Preschool wheeze

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Can we predict which preschool wheezers will develop asthma?

Prof. Saglani explored whether it is possible to predict which preschool children with wheezing are likely to develop asthma. Studies indicate that early-life wheezing has long-term consequences on lung function.¹ Despite advances in research, we are not improving at preventing preschool children with recurrent wheeze from experiencing repeated attacks. To address this, we need to identify which children are at high risk of poor outcomes and how to manage them effectively to reduce exacerbations.

Those with frequent, severe preschool wheeze are most likely to develop asthma by age 16, with lower lung function, higher allergen sensitization, and elevated FeNO¹. Due to ineffective exacerbation prevention, morbidity continues to rise.

Endotypes are more important than labels.

While existing definitions differentiate preschool wheeze and asthma, Prof. Saglani argued that the key question is not about labeling but rather understanding the specific type of wheeze or asthma a child has to ensure appropriate treatment. Relying solely on clinical features to classify these patients is insufficient— we must move toward identifying their underlying endotype to guide targeted management.

Identifying steroid-responsive preschool wheezers

Blood eosinophil levels do not differentiate viral wheezers from multiple-trigger wheezers, and even lower airway bronchoalveolar lavage (BAL) eosinophils do not consistently distinguish these groups. Airway eosinophilia can be found in some, but not all, persistant wheezers and in some, but not all with a viral wheeze.² So which children will respond to ICS (inhaled corticosteroids)? A reliable bedside test is needed to identify children with lower airway eosinophilia — ensuring that ICS is prescribed only to those who will benefit.

Clinical trials have identified four latent classes of preschool wheezers, with only those having high sensitization and elevated blood eosinophils showing reduced exacerbations with ICS³. A recent study⁴ found that eosinophil counts above 300 cells/μL at baseline were linked to a higher risk of exacerbations, underscoring the need for a biomarker to guide treatment decisions. The challenge remains in translating these findings into clinical practice.

To address this challenge, Prof. Saglani and colleagues have developed a “point-of-care” test based on a predictive decision tree model incorporating eosinophils, neutrophils, atopy status, and symptoms. This tool aims to identify steroid-responsive preschool wheezers and reduce their risk of exacerbations and long-term complications.

The challenge of non-steroid-responsive wheezers

However, a significant proportion of preschool wheezers are non-atopic and do not have elevated eosinophils. Managing these children remains a major challenge. Studies show that 66% of severe wheezers have rhinovirus in their lower airways, and up to 50% have lower airway bacterial infections⁵. The most frequently detected bacteria include Moraxella catarrhalis, Haemophilus influenzae, and Streptococcus pneumoniae.

To better understand the relationship between steroid responsiveness, infection, and inflammation, Prof. Saglani and colleagues conducted a cluster analysis incorporating atopy status, lower airway infections, and inflammation in severe preschool wheezers⁶. They identified two clusters:

Interestingly, this indicate that the type of bacterial infection correlates with sensitization status, suggesting that airway microbiota may play a role in disease progression. A multi-omics factor analysis⁷ further revealed that children with a higher abundance of Haemophilus influenzae were more likely to follow a disease-associated trajectory.

The role of structural changes in disease progression

A surprising finding from this analysis was that disease progression was not primarily driven by immune cells but rather by structural cells. Gene signatures associated with airway remodeling were more strongly linked to the transition from wheeze to asthma than immune-related signatures. Two independent cohorts^{8, 9} provided additional evidence that early-life alterations in airway smooth muscle may determine whether a child develops persistent wheezing and asthma.

Moving forward: targeted strategies for preschool wheeze

In summary, the preschool children at greatest risk are those who experience severe and frequent wheeze attacks, as they are more likely to develop asthma, impaired lung function, and possibly COPD later in life. Factors driving this risk include airway inflammation, eosinophilia, and allergen sensitization. These children can be identified through bedside tests such as skin prick tests and blood eosinophil measurements to determine their likelihood of responding to ICS and to guide treatment accordingly.

However, there is another subgroup of children with airway dysbiosis, often linked to rhinovirus. The atopic group tends to have more Moraxella catarrhalis, while the non-atopic group is associated with Haemophilus influenzae. The challenge is that we currently lack a non-invasive biomarker to assess the lower airway bacterial profile—bronchoscopy or BAL is typically required. Nonetheless, Prof. Saglani suggests that addressing airway dysbiosis through targeted antibiotics or bacterial lysates may help prevent disease progression.

Finally, an often-overlooked aspect of preschool wheeze progression is structural airway changes. Emerging evidence suggests that early-life alterations in smooth muscle cells may play a crucial role in disease development, yet no current treatment targets these changes. Identifying biomarkers for airway remodeling could open new avenues for intervention, potentially reducing disease severity and preventing long-term complications in adulthood.

Ingvild Bjellmo Johnsen
Medical Advisor Respiratory, Chiesi Nordic

ID 13778-10.03.2025