Anatomical and histopathological approaches to asthma phenotyping

Asthma is typically characterized by variable respiratory symptoms and airflow limitation. Along with the pathophysiology and symptoms are immunological and inflammatory processes. The last decades research has revealed that the immunology of asthma is highly heterogeneous. This has clinical consequences and identifi-cation of immunological phenotypes is currently used to guide biological treatment. The focus of this review is on another dimension of asthma diversity, namely anatomical heterogeneity. Immunopathological alterations may go beyond the central airways to also involve the distal airways, the alveolar parenchyma, and pulmonary vessels. Also, extrapulmonary tissues are affected. The anatomical distribution of inflammation in asthma has remained relatively poorly discussed despite its potential implication on both clinical presentation and response to treatment. There is today evidence that a significant proportion of the asthma patients has small airway disease with type 2 immunity, eosinophilia and smooth muscle infiltration of mast cells. The small airways in asthma are also subjected to remodelling, constriction, and luminal plugging, events that are likely to contribute to the elevated distal airway resistance seen in some patients. In cases when the inflammation extends into the alveolar parenchyma alveolar FCER1-high mast cells, eosinophilia, type 2 immunity and activated alveolar macrophages, together with modest interstitial remodelling, create a complex immunopathological picture. Importantly, the distal lung inflammation in asthma can be pharmacologically targeted by use of inhalers with more distal drug deposition. Biological treatments, which are readily distributed to the distal lung, may also be beneficial in eligible patients with more severe and anatomically widespread disease.