Characterizing wheeze phenotypes to identify endotypes of childhood asthma, and the implications for future management

Belgrave, Danielle; Čustović, Adnan; Simpson, Angela

doi:10.1586/1744666x.2013.836450

Cited by 41 publications

(45 citation statements)

References 89 publications

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“…36 The age at which a child initially wheezes has been described as a key discriminator of childhood wheeze phenotypes in multiple birth cohort studies, and our results which identified an early-onset and a late-onset asthma subtype are consistent with other previously published work. 20,21,37 However, unlike most previous studies, we identified both an early-onset non-atopic subtype and an early-onset atopic subtype.…”

Section: Discussioncontrasting

confidence: 95%

Features of asthma which provide meaningful insights for understanding the disease heterogeneity

Deliu

Yavuz

Sperrin

et al. 2017

Clin Experimental Allergy

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SummaryBackgroundData‐driven methods such as hierarchical clustering (HC) and principal component analysis (PCA) have been used to identify asthma subtypes, with inconsistent results.ObjectiveTo develop a framework for the discovery of stable and clinically meaningful asthma subtypes.MethodsWe performed HC in a rich data set from 613 asthmatic children, using 45 clinical variables (Model 1), and after PCA dimensionality reduction (Model 2). Clinical experts then identified a set of asthma features/domains which informed clusters in the two analyses. In Model 3, we reclustered the data using these features to ascertain whether this improved the discovery process.ResultsCluster stability was poor in Models 1 and 2. Clinical experts highlighted four asthma features/domains which differentiated the clusters in two models: age of onset, allergic sensitization, severity, and recent exacerbations. In Model 3 (HC using these four features), cluster stability improved substantially. The cluster assignment changed, providing more clinically interpretable results. In a 5‐cluster model, we labelled the clusters as: “Difficult asthma” (n = 132); “Early‐onset mild atopic” (n = 210); “Early‐onset mild non‐atopic: (n = 153); “Late‐onset” (n = 105); and “Exacerbation‐prone asthma” (n = 13). Multinomial regression demonstrated that lung function was significantly diminished among children with “Difficult asthma”; blood eosinophilia was a significant feature of “Difficult,” “Early‐onset mild atopic,” and “Late‐onset asthma.” Children with moderate‐to‐severe asthma were present in each cluster.Conclusions and clinical relevanceAn integrative approach of blending the data with clinical expert domain knowledge identified four features, which may be informative for ascertaining asthma endotypes. These findings suggest that variables which are key determinants of asthma presence, severity, or control may not be the most informative for determining asthma subtypes. Our results indicate that exacerbation‐prone asthma may be a separate asthma endotype and that severe asthma is not a single entity, but an extreme end of the spectrum of several different asthma endotypes.

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Section: Discussioncontrasting

confidence: 95%

Features of asthma which provide meaningful insights for understanding the disease heterogeneity

Deliu

Yavuz

Sperrin

et al. 2017

Clin Experimental Allergy

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“…Most genetic studies defined "asthma" as parentally or patient-reported "doctor-diagnosed asthma". Unless genetic studies find better ways to distinguish between different asthma subtypes under this umbrella diagnosis at a population level, it will be difficult (if not impossible) to discover their unique underlying genetic risk factors, as any signal will be diluted by phenotypic heterogeneity [83]. It is worth emphasizing that when a much more precise and specific definition of early-life onset asthma with recurrent, severe exacerbations in pre-school age was used in a GWAS, identified associations had a considerably greater effect size (e.g.…”

Section: Asthma Phenotypes and Genetic Studiesmentioning

confidence: 99%

Asthma phenotypes in childhood

Deliu

Belgrave

Sperrin

et al. 2016

Expert Review of Clinical Immunology

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Asthma is no longer thought of as a single disease, but rather a collection of varying symptoms expressing different disease patterns. One of the ongoing challenges is understanding the underlying pathophysiological mechanisms that may be responsible for the varying responses to treatment. Areas Covered: This review provides an overview of our current understanding of the asthma phenotype concept in childhood and describes key findings from both conventional and data-driven methods. Expert Commentary: With the vast amounts of data generated from cohorts, there is hope that we can elucidate distinct pathophysiological mechanisms, or endotypes. In return, this would lead to better patient stratification and disease management, thereby providing true personalised medicine.

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“…The concept of asthma endotypes has now been the subject of much research because endotypes address the underlying mechanism of a disease [17][18][19][20]. However, this is also confusing because of the highly redundant inflammatory pathways that can lead to disease.…”

Section: Severe Asthma-many Diseases Many Problemsmentioning

confidence: 99%

“…Ultimately, asthma, like many other diseases, is a heterogeneous disease with many phenotypes and endotypes [17,18]. Not one single treatment will fit all, and the art of medicine may be to find the right peg for the corresponding hole [22].…”

Section: Severe Asthma-many Diseases Many Problemsmentioning

confidence: 99%

Unmet Needs in Respiratory Diseases

Chang

2013

Clinic Rev Allerg Immunol

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The care of patients with respiratory diseases has improved vastly in the past 50 years. In spite of that, there are still massive challenges that have not been resolved. Although the incidence of tuberculosis has decreased in the developed world, it is still a significant public health problem in the rest of the world. There are still over 2 million deaths annually from tuberculosis, with most of these occurring in the developing world. Even with the development of new pharmaceuticals to treat tuberculosis, there is no indication that the disease will be eradicated. Respiratory syncytial virus, severe acute respiratory syndrome, and pertussis are other respiratory infectious diseases with special problems of their own, from vaccine development to vaccine coverage. Asthma, one of the most common chronic diseases in children, still accounts for significant mortality and morbidity, as well as high health care costs worldwide. Even in developed countries such as the USA, there are over 4,000 deaths per year. Severe asthma presents a special problem, but the question is whether there can be one treatment pathway for all patients with severe asthma. Severe asthma is a heterogeneous disease with many phenotypes and endotypes. The gene for cystic fibrosis was discovered over 24 years ago. The promise of gene therapy as a cure for the disease has fizzled out, and while new antimicrobials and other pharmaceuticals promise improved longevity and better quality of life, the average life span of a patient with cystic fibrosis is still at about 35 years. What are the prospects for gene therapy in the twenty-first century? Autoimmune diseases of the lung pose a different set of challenges, including the development of biomarkers to diagnose and monitor the disease and biological modulators to treat the disease.

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Characterizing wheeze phenotypes to identify endotypes of childhood asthma, and the implications for future management

Cited by 41 publications

References 89 publications

Features of asthma which provide meaningful insights for understanding the disease heterogeneity

Features of asthma which provide meaningful insights for understanding the disease heterogeneity

Asthma phenotypes in childhood

Unmet Needs in Respiratory Diseases

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