Asthma is the most common chronic disease in childhood, and according to the Global Asthma report, 14% of children worldwide report asthma symptoms [1]. The highest disease burden is seen in westernized cultures where close to 50% of young children will experience wheezing at least once in their preschool years [1], [2] and one out of five will develop repeated wheezing symptoms and morbidity [1].

Asthma is a complex and heterogeneous “umbrella diagnosis” comprised of overlapping clinical presentations, termed asthma “phenotypes” (Figure 1) that share a common clinical symptom of episodic wheezing. Asthma is characterized by reversible airway narrowing, variable airflow obstruction, airway hyperresponsiveness and airway inflammation [1], [2]. In the last decade, there has been a deeper understanding of the complexity of the differing inflammatory underpinnings and mechanistic pathways that underly different clinical asthma phenotypes. In older children and adults, this has been through deeper phenotyping of clinical traits such as lung function, airway inflammation, biomarker assessment and biological assessments that include genomics. This approach has enabled deeper understanding of the shared and distinct biological mechanisms that underlie asthma including immunological, inflammatory, metabolic, and remodeling pathways. These findings offer insight into the mechanisms that drive disease [3] leading us to asthma “endotyping” (Figure 1).

When it comes to understanding differences in heterogeneity in asthma between adults, older children (>12 years) and younger children, there are some key differences to consider. For one, asthma in young children tends to be more heterogeneous than in older children, with a wider range of clinical presentations based on timing of symptom onset and triggers. Another important consideration is that asthma in older children and adults is defined by assessing treatable traits such as lung function (airway caliber), hyperreactivity and inflammation with or without comorbidities [3]. However, objective tests to assess asthma traits, such as airflow obstruction measured by spirometry and airway hyperresponsiveness measured by bronchial provocation tests are challenging to perform in young children. Instead, clinicians caring for these young children depend on symptom history and clinical response to therapy.

Longitudinal cohort studies have studied wheeze symptoms in children over time to develop longitudinal “wheeze phenotypes”. These “wheeze phenotypes” characterize symptom onset and persistence into groups recognized by most pediatricians. In 1995 the Tucson Study, described three distinct phenotypes in their cohort study to age 6 years: transient early wheeze (wheeze in infancy that resolves by age 6 years), late-onset wheeze (wheeze with onset between 3-6 years), and persistent wheeze (wheeze in infancy that persists through preschool age to 6 years) [4]. Subsequently the ALSPAC cohort study enrolled 6,265 children and used an agnostic data driven approach and identified five phenotypes of wheezing in early life: never wheeze, transient, prolonged early, intermediate onset and late onset wheezing by age 7 years [5]. Similarly in 2022, the Canadian CHILD Study also used a data driven approach to analyze data starting from birth and described four longitudinal wheeze phenotypes; never wheeze, transient wheeze, intermediate onset, and persistent wheeze phenotypes [6]. The CHILD Study had significantly more observations from the first 3 years of life than the previous wheeze cohorts allowing a greater understanding of the heterogeneity in symptoms and persistence in the very young child. CHILD Study also demonstrated that there were significant differences in the sex distribution, genetics, underlying biology, and risk factors that were distinct to each wheeze phenotype [6]. For example, the wheeze trajectories displayed differences in their genetic predisposition for asthma, quantified through asthma gene risk scores (GRS). Participants were assigned a GRS for asthma using single nucleotide polymorphisms (SNPs) identified in the recent Genome Wide Association Study (GWAS) for asthma by Pividori et al. [7] and Demenais et al. [8]. Notably only children with the intermediate wheeze phenotype (wheeze onset between 2-3 years of age and persistent to age 5 years) showed an association with elevated genetic risk for allergic asthma [6]. In contrast, children with persistent wheeze had maternal history of asthma, acting through the passing down of genetic material and via “pro-asthmatic” mediators or lifestyle factors acting prenatally. In addition, differences in longitudinal lung function were observed between the wheeze trajectories. Although spirometry at age 5 was lower in all wheeze phenotypes, the persistent wheeze trajectory exhibited the lowest lung function of all phenotypes. Finally, striking differences were observed in eosinophil counts and atopic sensitization, suggesting differences in inflammation between the wheeze trajectories. In summary, these distinct wheeze phenotypes in very young children points towards distinct subgroups of “asthmatic” children who differ in genetics, lung function, and inflammation, that distinguish these wheeze trajectories from one another.

The heterogeneity observed in wheeze trajectories highlights the complexity of early wheezing and pediatric asthma, including differences in critical exposure windows and variable disease onset. It is likely that distinct mechanisms, or endotypes, underlie different wheeze trajectories, as evidenced by the diverse predictors associated with each. Understanding the mechanistic heterogeneity in early types of childhood wheeze trajectory, or endotypes, is crucial for developing effective prevention and treatment.

To achieve this understanding, this review aims to explore the immunological development and underlying differences in the biology of childhood asthma. We provide an overview of recent research investigating both genetically encoded and non-encoded heritable factors that contribute to immune development in asthma, as well as the environmental and microbial factors that play a role in disease onset. By examining these factors, we can gain insights into the complex interplay between genetics, environment, and immune function in the development of asthma.