Overview
Childhood asthma is not a single, uniform disease. Some children develop symptoms early in life, while others become symptomatic later. This study looked at whether changes in gene activity in the blood during early childhood could help explain who goes on to develop asthma and which immune pathways are involved over time.
The researchers found a clear shift in immune signaling: at age 1 year, children who later developed asthma showed a gene pattern linked mainly to neutrophilic inflammation and activation of the NLRP3 inflammasome. By 4.5 years of age, this pattern changed to a persistent eosinophil-related signature that remained present through 10.5 years. This suggests that the period between 1 and 4.5 years may be a particularly vulnerable window for the development of asthma biology.
Why this study matters
Asthma in children often develops gradually, and the immune changes that lead to disease may begin long before a child has obvious wheezing or breathing problems. Understanding these early molecular changes can help researchers identify children at risk sooner and may eventually lead to more targeted prevention or treatment strategies.
Most asthma research focuses on symptoms, lung function, or allergy testing after the disease has already appeared. In contrast, this study used repeated blood samples across childhood to track how gene expression changed over time, offering a more detailed view of the biological process leading to asthma.
Study design
The investigators analyzed whole-blood gene expression in children from the Protection against Allergy Study in Rural Environments, also known as PASTURE. This is a birth cohort study designed to understand how early-life environment influences allergic disease and asthma.
A total of 378 children were included, with blood samples collected at 4 time points: age 1 year, 4.5 years, 6 years, and 10.5 years. The researchers compared children who later developed asthma between ages 6 and 10.5 years with children who did not develop asthma. In total, 83 children had asthma and 295 served as nonasthmatic controls.
The team used several methods:
They looked for genes that were differently expressed over time between the two groups.
They performed weighted gene co-expression network analysis to identify groups of genes that behave similarly.
They also studied cis-expression quantitative trait loci, which are genetic variants that influence gene expression.
Main findings at age 1 year: a neutrophil-related pattern
At 1 year of age, the children who later developed asthma already showed a distinct blood gene signature. Forty-two genes were associated with this early difference, and most were more active than in healthy controls.
These genes were mainly linked to neutrophilic inflammation, a type of immune response involving neutrophils, which are white blood cells that act quickly during inflammation or infection. The signature also pointed to the NLRP3 inflammasome, a molecular complex involved in innate immune activation and inflammatory signaling.
This early pattern suggests that asthma risk may begin with broad inflammatory pathways rather than the classic allergy-related eosinophilic response seen later in many children.
Shift by age 4.5 years: emergence of an eosinophilic signature
By 4.5 years of age, the gene expression pattern had changed. Instead of the early neutrophil-focused signature, the children with asthma showed a new set of 40 genes linked to eosinophils, another type of white blood cell strongly associated with allergic inflammation and many forms of asthma.
Importantly, this eosinophil-related signature did not disappear. It remained increased in children with asthma at ages 6 and 10.5 years, suggesting a persistent inflammatory program rather than a temporary change.
This is clinically important because eosinophilic asthma often responds better to treatments that target type 2 inflammation, including inhaled corticosteroids and, in selected severe cases, biologic therapies such as anti-IgE or anti-IL-5/IL-5 receptor agents. Although this study did not test treatments, it helps explain why some children develop an asthma phenotype that remains eosinophil-driven over time.
Network analysis confirmed the pattern
The co-expression network analysis supported the main findings. It identified:
A neutrophilic module at age 1 year
Eosinophilic modules at ages 4.5, 6, and 10.5 years
These modules were associated with asthma, reinforcing the idea that the disease follows a developmental trajectory. In other words, the immune biology of future asthma may not be static; it appears to evolve from an early innate inflammatory state into a more persistent eosinophilic pattern.
Link with airway inflammation
The researchers also measured fractional exhaled nitric oxide, or FeNO, at age 6 years. FeNO is a noninvasive marker of airway inflammation, especially eosinophilic or type 2 inflammation.
They found that FeNO was associated with the eosinophilic gene module at age 6 years (P = .003). This supports the biological relevance of the blood-based gene signature and suggests that the molecular changes seen in blood reflect inflammatory activity in the airways as well.
Role of genetic variants
A particularly interesting part of the study was the analysis of genetic variants that influence gene expression. The investigators identified 86 single-nucleotide polymorphisms, or SNPs, that modulated the expression of 10 eosinophil-associated genes and GSDMB, a gene previously linked to asthma risk.
These findings suggest that inherited genetic differences may help shape the persistent eosinophilic signature seen in children with asthma. To test this idea further, the researchers created a variant-based genetic risk score. This score was associated with asthma diagnosis, with an adjusted odds ratio of 1.47 and a 95% confidence interval of 1.13 to 1.93.
In practical terms, this means children carrying a higher burden of these risk variants were more likely to have asthma in this cohort.
What the results may mean biologically
This study supports a model in which childhood asthma begins with early innate immune activation and later transitions into a more persistent eosinophilic inflammatory state. The first phase, seen at 1 year, may reflect early-life exposures, immune maturation, or environmental triggers such as infections, microbial exposure, or airway irritation. The second phase may reflect a more stable asthma endotype, one influenced by both genetics and immune development.
The findings also highlight the period between 1 and 4.5 years as a critical window. During this stage, the immune system may be especially malleable, and biological changes that eventually lead to asthma may become established.
Clinical implications
Although this research is not a treatment trial, it has several potential clinical implications:
It may eventually help identify children at high risk before symptoms become severe.
It suggests that early-life prevention strategies may need to begin well before school age.
It reinforces the value of FeNO and other markers of eosinophilic inflammation in characterizing asthma.
It supports the idea that asthma is biologically heterogeneous, with different inflammatory pathways dominating at different stages.
For clinicians, this means that asthma in young children should not be viewed as one uniform condition. Some children may have more neutrophil-driven early inflammation, while others may shift toward or remain in eosinophilic disease. Recognizing these patterns may improve future precision medicine approaches.
Limitations
As with any cohort study, there are limitations. Blood gene expression is informative, but it is only a surrogate for what is happening in airway tissues. Also, association does not prove causation. The study shows that the gene signatures are linked to later asthma, but it cannot fully determine whether these changes cause asthma or simply accompany its development.
The cohort also comes from a specific rural European population, so results may not generalize equally to all children worldwide. Environmental exposures, genetics, and asthma phenotypes can differ across populations.
Even so, the longitudinal design and repeated sampling make this study especially valuable, because it tracks biological changes over time rather than relying on a single snapshot.
Take-home message
This study found that children who later develop asthma show an early neutrophil-associated gene signature at age 1 year, followed by a persistent eosinophil-associated signature from 4.5 to 10.5 years. Genetic variants strongly influenced the eosinophilic pattern, and the findings point to a vulnerable developmental window between 1 and 4.5 years.
Overall, the study improves our understanding of how childhood asthma evolves at the molecular level and may help guide future efforts in early detection, prevention, and targeted therapy.
