Atopic phenotypes and their implication in the atopic march

ABSTRACT

Introduction

Eczema, allergic rhinitis, and asthma are traditionally considered atopic (or allergic) diseases. They are complex, multifactorial, and are caused by a variety of different mechanisms, which result in multiple heterogeneous clinical phenotypes. Atopic march is usually interpreted as the sequential development of symptoms from eczema in infancy, to asthma, and then allergic rhinitis. Areas covered: The authors reviewed the evidence on the multimorbidity of eczema, asthma, and rhinitis, and the implication of results of data-driven analyses on the concept framework of atopic march. A literature search was conducted in the PubMed and Web of Science for peer-reviewed articles published until July 2020. Application of Bayesian machine learning framework to rich phenotypic data from birth cohorts demonstrated that the postulated linear progression of symptoms (atopic march) does not capture the heterogeneity of allergic phenotypes. Expert opinion: Eczema, wheeze, and rhinitis co-exist more often than would be expected by chance, but their relationship can be best understood in a multimorbidity framework, rather than through atopic march sequence. The observation of their co-occurrence does not imply any specific relationship between them, and certainly not a progressive or causal one. It is unlikely that a sngle mechanism such as allergic sensitization underpins different multimorbidity manifestations.

Keywords:

• eczema
• allergic rhinitis
• asthma
• atopic march
• allergic sensitization
• personalized medicine
• machine learning

Article highlights

• Eczema, allergic rhinitis, and asthma (collectively, allergic diseases) are complex and multifactorial, and may be caused by a variety of different mechanisms which result in multiple heterogeneous clinical presentations.

• Atopic march refers to a sequential development of symptoms (or diseases) from eczema in infancy to asthma, and then allergic rhinitis in later childhood.

• Bayesian machine learning framework revealed that the atopic march model of a linear progression from one symptom to another is not, in most cases, an accurate descriptor of the natural history of atopic diseases in individual patients. Therefore, an exclusive temporal sequence of events implied by the term atopic march does not capture the heterogeneity of allergic phenotypes, and is not a useful concept.

• Rather than following a specific sequential development of symptoms, allergic diseases likely co-exist in a multimorbidity framework in which no single condition holds priority over any of the co-occurring conditions.

• The current approach to treating atopic diseases is diagnosis-based. As a consequence, patients belonging to distinct subtypes of allergic diseases are forced into a single group for an empirical treatment.

• The only way to develop a personalized approach is to disaggregate “atopic phenotypes” and move towards an understanding of the underlying causal drivers of such heterogeneity with a view to developing mechanism-based treatments.

• Hay fever or “allergic airways disease” may be one endotype of atopic diseases given that: (1) we understand the underlying mechanism (allergic sensitization); (2) we have biomarkers for personalized treatment (specific IgE of skin test); and (3) the mechanism-based treatment (allergen-specific immunotherapy) is available.

• In the near future, we will have to reform the taxonomy of atopic diseases from traditional symptom-based criteria towards a mechanism-based framework. This change will be timely and meaningful only when currently used symptom-based diagnoses are surpassed by the discovery and genuine understanding of disease endotypes. Until such a time comes, we should consider categorizing multimorbid allergic diseases as a spectrum, and use the term “atopy spectrum disorders.”

Disclosure statement

A Custovic reports personal fees from Novartis, personal fees from Thermo Fisher Scientific, personal fees from Philips, personal fees from Sanofi, personal fees from Stallergenes Greer, outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Dedication

This article is dedicated to the memory of our wonderful colleague and friend Dr. John Henderson (1958-2019), whose contribution to the understanding of heterogeneity of childhood asthma cannot be overstated. Rainbow-chasers and UNICORN riders forever.

Additional information

Funding

This paper was not funded.