Severe refractory asthma: an update

1. Reinier R.L. Wener⇑ and 
2. Elisabeth H. Bel

+Author Affiliations

1. Dept of Respiratory Medicine, Academic Medical Centre, Amsterdam, The Netherlands

1. R.R.L. Wener, Dept of Respiratory Medicine, Academic Medical Center, P.O. Box 22660, 1100 DE Amsterdam, the Netherlands. E-mail: r.r.wener@amc.uva.nl

Abstract

Asthma is a heterogeneous disease in which adequate asthma control cannot be achieved in a substantial proportion despite currently available treatment possibilities. This subgroup has been defined as “severe refractory” asthma. Over the past years considerable progress has been made regarding a more exact definition of severe refractory asthma. A systematic approach to evaluate the asthma patient has been postulated. Further detailed classification into distinct phenotypes is ongoing to target the right treatment to the right patient. And, new therapeutic targeted treatment options are currently in development to provide possible new targets to improve disease state, symptoms and quality of life. This review will provide an update on the latest advancements with regard to all these domains.

This Article

1. doi:10.1183/09059180.00001913
   Eur Respir Rev September 1, 2013 vol. 22 no. 129227-235

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4. Disclosures

Footnotes

• Provenance: Publication of this peer-reviewed article was supported by the World Scleroderma Foundation, Switzerland (principal sponsor, European Respiratory Review issue 129).
• Conflict of interest: Disclosures can be found alongside the online version of this article at err.ersjournals.com

• Received March 30, 2013.
• Accepted April 25, 2013.

• ©ERS 2013

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• Future perspectives on rare pulmonary diseases and rare presentations of common disordersEur Respir Rev 2013 22:199-201
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Epidemiologic Methods of Assessing Asthma and Wheezing Episodes in Longitudinal Studies: Measures of Change and Stability.

J-STAGE Home  >  Publications - Top  > Bibliographic Information

Journal of Epidemiology
Article ID: JE20120201

Language:      English     Japanese   

http://dx.doi.org/10.2188/jea.JE20120201

 

DN/JST.JSTAGE/jea/JE2012020
1

  Advance Publication  

Nelís Soto-Ramírez¹⁾, Ali H. Ziyab²⁾, Wilfried Karmaus¹⁾, Hongmei Zhang²⁾, Ramesh J. Kurukulaaratchy³⁾, Susan Ewart⁴⁾, Syed Hasan Arshad³⁾

1) Division of Epidemiology, Biostatistics, and Environmental Health, University of Memphis 2) Department of Epidemiology and Biostatistics, University of South Carolina 3) David Hide Asthma and Allergy Research Centre, Isle of Wight, and University of Southampton 4) Michigan State University

 [Advance Publication] Released 2013/08/31

Keywords: asthma, cohort study, incidence, prevalence, trajectory, transition probability

•  Full Text PDF [474K]

• Abstracts
• References(24)

Background: In settings in which diseases wax and wane, there is a need to measure disease dynamics in longitudinal studies. Traditional measures of disease occurrence (eg, cumulative incidence) do not address change or stability or are limited to stable cohorts (eg, incidence) and may thus lead to erroneous conclusions. To illustrate how different measures can be used to detect disease dynamics, we investigated sex differences in the occurrence of asthma and wheezing, using a population-based study cohort that covered the first 18 years of life.
Methods: In the Isle of Wight birth cohort (n = 1456), prevalence, incidence, cumulative incidence, positive and negative transitions, and remission were determined at ages 1 or 2, 4, 10, and 18 years. Latent transition analysis was used to simultaneously identify classes of asthma and wheezing (related phenotypes) and characterize transition probabilities over time. Trajectory analysis was used to characterize the natural history of asthma and wheezing.
Results: Regarding time-specific changes, positive and negative transition probabilities were more informative than other measures of associations because they revealed a sex switchover in asthma prevalence (P < 0.05). Transition probabilities were able to identify the origin of a sex-specific dynamic; in particular, prior wheezing transitioned to asthma at age 18 years among girls but not among boys. In comparison with latent transition analysis, trajectory analysis did not directly identify a switchover in prevalence among boys and girls.
Conclusions: In longitudinal analyses, transition analyses that impose minimal restrictions on data are needed in order to produce appropriate information on disease dynamics.

•  Full Text PDF [474K]

Copyright © 2013 Nelís Soto-Ramírez et al. This is an open access article distributed under the terms of Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Key Role of Group V Secreted Phospholipase A2 in Th2 Cytokine and Dendritic Cell-Driven Airway Hyperresponsiveness and Remodeling

• PLoS One
• v.8(2); 2013
• PMC3581544

PLoS One. 2013; 8(2): e56172.

Published online 2013 February 25. doi:  10.1371/journal.pone.0056172

PMCID: PMC3581544

William R. Henderson Jr,1,* Xin Ye,1,¤ Ying Lai,2 Zhanglin Ni,2 James G. Bollinger,2 Ying-Tzang Tien,3 Emil Y. Chi,3and Michael H. Gelb2,4,*

Christian Taube, Editor

Author information ► Article notes ► Copyright and License information ►

Abstract

Background

Previous work has shown that disruption of the gene for group X secreted phospholipase A2 (sPLA2-X) markedly diminishes airway hyperresponsiveness and remodeling in a mouse asthma model. With the large number of additional sPLA2s in the mammalian genome, the involvement of other sPLA2s in the asthma model is possible – in particular, the group V sPLA2 (sPLA2-V) that like sPLA2-X is highly active at hydrolyzing membranes of mammalian cells.

Methodology and Principal Findings

The allergen-driven asthma phenotype was significantly reduced in sPLA2-V-deficient mice but to a lesser extent than observed previously in sPLA2-X-deficient mice. The most striking difference observed between the sPLA2-V and sPLA2-X knockouts was the significant impairment of the primary immune response to the allergen ovalbumin (OVA) in the sPLA2-V−/− mice. The impairment in eicosanoid generation and dendritic cell activation in sPLA2-V−/− mice diminishes Th2 cytokine responses in the airways.

Conclusions

This paper illustrates the diverse roles of sPLA2s in the immunopathogenesis of the asthma phenotype and directs attention to developing specific inhibitors of sPLA2-V as a potential new therapy to treat asthma and other allergic disorders.

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A pseudoleukemic blood differentiation in a 13-year-old child: an extraordinary presentation of Churg-Strauss syndrome

• Springer Open Choice
• PMC3594815

Clinical Rheumatology

Clin Rheumatol. 2013 March; 32(Suppl 1): 7–9.

Published online 2009 September 9. doi:  10.1007/s10067-009-1265-1

PMCID: PMC3594815

E. R. Mutsaers, R. Witteveen, W. van den Bosch-Ruis, T. W. Kuijpers, M. A. van Houten, and J. M. van den Berg

Author information ► Article notes ► Copyright and License information ►

Abstract

Churg-Strauss syndrome (CSS) is a rare systemic vasculitis of the small- and medium-size vessels. It is mostly seen in elderly patients presenting as de novo asthma, eosinophilia, and vasculitic organ involvement. In childhood, CSS is extremely rare. The course of pediatric CSS is usually severe and often lethal. We present a case of a 13-year-old girl with a short history of asthma, marked eosinophilia, and multiorgan involvement. The extremely high level of blood eosinophilic granulocytes (51.6×109/L) prompted a workup for eosinophilic leukemia before the diagnosis CSS could be made. Subsequently, the disease was successfully treated. This case report shows a classical case of childhood CSS, remarkable because of the presence of extreme hypereosinophilia. It underlines the importance of CSS as a life-threatening cause of hypereosinophilia in children.

Keywords: Childhood, Churg-Strauss syndrome, CSS, Hypereosinophilia

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Mast Cell Dependent Vascular Changes Associated with an Acute Response to Cold Immersion in Primary Contact Urticaria

PLoS One. 2013; 8(2): e56773.

Published online 2013 February 22. doi:  10.1371/journal.pone.0056773

PMCID: PMC3579929

Joseph Meyer,1 Alexander M. Gorbach,1 Wei-Min Liu,1 Nevenka Medic,2 Michael Young,3 Celeste Nelson,2 Sarah Arceo,2 Avanti Desai,2 Dean D. Metcalfe,2 and Hirsh D. Komarow2,*

Christian Schulz, Editor

Author information ► Article notes ► Copyright and License information ►

Abstract

Background

While a number of the consequences of mast cell degranulation within tissues have been documented including tissue-specific changes such as bronchospasm and the subsequent cellular infiltrate, there is little known about the immediate effects of mast cell degranulation on the associated vasculature, critical to understanding the evolution of mast cell dependent inflammation.

Objective

To characterize the microcirculatory events that follow mast cell degranulation.

Methodology/Principal Findings

Perturbations in dermal blood flow, temperature and skin color were analyzed using laser-speckle contrast imaging, infrared and polarized-light colorimetry following cold-hand immersion (CHI) challenge in patients with cold-induced urticaria compared to the response in healthy controls. Evidence for mast cell degranulation was established by documentation of serum histamine levels and the localized release of tryptase in post-challenge urticarial biopsies. Laser-speckle contrast imaging quantified the attenuated response to cold challenge in patients on cetirizine. We found that the histamine-associated vascular response accompanying mast cell degranulation is rapid and extensive. At the tissue level, it is characterized by a uniform pattern of increased blood flow, thermal warming, vasodilation, and recruitment of collateral circulation. These vascular responses are modified by the administration of an antihistamine.

Conclusions/Significance

Monitoring the hemodynamic responses within tissues that are associated with mast cell degranulation provides additional insight into the evolution of the acute inflammatory response and offers a unique approach to assess the effectiveness of treatment intervention.

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Effect of GSTM2-5 polymorphisms in relation to tobacco smoke exposures on lung function growth: a birth cohort study

Research article

Melannie Alexander, Wilfried Karmaus, John W Holloway, Hongmei Zhang, Graham Roberts, Ramesh J Kurukulaaratchy, Syed Hasan Arshad and Susan Ewart

For all author emails, please log on.

BMC Pulmonary Medicine 2013, 13:56 doi:10.1186/1471-2466-13-56

Published: 3 September 2013

Abstract (provisional)

Background

Genetic variation within GSTM2-5 genes may interfere with detoxification of environmental compounds, thereby having a detrimental effect on lung function following exposures such as tobacco smoke. We aim to investigate the influence of variants and associated methylation in the GSTM gene cluster with changes in lung function growth during adolescence.

Methods

Growth in forced expiratory volume (FEV1), forced vital capacity (FVC), and change in FEV1/FVC ratio measures were obtained from children in the Isle of Wight birth cohort at ages 10 and 18. Illumina GoldenGate assays were used to genotype 10 tagging polymorphisms from GSTM2 (rs574344 and rs12024479), GSTM3 (rs1537236, rs7483, and rs10735234), GSTM4 (rs668413, rs560018, and rs506008), and GSTM5 (rs929166 and rs11807) genes. Diplotypes were generated in the software Phase 3.0.2. DNA methylation was measured in over 450,000 CpG sites using the Infinium HumanMethylation450 BeadChip (Illumina 450K) in a subsample of 245 18-year olds from the Isle of Wight birth cohort. Gender, age, in utero smoke exposure, secondhand smoke exposure (SHS), and current smoking status were assessed via questionnaire; smoke exposures were validated with urine cotinine. We used linear mixed models to estimate the effect of GSTM diplotypes on lung function across time and examine interactions with tobacco smoke.

Results

1,121 (77%) out of 1,456 children had information on lung function at ages 10 or 18. After adjustment for false discovery rate, one diplotype in GSTM3 had a detrimental effect on changes in FEV1 (p=0.03), and another diplotype in GSTM3 reduced FVC (p=0.02) over time. No significant interactions with smoking were identified. SHS significantly modified the relationship between diplotypes and methylation levels in one GSTM2 CpG site; however, this site did not predict lung function outcomes at age 18. Joint effects of GSTM loci and CpG sites located within these loci on adolescent lung growth were detected.

Conclusions

Diplotypes within GSTM2-5 genes are associated with lung function growth across adolescence, but do not appear to modify the effect of tobacco smoke exposures on adolescent lung growth. Interactions between DNA methylation and diplotypes should be taken into account to gain further understanding on lung function in adolescence.

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The shape of the lymphocyte receptor repertoire: lessons from the B cell receptor

Front. Immunol., 02 September 2013 | doi: 10.3389/fimmu.2013.00263

Katherine J. L. Jackson*, Marie J. Kidd, Yan Wang and Andrew M. Collins

• School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia

Both the B cell receptor (BCR) and the T cell receptor (TCR) repertoires are generated through essentially identical processes of V(D)J recombination, exonuclease trimming of germline genes, and the random addition of non-template encoded nucleotides. The naïve TCR repertoire is constrained by thymic selection, and TCR repertoire studies have therefore focused strongly on the diversity of MHC-binding complementarity determining region (CDR) CDR3. The process of somatic point mutations has given B cell studies a major focus on variable (IGHV, IGLV, and IGKV) genes. This in turn has influenced how both the naïve and memory BCR repertoires have been studied. Diversity (D) genes are also more easily identified in BCR VDJ rearrangements than in TCR VDJ rearrangements, and this has allowed the processes and elements that contribute to the incredible diversity of the immunoglobulin heavy chain CDR3 to be analyzed in detail. This diversity can be contrasted with that of the light chain where a small number of polypeptide sequences dominate the repertoire. Biases in the use of different germline genes, in gene processing, and in the addition of non-template encoded nucleotides appear to be intrinsic to the recombination process, imparting “shape” to the repertoire of rearranged genes as a result of differences spanning many orders of magnitude in the probabilities that different BCRs will be generated. This may function to increase the precursor frequency of naïve B cells with important specificities, and the likely emergence of such B cell lineages upon antigen exposure is discussed with reference to public and private T cell clonotypes.

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Keywords: BCR repertoire, TCR repertoire, V(D)J recombination, public clonotypes, private clonotypes, combinatorial diversity, junctional diversity

Citation: Jackson KJL, Kidd MJ, Wang Y and Collins AM (2013) The shape of the lymphocyte receptor repertoire: lessons from the B cell receptor. Front. Immunol. 4:263. doi: 10.3389/fimmu.2013.00263

Received: 31 May 2013; Accepted: 19 August 2013;
Published online: 02 September 2013.

Edited by:

Ramit Mehr, Bar-Ilan University, Israel

Reviewed by:

Ramit Mehr, Bar-Ilan University, Israel
Gur Yaari, Yale University, USA
Nir Friedman, Weizmann Institute of Science, Israel

Copyright: © 2013 Jackson, Kidd, Wang and Collins. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Katherine J. L. Jackson, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia e-mail: katherine.jackson@unsw.edu.au