Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles

Juan Carlos Ivancevich Wednesday, 15 April 2015 15:54


Children with problematic severe asthma have poor disease control despite high doses of inhaled corticosteroids and additional therapy, leading to personal suffering, early deterioration of lung function, and significant consumption of health care resources. If no exacerbating factors, such as smoking or allergies, are found after extensive investigation, these children are given a diagnosis of therapy-resistant (or therapy-refractory) asthma (SA).


We sought to deepen our understanding of childhood SA by analyzing gene expression and modeling the underlying regulatory transcription factor networks in peripheral blood leukocytes.


Gene expression was analyzed by using Cap Analysis of Gene Expression in children with SA (n = 13), children with controlled persistent asthma (n = 15), and age-matched healthy control subjects (n = 9). Cap Analysis of Gene Expression sequencing detects the transcription start sites of known and novel mRNAs and noncoding RNAs.


Sample groups could be separated by hierarchical clustering on 1305 differentially expressed transcription start sites, including 816 known genes and several novel transcripts. Ten of 13 tested novel transcripts were validated by means of RT-PCR and Sanger sequencing. Expression of RAR-related orphan receptor A (RORA), which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with SA. Gene network modeling revealed decreased glucocorticoid receptor signaling and increased activity of the mitogen-activated protein kinase and Jun kinase cascades in patients with SA.


Circulating leukocytes from children with controlled asthma and those with SA have distinct gene expression profiles, demonstrating the possible development of specific molecular biomarkers and supporting the need for novel therapeutic approaches.

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Web Based Listing of Agents Associated with New Onset Work-Related Asthma

Juan Carlos Ivancevich Wednesday, 08 April 2015 12:59



Work-related asthma is common and yet remains a challenge to diagnose. Access to a listing of agents associated with work-related asthma has been suggested as useful in assisting in the diagnosis.


The Association of Occupational and Environmental Clinics (AOEC) developed criteria that were used to review the peer-reviewed medical literature published in English. Based on this review, substances were designated either as a sensitizing agent or an irritant. The reviews were conducted by a board certified internist/pulmonologist/occupational medicine specialist from 2002-2007 and a board certified internist/occupational medicine physician from 2008- date. All reviews were then reviewed by the nine member AOEC board of directors.


The original list of agents associated with new onset work-related asthma was derived from the tables of a text book on work-related asthma. After 13 years of review, there are 327 substances designated as asthma agents on the AOEC list; 173 (52.9%) coded as sensitizers, 35 (10.7%) as generally recognized as an asthma causing agent, four (1.2%) as irritants, two (0.6%) as both a sensitizer and an irritant and 113(34.6%) agents that still need to be reviewed.


The AOEC has developed a readily available web based listing of agents associated with new onset work-related asthma in adults. The listing is based on peer-reviewed criteria. The listing is updated twice a year. Regular review of the peer-reviewed medical literature is conducted to determine whether new substances should be added to the list. Clinicians should find the list useful when considering the diagnosis of work-related asthma.


Lung function changes from childhood to adolescence: a seven-year follow-up study

Juan Carlos Ivancevich Saturday, 04 April 2015 11:30
Open Access
Research article
Pavilio PiccioniRoberta TassinariAurelia CarossoCarlo CarenaMassimiliano Bugiani and Roberto Bono
Abstract (provisional) 
Background As part of an investigation into the respiratory health in children conducted in Torino, northwestern Italy, our aim was to assess development in lung function from childhood to adolescence, and to assess changes or persistence of asthma symptoms on the change of lung function parameters. Furthermore, the observed lung function data were compared with the Global Lung Function Initiative (GLI) reference values.

Methods We conducted a longitudinal study, which lasted 7 years, composed by first survey of 4–5 year-old children in 2003 and a follow-up in 2010. Both surveys consisted in collecting information on health by standardized SIDRIA questionnaire and spirometry testing with FVC, FEV1, FEV1/FVC% and FEF25–75 measurements. Results 242 subjects successfully completed both surveys. In terms of asthma symptoms (AS = asthma attacks or wheezing in the previous 12 months), 191/242 were asymptomatic, 13 reported AS only in the first survey (early transient), 23 had AS only in the second survey (late onset), and 15 had AS in both surveys (persistent). Comparing the lung function parameters observed with the predicted by GLI only small differences were detected, except for FVC and FEF25–75, for which more than 5% of subjects had Z-score values beyond the Z-score normal limits. Furthermore, as well as did not significantly affect developmental changes in FVC and FEV1, the decrease in FEV1/FVC ratio was significantly higher in subjects with AS at the time of follow-up (late onset and persistent phenotypes) while the increase in FEF25–75 was significantly smaller in subjects with persistent AS (p - 0.05).

Conclusions The GLI equations are valid in evaluating lung function during development, at least in terms of lung volume measurements. Findings also suggest that the FEF25–75 may be a useful tool for clinical and epidemiological studies of childhood asthma.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Stratification of patients with severe asthma

Juan Carlos Ivancevich Monday, 06 April 2015 02:01
Targeting interleukin 5 for eosinophilic asthma – discussion with Jean Bousquet and Richard Lane
Increased eosinophil counts have been recognised to be linked to asthma severity and are a risk factor for asthma exacerbations. Therefore, decreasing eosinophil count by targeting the interleukin-5-mediated signalling pathway could help to reduce airway inflammation and improve asthma treatment control. In The Lancet Respiratory Medicine, Mario Castro and colleagues1 report data from two large, randomised, placebo-controlled trials, in which reslizumab, a neutralising monoclonal antibody for interleukin 5, was safe and effective in patients with severe eosinophilic asthma.
Supplementary audio

This article is available free of charge.


Eosinophilia in asthma: the easy way is not always the best

Juan Carlos Ivancevich Monday, 30 March 2015 13:13
According to the latest version of the Global Initiative for Asthma strategy document,1 asthma is a heterogeneous disease with clinical manifestations sustained by different molecular mechanisms; in particular, these manifestations could be (but are not invariably) associated with chronic airway inflammation. Indeed, part of the heterogeneity of asthma might be due to different intensities or patterns of airway inflammation (eg, eosinophilic vs neutrophilic).
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