Saglani S. Pediatr Allergy Immunol. 2024; 35:e14180. doi:10.1111/pai.14180
Abstract
Recurrent wheezing in preschool children is heterogeneous and results from numerous genetic and environmental risk factors, which result in the same final clinical manifestation of acute episodes of wheezing but have distinct underlying mechanisms. Effective disease-modifying approaches, therefore, need to target the pathways driving the symptoms. We have good evidence to show that targeting airway eosinophilia alone in early-life preschool wheezing and using inhaled corticosteroids is not disease-modifying. Although airway remodelling develops early in preschool wheezing, the challenge is identifying suitable treatments for structural airway changes. There is increasing evidence for the role of lower airway bacterial infection contributing to wheeze episodes, but clinical trials investigating the impact of targeted antibiotic treatment on disease modification are needed. There is also increasing data supporting an association between lower airway neutrophilia and wheezing in a subgroup of preschool children, but direct causation and the role of neutrophil function remain unknown. Finally, there is encouraging preliminary data for the role of inactivated mixed bacterial lysates in children with non-allergic, infection-associated wheeze episodes, but the impact on longer-term outcomes and their mechanism of action is unknown. This review outlines a range of potential novel targets and approaches that may enable secondary prevention of asthma from preschool wheezing. In parallel, the potential for harm when interventions are introduced indiscriminately is highlighted. Some of the challenges that need to be addressed, including trial designs allowing tailored interventions, the need for non-invasive biomarkers for targeted interventions, and ensuring extended and long-term follow-up after intervention, are highlighted.
Key messages
- Recurrent preschool wheeze has a heterogeneous pathology; thus, interventions for disease modification need to target the underlying endotype.
- The benefits of inhaled corticosteroids in allergic/eosinophilic preschool wheeze are only apparent while they are being taken. Once stopped, they do not prevent the progression of preschool wheezing to asthma.
- There is increasing evidence that lower airway bacterial infection is associated with recurrent preschool wheeze, but the impact of targeted antibiotics in achieving disease modification is unknown.
- Mixed bacterial lysates may be effective in achieving disease modification, particularly in non-allergic, infection-induced recurrent preschool wheeze. However, definitive evidence of efficacy is lacking, and their mechanism of action needs to be understood.
- Lower airway neutrophilia is associated with recurrent preschool wheeze, but whether the neutrophils are pro-inflammatory and pathogenic, dysfunctional, secondary to bacterial infection, or protective, remains unknown.
- Airway remodelling develops early in recurrent preschool wheeze and relates closely to abnormal lung function. Targeting inflammation alone, without considering airway remodelling, may be insufficient to achieve disease modification.