD a b cProf Sebastian L Johnston FRCP a b c d Corresponding AuthorThis email address is being protected from spambots. You need JavaScript enabled to view it.

Summary

Macrolides, such as clarithromycin and azithromycin, possess antimicrobial, immunomodulatory, and potential antiviral properties. They represent a potential therapeutic option for asthma, a chronic inflammatory disorder characterised by airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Results from clinical trials, however, have been contentious. The findings could be confounded by many factors, including the heterogeneity of asthma, treatment duration, dose, and differing outcome measures. Recent evidence suggests improved effectiveness of macrolides in patients with sub-optimally controlled severe neutrophilic asthma and in asthma exacerbations. We examine the evidence from clinical trials and discuss macrolide properties and their relevance to the pathophysiology of asthma. At present, the use of macrolides in chronic asthma or acute exacerbations is not justified. Further work, including proteomic, genomic, and microbiome studies, will advance our knowledge of asthma phenotypes, and help to identify a macrolide-responsive subgroup. Future clinical trials should target this subgroup and place emphasis on clinically relevant outcomes such as asthma exacerbations.
 
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