| Certain childhood populations may be broadly split into three clusters, each representing a unique trajectory of immune function and susceptibility to respiratory infections: low-risk non- atopic Cluster 1 with transient wheeze; low-risk but allergy-susceptible Cluster 2 with mixed wheeze; and strongly-atopic high-risk Cluster 3 with persistent wheeze. |
| Cluster 3 is consistent with an early-sensitised and multi-sensitised phenotype. |
| HDM hypersensitivity is an important predictor of wheeze in allergic or allergy -susceptible individuals. |
| Food and peanut hypersensitivities are important contributors to membership in high-risk Cluster 3. This may be pathophysiologically related to eczema, multi-sensitisation and the atopic march. |
| In CAS, IgG4 flags for clusters with susceptibility to atopic disease (CAS2 and CAS3), while early and multiple-allergen elevation in IgE predicts frank atopic disease. The pathophysiological role of IgG4 remains unclear. |
| Allergic and infective processes act additively to intensify airway inflammation during respiratory pathogen clearance. Some (Cluster 3) may be more susceptible to this effect than others that lack strong allergic sensitisation (Cluster 1). |
| Tests for atopy (IgE, SPT, cytokines) do not overlap perfectly. Therefore, atopy may be better defined by the composite result from a battery of tests encapsulated in a predictive model, rather than just a single test or threshold. |
| The microbiome acts differently on asthma risk depending on cluster membership. In CAS, early-life asymptomatic colonisation with infection-associated MPGs is associated with risk of persistent wheeze in allergy-susceptible clusters (CAS2, CAS3), while it is potentially protective in non-atopic children (CAS1) |
| Different childhood populations may share similar trajectories of asthma susceptibility, but there may be subtle differences in terms of the types of tests, allergens, or biological signals that are most informative (SPT, IgE, cytokines, etc.). |
